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Do volatile anesthetics selectively inhibit the Ca ( 2+ ) -transporting ATPase in neuronal and erythrocyte plasma membranes? | The activity of the plasma membrane Ca(2+)-transporting adenosine triphosphatase (PMCA) is inhibited by volatile anesthetics at clinical concentrations. The goal of the current study was to determine whether the inhibition is selective as compared to other adenosine triphosphatases (ATPases) and another group of general anesthetics, barbiturates. In addition, the authors determined whether the response to anesthetics of the enzymes in neuronal membranes is similar to that in erythrocyte membranes. The effects of halothane, isoflurane, and sodium pentobarbital on four different ATPase activities were studied at 37 degrees C in two distinct plasma membrane preparations, human red blood cells and synaptosomal membranes from rat cerebellum. Inhibition patterns of the PMCA by halothane and isoflurane at anesthetic concentrations were vary similar in red blood cells and synaptosomal membranes. The half-maximal inhibition (I50) occurred at 0.25-0.30 mM halothane and 0.30-0.32 mM isoflurane. The PMCA in both membranes was significantly more sensitive to the inhibitory action of volatile anesthetics (I50 = 0.75-1.15 minimum alveolar concentration) than were other ATPases, such as the Na+,K+-ATPase (I50 approximately 3 minimum alveolar concentration) or Mg(2+)-ATPase (I50 > or = 5 minimum alveolar concentration). In contrast, sodium pentobarbital inhibited the PMCA in both membranes only at approximately 100-200-fold above its anesthetic concentrations. The other ATPases were inhibited at similar pentobarbital concentrations (I50 = 11-22 mM). | The aim of the study is to investigate whether body mass index (BMI) affected pathological characteristics and biochemical recurrence (BCR) of prostate cancer after radical prostatectomy in Chinese men. Medical records of 211 Chinese patients who underwent radical prostatectomy between 2006 and 2014 were retrospectively reviewed, with follow-up time of 24.5 ± 27.0 months. Multivariate logistic and Cox regression analyses were applied to address the impact of BMI on adverse pathological outcomes and BCR following prostatectomy. A meta-analysis of published studies from MEDLINE or EMBASE was conducted to determine the relationship between BMI and BCR following prostatectomy among Asian populations. Higher BMI was positively correlated with higher biopsy Gleason score (odds ratios (OR) 1.163, 95 % confidence interval (CI) 1.023-1.322, P = 0.021) and pathological Gleason score (OR 1.220, 95 % CI 1.056-1.410, P = 0.007) in multivariate analysis. BCR was detected in 48 patients (22.7 %). Multivariate Cox proportional hazards analysis revealed that higher BMI (hazard ratio (HR) 1.145, 95 % CI 1.029-1.273, P = 0.013) and prostate-specific antigen (HR 1.659, 95 % CI 1.102-2.497, P = 0.015) levels were independent predictors of BCR. The meta-analysis enrolled eight Asian studies of 4145 patients treated by radical prostatectomy. Based on random-effects approach, a 5 kg/m(2) increase in BMI was correlated with 28 % higher risk of BCR (HR 1.22, 95 % CI 0.86-1.72) without statistical significance. |
Does severe nutritional risk predict decreased long-term survival in geriatric patients undergoing pancreaticoduodenectomy for benign disease? | Weight loss and malnutrition are poorly tolerated by geriatric patients, and pancreaticoduodenectomy (PD) can result in chronic malabsorption and weight loss. We sought to determine how preoperative severe nutritional risk (SNR), as defined by the American College of Surgeons National Surgical Quality Improvement Program/American Geriatric Society Best Practice Guidelines, affects long-term survival after PD for benign disease among geriatric and nongeriatric patients. All patients undergoing PD for nonmalignant conditions at a single center between 1995 and 2013 were followed for survival, excluding patients who died within 90 days of surgery. Survival of geriatric (age ≥65 years) and nongeriatric (age <65 years) patients with and without SNR was compared using Kaplan Meier methods. Cox regression was performed. There were 320 patients who underwent PD for benign disease. Over the course of the study, the proportion of geriatric patients undergoing PD for benign conditions increased from 25% to 46%. In addition to being older, geriatric patients undergoing PD for benign disease were significantly more likely to have coronary artery disease (CAD) and hypertension. Geriatric patients with preoperative SNR had significantly decreased long-term survival after PD for benign disease (p < 0.001), with roughly 1 in 3 patients dead at 5 years compared with 1 in 14 patients without SNR. Survival was not significantly different among nongeriatric patients with and without SNR. In geriatric patients, age, CAD, and SNR were significantly associated with decreased survival on both univariate and multivariate analysis. | IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C/CAAT-enhancer-binding proteins (C/EBP) -β, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes. |
Does methylphenidate restore link between stop-signal sensory impact and successful stopping in adults with attention-deficit/hyperactivity disorder? | The ability to revise one's action plans, as reflected in so-called stopping performance, is of fundamental importance to adaptive behavior. Previous studies in children and adults with attention-deficit/hyperactivity disorder (ADHD) have revealed impaired stopping, which improved after the administration of methylphenidate (MPH). Event-related brain potentials revealed that one crucial mechanism in adequate stopping is the link between the cortical areas that process the signal to stop and the motor system (stop N1). This stop N1 was severely compromised in adults with ADHD. The present study investigates whether methylphenidate can restore the stop N1, in addition to improving stopping performance. The acute effect of a serotonergic reuptake inhibition on these parameters was also assessed. Twelve adult combined-type ADHD patients received either placebo, MPH .4 mg/kg or .6 mg/kg, or 20 mg paroxetine in a double-blind, randomized, within-subjects design. The .6 mg/kg dose of methylphenidate improved stopping performance, whereas it did not affect go reaction time (RT). It also restored the stop N1 that was absent under placebo. Methylphenidate reduced a later stop-related potential, the stop P3, which may reflect monitoring of failed stops. Paroxetine had no effect on stopping performance or on stop N1, but it reduced stop P3. | Accumulation of advanced glycation end products (AGEs) contributes to the development of diabetic ulcers. Recent evidence indicates that AGEs administration enhanced autophagy in many cell types. As a positive trigger of autophagy, the effect of AGEs on autophagy in skin tissues and fibroblasts remains unknown. Skin tissues were isolated from Spreqne-Dawley rats and immunohistochemical staining was performed to analyze the location of LC3 and FOXO1 in skin tissues. Then primary cultured foreskin fibroblast cells with treated with AGEs and the effect of AGEs on autophagy was investigated. Protein level expressions of LC3, Beclin-1 and FOXO1 in fibroblasts were analyzed by Western blotting. Autophagic flux is detected with autophagy inhibitor chloroquine and mRFP-GFP-LC3 tandem construct. Compared with skin from normal rats, immunohistochemical staining shows a predominant LC3 localization in fibroblasts cytoplasm in diabetic rats. Elevated expression of FOXO1 also existed in diabetic rats dermis fibroblasts when compared with normal rats in immunohistochemical analysis. In human skin fibroblasts cells, AGEs administration stimulated the autophagy related LC3-II/LC3-I and Beclin-1 expressions and increased autophagy flux. In mRFP-GFP-LC3 puncta formation assays, both autolysosome and autophagosome were increased in human fibroblasts after treatment with AGEs. Fibroblasts exposed to AGEs also have increased FOXO1 expression compared with control group. |
Does weekend compared with weekday presentation affect outcomes of patients presenting with non-ST elevation acute coronary syndrome? | In non-ST elevation acute coronary syndromes (NSTEACS), early invasive management improves survival. However, since treatment strategies are urgent, not emergent, decisions to postpone invasive management due to weekend admission could affect outcome. Using the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH), a population-based registry capturing all cardiac admissions in southern Alberta, we compared time to cardiac catheterization, modality of revascularization, and crude and risk-adjusted mortality for NSTEACS patients presenting on weekends vs. weekdays. From 1 April 2005 to 31 October 2010, 11,981 patients were admitted to care facilities in southern Alberta (32.1% on weekends and 67.9% on weekdays). Baseline characteristics were similar. Mean time to cardiac catheterization was 67.2 h in the weekend group, compared to 62.4 h in the weekday group (p=0.03), with 34.7% of weekend and 45.1% of weekday patients receiving catheterization within 24 h of admission (p<0.0001), and 49.1 and 59.9%, respectively, within 48 h (p=0.002). Mortality at 30 days was 2.2% in the weekend group compared to 2.0% in the weekday group (p=0.58). The crude hazard ratio (HR) for 30-day mortality in the weekend group was 1.08 (95% CI 0.83-1.40). After adjusting for baseline risk factors, the HR for mortality remained non-significant (HR 1.06, 95% CI 0.82-1.38). Mortality at 1 year was also similar. | The objective of this study was to test the hypothesis that ovarian kisspeptin (kiss1) and its receptor (kiss1r) expression are affected by age, obesity, and the age- and obesity-related chemokine monocyte chemoattractant protein-1 (MCP-1). Ovaries from reproductive-aged and older C57BL/6J mice fed normal chow (NC) or high-fat (HF) diet, ovaries from age-matched young MCP-1 knockout and young control mice on NC, and finally, cumulus and mural granulosa cells (GCs) from women who underwent in vitro fertilization (IVF) were collected. Kiss1, kiss1r, anti-Mullerian hormone (AMH), and AMH receptor (AMHR-II) messenger RNA (mRNA) expression levels were quantified using real-time polymerase chain reaction (RT-PCR). In mouse ovaries, kiss1 and kiss1r mRNA levels were significantly higher in old compared to reproductive-aged mice, and diet-induced obesity did not alter kiss1 or kiss1r mRNA levels. Compared to young control mice, young MCP-1 knockout mice had significantly lower ovarian kiss1 mRNA but significantly higher AMH and AMHR-II mRNA levels. In human cumulus GCs, kiss1r mRNA levels were positively correlated with age but not with BMI. There was no expression of kiss1 mRNA in either cumulus or mural GCs. |
Does antenatal diagnosis of fetal genotype determine if maternal hyperglycemia due to a glucokinase mutation requires treatment? | In women with hyperglycemia due to heterozygous glucokinase (GCK) mutations, the fetal genotype determines its growth. If the fetus inherits the mutation, birth weight is normal when maternal hyperglycemia is not treated, whereas intensive treatment may adversely reduce fetal growth. However, fetal genotype is not usually known antenatally, making treatment decisions difficult. We report two women with gestational diabetes mellitus resulting from GCK mutations with hyperglycemia sufficient to merit treatment. In both women, DNA from chorionic villus sampling, performed after high-risk aneuploidy screening, showed the fetus had inherited the GCK mutation. Therefore, maternal hyperglycemia was not treated. Both offspring had a normal birth weight and no peripartum complications. | Although posttraumatic stress disorder (PTSD) and chronic pain frequently occur in tandem, the pathophysiological mechanisms mediating this comorbidity are poorly understood. Because excessive inflammation occurs in both conditions, we examined the cerebrospinal fluid (CSF) concentrations of inflammatory response mediators interleukin 1-beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNFα) and interleukin 10 (IL-10) after prolonged suprathreshold pain stimulus in 21 male combat veterans; 10 with PTSD and 11 combat controls (CC). After completing baseline quantitative sensory testing (QST) and psychological profiling, all patients received an injection of capsaicin into the quadriceps muscle. Spontaneously reported pain was measured for 30min after the capsaicin injection. The evoked pain measure of temporal summation was tested between 70 and 110min post capsaicin injection. Inflammatory (IL-1β, IL-6, IL-8 TNFα) and anti-inflammatory (IL-10) CSF cytokines were measured before (baseline) and after capsaicin injection over a time frame of 110min. Following intramuscular capsaicin injection, pro-inflammatory cytokines [TNFα, IL-6, IL-8] significantly increased (percent rise from baseline) in both groups, whereas IL-1β significantly increased in the PTSD group only. The anti-inflammatory cytokine IL-10 showed an immediate (within 10min) increase in the CC group; however, the IL-10 increase in the PTSD group was delayed and not consistently elevated until 70min post injection. |
Does lysophosphatidylserine have Bilateral Effects on Macrophages in the Pathogenesis of Atherosclerosis? | Lysophospholipids, particularly sphingosine 1-phosphate and lysophosphatidic acid, are known to be involved in the pathogenesis of atherosclerosis; however, the role of lysophosphatidylserine (LysoPS) in the onset of atherosclerotic diseases remains uncertain. We investigated the effects of LysoPS on the uptake of oxidized low-density lipoprotein (oxLDL) and the modulation of inflammatory mediators and ER stress utilizing RAW264.7 cells and mouse peritoneal macrophages (MPMs). We found that LysoPS augmented cholesterol accumulation in both models. Consistent with these findings, LysoPS increased the expression of scavenger receptors (CD36, MSR1, LOX1 and TLR4). Regarding the involvement of these lipids in inflammation, LysoPS significantly decreased the expression of inflammatory mediators in lipopolysaccharide (LPS)-treated RAW264.7 cells and MPMs. LysoPS also attenuated ER stress in LPS-untreated RAW264.7 cells. The expression patterns of LysoPS receptors differed considerably among the LPS-untreated RAW264.7 cells, LPS-treated RAW264.7 cells and MPMs. | To investigate the surgical techniques and speech performance of multichannel auditory brainstem implant (ABI) in patients with bilateral acoustic neuromas (neurofibromatosis type 2). The nucleus 21 channel auditory brainstem implant was implanted into the lateral recess of the fourth ventricle through the translabyrinthine approach in 7 patients after removal of the tumor. The accurate placement of electrode array was ensured by the electromyogram monitoring of the 7th and 9th nerves and the electrically evoked auditory brainstem responses (EABR). Initial switch-on occurred six weeks postoperatively. Speech evaluation was performed every 3 months for the first year and annually thereafter. During the surgery, the lateral recess could be found and the typical EABR could be recorded in 6 cases. They later reported a significant benefit from the device. Two of the cases have achieved functional open-set speech understanding. In contrast, one patient with no EABR because of difficulty of the anatomic location during the surgery had no sensations postoperatively. |
Is gastric emptying affected by sleeve gastrectomy -- scintigraphic evaluation of gastric emptying after sleeve gastrectomy without removal of the gastric antrum? | The aim of this study is to clarify whether laparoscopic sleeve gastrectomy (LSG) to treat morbid obesity causes changes in gastric emptying. Gastric emptying scintigraphy was performed before and 3 months after LSG, in 21 consecutive morbidly obese patients. After an overnight fast, subjects consumed a standard semi-solid meal, to which 0.5 mCi Tc99-labeled sulfur colloid had been added. The meal was consumed within 10 min. Scintigraphic imaging was performed with a gamma camera immediately after the completion of the meal as well as after 30, 60, 120, 180, and 240 min. Quantitative and qualitative analysis was performed by drawing a region of interest (ROI) enclosing the stomach on the anterior and the posterior images. Time 0 was considered the time of meal completion (all the ingested activity) and was defined as 100% retention. The same ROI was used on all consecutive images of the same projection for the same patient. The geometric mean of the anterior and the posterior counts for each time point is calculated and corrected for Tc(99m) decay. Gastric emptying curves were constructed. T 1/2 is the time interval between completion of the meal and the point at which half of the meal (by radioactivity counts) has left the stomach. Retention is expressed as the percent remaining in the stomach at each time point (half, 1, 2, 3, 4 h). The mean T 1/2 raw data was 62.39+/-19.83 and 56.79+/-18.72 min (p=0.36, t=-0.92, NS) before and 3 months after LSG, respectively. The T 1/2 linear was 103.64+/-9.82 and 106.92+/-14.55, (p=0.43, t=-0.43, NS), and the linear fit slope 0.48+/-0.04 and 0.47+/-0.05 (p=0.48, t=0.7, NS). | To investigate the effect of rhein on endothelial plasminogen activator inhibitor-1 (PAI-1) mRNA expression and protein production induced by transforming growth factor beta1 (TGFbeta1), and to explore the mechanism of the protective action of rhein on endothelial cells. A human umbilical endothelium derived cell line (ECV-304) from ATCC was used in this study. The PAI-1 mRNA expression and protein synthesis in the endothelial cells were detected by Northern blot and flow cytometry analysis, respectively. The activity of phospho-p44/p42 MAP kinase induced by TGFbeta1 was determined by immunoprecipitation analysis and western blot. TGFbeta1 rapidly increased PAI-1 mRNA expression in the endothelial cells, and this effect lasted at least 24 hours. The upregulation of PAI-1 mRNA expression induced by TGFbeta1 in endothelial cells was inhibited by rhein in a dose-dependent manner. In addition, rhein inhibited endothelial PAI-1 protein production. Further study revealed that rhein had a significant inhibitory effect on the activity of phospho-p44/p42 MAP kinase induced by TGFbeta1 in human endothelial cells. |
Does microsomal Prostaglandin E Synthase-1-Derived PGE2 inhibit Vascular Smooth Muscle Cell Calcification? | Chronic administration of selective cyclooxygenase-2 (COX-2) inhibitors leads to an increased risk of adverse cardiovascular events, including myocardial infarction and stroke. Vascular smooth muscle cell (VSMC) calcification, a common complication of chronic kidney disease, is directly related to cardiovascular morbidity and mortality. Here, we tested whether specific COX-2 inhibition affects vascular calcification during chronic renal failure. The COX-2-specific inhibitors NS398 and SC236 significantly increased high-phosphate (Pi)-induced VSMC calcification. Similarly, COX-2(-/-) VSMCs, COX-2(-/-) aortas rings treated with high Pi and adenine diet-induced COX-2(-/-) chronic renal failure mice displayed enhanced calcium deposition. Metabolomic analysis revealed the differential suppression of PGE2 production by COX-1- and COX-2-specific inhibitors in high-Pi-stimulated VSMCs, indicating the involvement of PGE2 during COX-2 inhibition-aggravated vascular calcification. Indeed, exogenous PGE2 reduced alkaline phosphatase activity, osteogenic transdifferentiation, apoptosis, and calcification of VSMCs. In accordance, downregulation of microsomal prostaglandin E synthase (mPGES)-1 in VSMCs, mPGES-1(-/-) aorta with high-Pi stimulation and mPGES-1(-/-) chronic renal failure mice resulted in enhanced vascular mineralization. Further applications of RNAi and specific antagonists for PGE2 receptors indicated EP4 may mediate PGE2-inhibited vascular calcification. | Continuity of care has traditionally been regarded as a core quality of general practice, but the long-term doctor-patient relationship has been put under pressure. In many places practices are expanding, with larger teams and more registered patients, thereby threatening the possibility of patients staying with their own general practitioner (GP). GPs often take it for granted that interpersonal continuity is valuable. However, little is known about how patient satisfaction is related to interpersonal continuity. The purpose of this study is to explore the creation of patient satisfaction or dissatisfaction in the interpersonal relation with the GP, and in a comprehensive way to investigate how this is related to continuity of care. Qualitative study based on 22 interviews with patients from two practices in Denmark. A total of 12 patients saw a regular doctor and 10 saw an unfamiliar doctor. The patients were selected after an observed consultation and sampled purposefully according to reason for encounter, age and sex. Interpretative phenomenological analysis (IPA) was used to study how patients perceive meeting either a regular or an unfamiliar GP. The analysis explored the patients' perception of their interpersonal relationship with their GP, and interpreted the accounts by using social psychological theories. A long-term continuous relationship with the GP could be satisfactory, but it could also be the reverse. The same pattern was shown in case of an unfamiliar GP. Therefore, patient satisfaction and interpersonal continuity were not causally related. On the contrary, there was a general pattern of how the satisfactory and trustful doctor-patient relationship from the patients' point of view could be created, maintained or destroyed. A pattern where the process of recognition, by respecting and remembering, on the one hand created and maintained satisfaction while humiliation on the other hand destroyed satisfaction in the relationship. |
Is an absent pulse sensitive for the early detection of peripheral arterial disease? | This study's objective was to determine the test characteristics of pedal pulse palpation in the diagnosis of peripheral arterial disease (PAD) when compared to the more widely recommended screening tool, the ankle-brachial index (ABI). We screened patients > 50 years of age for PAD within primary care clinics in Houston. PAD was diagnosed by an ABI of <0.9. At each visit, pedal pulse palpation was performed for each leg. Of the patients who screened positive for PAD by ABI, we determined the sensitivity, specificity, and positive predictive value of pulse palpation. We enrolled 403 patients with a mean age of 63.8 +/- .36 years. The prevalence of PAD was 16.6% (67 patients total). Of the 45 patients with disease involving their left leg, 37 (82.2%) had a palpable pulse. Of the 37 patients with disease involving their right leg, 25 (67.6%) had a palpable pulse. The sensitivity of a non-detectable pulse for the diagnosis of PAD was 17.8% and 32.4% for the left leg and the right leg, respectively. The specificity of pulse palpation for the detection of PAD was 98.7% and 97.8% for the left leg and the right leg, respectively. | SPARC (secreted protein acidic, rich in cysteine) is a matricellular protein that has been found to be activated in a number of human cancers. More recently, it has been shown to be upregulated in human gastric and colorectal cancer. We therefore wished to address the functional importance of SPARC upregulation to intestinal tumorigenesis in vivo. SPARC upregulation was determined in intestinal adenomas of tumour-prone Apc(Min/+) mice at both the RNA and the protein level. To determine the functional importance of SPARC for intestinal tumorigenesis we then intercrossed Sparc knockout mice with Apc(Min/+) mice (n = 20). Intestinal enterocyte migration was examined using bromodeoxyuridine labelling studies. Levels of murine Sparc and several related proteins were upregulated in adenomas arising in Apc(Min/+) mice. A deficiency of Sparc strongly suppressed adenoma formation in Apc(Min/+) mice (p>or=0.0001). Importantly, a deficiency of Sparc also accelerated enterocyte migration (p = 0.01), as perturbed slow epithelial migration may underpin adenoma formation in the intestine. |
Does cotransplantation of human mesenchymal stem cells enhance human myelopoiesis and megakaryocytopoiesis in NOD/SCID mice? | For approximately 5% of autologous transplant recipients and a higher proportion of allogeneic transplant recipients, low level and delayed platelet engraftment is an ongoing problem. Mesenchymal stem cells (MSC), which can be derived from bone marrow as well as other organs, are capable of differentiation into multiple cell types and also support hematopoiesis in vitro. Because cotransplantation of marrow-derived stromal cells has been shown to enhance engraftment of human hematopoietic stem cells, we hypothesized that cotransplantation of MSC could enhance platelet and myeloid cell development. We tested this hypothesis by transplantation of CD34-selected mobilized human peripheral blood stem cells (PBSC) into sublethally irradiated NOD/SCID mice with or without culture-expanded human MSC and evaluated human myeloid, lymphoid, and megakaryocytic engraftment with flow cytometry and in vitro cultures. We find that MSC cotransplantation enhances human cell engraftment when a limiting dose (<1 x 10(6)) of CD34 cells is administered. This enhancement is characterized by a shift in the differentiation of human cells from predominantly B lymphocytes to predominantly CD13(+), CD14(+), and CD33(+) myeloid cells with a corresponding increase in myeloid CFU in the marrow. Megakaryocytopoiesis is enhanced by MSC cotransplantation as assessed by an increase in both marrow CFU-MK and circulating human platelets. In contrast, MSC do not affect the percentage of human bone marrow cells that expresses CD34(+). | Barrett's epithelium is currently believed to be related to acid gastroesophageal reflux. The aim was to determine the role of pancreatic-biliary reflux in the genesis of Barrett's epithelium. The study population comprised 1055 cases (606 men and 449 women; median age, 67 years) who had undergone an upper endoscopy at the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. The study population was composed of 869 cases with intact stomachs and 186 cases with distal-gastrectomies. The presence and the progression of Barrett's epithelium were diagnosed based on the Prague C & M Criteria. The correlations of clinical factors, including distal-gastrectomy, with the presence and the progression of Barrett's epithelium were examined. The study demonstrated that 42.2% of the total population was diagnosed to have Barrett's epithelium and, in 12.6% of the cases with Barrett's epithelium, the progression of Barrett's epithelium was observed during the median 72 month followup. A distal gastrectomy was not significantly correlated with either the incidence or progression of Barrett's epithelium. |
Does polarization of the vacuolar adenosine triphosphatase delineate a transition to high-grade pancreatic intraepithelial neoplasm lesions? | A functional vacuolar adenosine triphosphatase (v-ATPase) complex regulates canonical Wnt/β-catenin signaling. The goal of this study was to identify the distribution of the v-ATPase in human and murine models of pancreatic intraepithelial neoplasms (PanINs) and assess its role in Wnt/β-catenin signaling. We evaluated the immunolabeling pattern of the v-ATPase in human PanIN specimens and murine PanIN-1 and PanIN-2 lesions obtained from Ptf1a(Cre/+); LSL-Kras(G12D) mice. Wnt/β-catenin signaling was interrogated in primary PanIN cells by examining the phosphorylated levels of its surface coreceptor, low-density lipoprotein receptor-related protein-6 (LRP6), and its intracellular effector, nonphosphorylated β-catenin. The response of primary PanIN cells to epidermal growth factor (EGF) was assessed in the absence and presence of the v-ATPase inhibitor, concanamycin. In advanced (PanIN-2), but not early (PanIN-1), lesions, the v-ATPase assumed a polarized phenotype. Blocking the v-ATPase disrupted Wnt/β-catenin signaling in primary PanIN cells despite significantly higher levels of the total and activated Wnt cell surface coreceptor, LRP6. Vacuolar adenosine triphosphatase blockade significantly decreased the total and activated levels of EGF receptor, a determinant of PanIN progression. The activation of EGF receptor and its intracellular mediator, p44/42 mitogen-activated protein kinase, was also reduced by v-ATPase blockade. This led to diminished proliferation in response to EGF ligand. | In the context of advanced immunosuppression, M. tuberculosis is known to cause detectable mycobacteremia. However, little is known about the intra-patient mycobacterial microevolution and the direction of seeding between the sputum and blood compartments. From a diagnostic study of HIV-infected TB patients, 51 pairs of concurrent blood and sputum M. tuberculosis isolates from the same patient were available. In a previous analysis, we identified a subset with genotypic concordance, based on spoligotyping and 24 locus MIRU-VNTR. These paired isolates with identical genotypes were analyzed by whole genome sequencing and phylogenetic analysis. Of the 25 concordant pairs (49 % of the 51 paired isolates), 15 (60 %) remained viable for extraction of high quality DNA for whole genome sequencing. Two patient pairs were excluded due to poor quality sequence reads. The median CD4 cell count was 32 (IQR; 16-101)/mm(3) and ten (77 %) patients were on ART. No drug resistance mutations were identified in any of the sequences analyzed. Three (23.1 %) of 13 patients had SNPs separating paired isolates from blood and sputum compartments, indicating evidence of microevolution. Using a phylogenetic approach to identify the ancestral compartment, in two (15 %) patients the blood isolate was ancestral to the sputum isolate, in one (8 %) it was the opposite, and ten (77 %) of the pairs were identical. |
Does [ High-dose glucose induce human retinal endothelial cell apoptosis ]? | To examine the direct effect of high glucose levels on primary cultured human retinal capillary endothelial cells (HRCEC). HRCECs were isolated from donated eyes and cultured for 6 days in the media containing 5 or 25 mmol/L glucose. The cell viability was determined by trypan blue exclusion assay and cell cycle analyzed by flow cytometry, with the cell apoptosis assayed by TUNEL method. The cell viability was significantly decreased after exposure to 25 mmol/L glucose, and the number of apoptotic cells determined by flow cytometry and TUNEL was significantly increased in response to high-dose glucose treatment. | Population-based studies suggest that pain in the lower body is common and that pain at multiple sites is more prevalent than single-site pain. Obesity is a risk factor for multisite musculoskeletal pain, but there are limited data on the role of body composition. Therefore, we sought to determine whether body composition is associated with multisite musculoskeletal pain involving the low back, knee, and foot. A total of 133 participants were recruited for a study examining the relationship between obesity and musculoskeletal disease. Participants completed validated questionnaires that examined levels of pain at the low back, knee, and foot. Body composition was assessed using dual-energy x-ray absorptiometry. Multisite pain was common, with 26.3% of participants reporting pain at 2 sites and 31.6% at 3 sites, and only 20% were pain free. The low back was the most common site of pain (63%). Greater fat mass and fat mass index, but not fat-free mass, were associated with pain at a greater number of sites, independent of age, gender, and fat-free mass (P < .01). Longitudinal studies exploring the mechanism of action by which increased fat mass is associated with pain may provide important insights into therapeutic strategies for the prevention of multisite pain. |
Are intrathecal mepivacaine and prilocaine less neurotoxic than lidocaine in a rat intrathecal model? | Histologic evidence of the comparative neurotoxicity of lidocaine, mepivacaine, and prilocaine is incomplete. We compared the intrathecal neurotoxicity in rats among these 3 drugs based on morphologic and neurofunctional findings. Rats (n=169) randomly received 0.12 microL/g of 0%, 2%, 5%, 7.5%, 10%, or 20% lidocaine, mepivacaine, or prilocaine or 25% glucose dissolved in distilled water via a chronically implanted intrathecal catheter. The effect of the agents on neurofunction was evaluated by movement of the hind limb (behavior test) and by sensory threshold (paw-stimulation test). The L1 spinal cord, the posterior and anterior roots, and the cauda equina were removed en bloc 5 days later and examined by light and electron microscopy. A significant decrease in sensory threshold or irreversible hind-limb limitation was observed only in rats receiving 20% lidocaine. Morphologic abnormalities characterized by axonal degeneration were observed in rats receiving > or =7.5% lidocaine, 20% mepivacaine, and 20% prilocaine, at the posterior white matter and the proximal portion of the posterior root just at the entrance into the spinal cord. The incidence of lesions was significantly higher in rats receiving lidocaine than mepivacaine and prilocaine. | Elevated circulating levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen (FG) have been repeatedly associated with many adverse outcomes in patients with chronic obstructive pulmonary disease (COPD). To date, it remains unclear whether and to what extent systemic inflammation is primary or secondary in the pathogenesis of COPD. The aim of this study was to examine the association between haplotypes of CRP, IL6 and FGB genes, systemic inflammation, COPD risk and COPD-related phenotypes (respiratory impairment, exercise capacity and body composition). Eighteen SNPs in three genes, representing optimal haplotype-tagging sets, were genotyped in 355 COPD patients and 195 healthy smokers. Plasma levels of CRP, IL-6 and FG were measured in the total study group. Differences in haplotype distributions were tested using the global and haplotype-specific statistics. Raised plasma levels of CRP, IL-6 and fibrinogen were demonstrated in COPD patients. However, COPD population was very heterogeneous: about 40% of patients had no evidence of systemic inflammation (CRP < 3 mg/uL or no inflammatory markers in their top quartile). Global test for haplotype effect indicated association of CRP gene and CRP plasma levels (P = 0.0004) and IL6 gene and COPD (P = 0.003). Subsequent analysis has shown that IL6 haplotype H2, associated with an increased COPD risk (p = 0.004, OR = 4.82; 1.64 to 4.18), was also associated with very low CRP levels (p = 0.0005). None of the genes were associated with COPD-related phenotypes. |
Does tanshinone IIA attenuate neuropathic pain via inhibiting glial activation and immune response? | Neuropathic pain, characterized by spontaneous pain, hyperalgesia and allodynia, is a devastating neurological disease that seriously affects patients' quality of life. We have previously shown that tanshinone IIA (TIIA), an important lipophilic component of Danshen, had significant anti-nociceptive effect in somatic and visceral pain, it is surprisingly noted that few pharmacological studies have been carried out to explore the possible analgesic action of TIIA on neuropathic pain and the underlying mechanisms. Therefore, in the present study, by using spinal nerve ligation (SNL) pain model, the antinociceptive and antihyperalgesic effects of TIIA on neuropathic pain were evaluated by intraperitoneal administration in rats. The results indicated that TIIA dose-dependently inhibited SNL-induced mechanical hyperalgesia. As revealed by OX42 levels, TIIA effectively repressed the activation of spinal microglial activation in SNL-induced neuropathic pain. Meanwhile, TIIA also decreased the expressions of inflammatory cytokines TNF-α and IL-1β in the spinal cord. Furthermore, TIIA inhibited oxidative stress by significantly rescuing the superoxide dismutase (SOD) activity and decreasing the malondialdehyde (MDA). Moreover, TIIA depressed SNL-induced MAPKs activation in spinal cord. | To determine the efficacy of screening women under age 50 with a significant family history of breast cancer. Results from 22 Breast Units in the UK identified as being able to provide data were surveyed and pooled through regional data managers or consultant breast specialists. Data relating to 8783 women screened and 9075 woman years of follow-up was analysed. Cancer incidence was 11.3/1000/year. The rate of cancer detection was 4. 78/1000 at prevalent screening and 4.52/1000 at incident screening. Median age at diagnosis was 43 years. Interval cancers presented at a rate of 2.45/1000. Comparison with the National Health Service Breast Screening Programme for women aged 50-64 revealed a similar rate of cancer detection and a similar incidence of ductal carcinoma in situ. The pathological features of screen-detected cancers in this study strongly suggest that prognosis for these women is more favourable than if they had presented symptomatically. |
Is autonomic rectal dysfunction in patients with multiple sclerosis and bowel symptoms secondary to spinal cord disease? | Most patients with multiple sclerosis report bowel symptoms, but the underlying pathophysiology is unclear. We hypothesize that rectal dysfunction in multiple sclerosis is secondary to involvement of the spinal cord by the disease and that this can be measured by assessing rectal compliance. This was a case-control study. The study took place in a neurogastroenterology clinic and tertiary referral center. Forty-five patients with multiple sclerosis, 19 with a spinal cord injury above T5, and 25 normal control subjects were included in this study. Patients with multiple sclerosis were subdivided into 2 groups according to the Expanded Disability Status Scale, below 5 (multiple sclerosis minor disability, n = 25) or above 5 (multiple sclerosis major disability, n = 20), as a reflection of spinal cord involvement. Rectal compliance, Wexner constipation, and Wexner incontinence scores were measured. Data are presented as mean and SD. Expanded Disability Status Scale correlated with rectal compliance but not with Wexner constipation or Wexner incontinence scores. Post hoc analysis showed no significant difference in Wexner constipation and Wexner incontinence between the 2 multiple sclerosis groups. | High concentrations of fibroblast growth factors (FGFs) are found in the heart. Even higher levels are measured during ischemia. Exogenous administration of FGF to ischemic myocardium promotes synthesis of collateral coronary circulation and induces local myocardial hypertrophy. The kinetics and the contribution of the heart and lungs to circulating basic FGF (bFGF) levels during cardiac surgery were characterized. Plasma bFGF levels were measured in seven adults undergoing coronary artery bypass operations and 11 neonates undergoing congenital cardiac anomaly repair during cardiopulmonary bypass. In both the adult and the neonatal groups, bFGF plasma levels increased significantly immediately after removal of the aortic cross-clamp (adult group 15.43+/-6.3 aorta cross-clamped versus 29+/-4.1 after release, P=0.011; neonatal group 17.09+/-9.43 aorta cross-clamped versus 43.55+/-14.25 after release, P=0.004) and declined thereafter. In the adult group, higher levels of bFGF were recorded in blood recovered from the coronary sinus than in the aortic root during aortic cross-clamping (63.14+/-14.42 versus 43.86+/-12.05, P=0.011), and in both, levels were significantly higher than the peripheral measurements. |
Does implantation of different malignant human cell lines in an athymic mouse alter success and growth rates of either xenograft? | Human xenografts in athymic mice are frequently used as preclinical models of cancer to investigate the targeting of drugs. In order to distinguish specific from nonspecific targeting of the xenograft, the mice can be implanted with different malignant cell lines. We studied in xenograft success and growth rates after implantation of human lymphoma and breast cancer cells to begin an assessment of the validity of this approach for distinguishing specific from nonspecific targeting. Investigations were undertaken to determine the effect of two different cell-line xenografts, and prior radiation needed for one of the xenografts, on implantation success and growth rates. Female athymic mice were given 4 Gy of external beam radiation 4 days prior to subcutaneous (s.c.) abdominal implantation of 6 x 10(6) Raji human lymphoma cells. One week later, 3 x 10(6) hamster blood transfusion (HBT) 3477 human breast cancer cells were implanted s.c. in a contralateral abdominal site. Xenografts were evaluated frequently thereafter. Xenograft success and growth rates were compared to those observed in "historical" control groups, wherein only a single xenograft of each type was implanted. Raji xenografts developed from 73.7% of the implantations, and 100% of the HBT 3477 xenografts were successful in the experimental group. The "historical" Raji xenograft success rate was 74.1% (+/-9.3%), and the "historical" HBT 3477 xenografts success rate was 99.0% (+/-1.1%). HBT 3477 xenografts did not affect the growth rate of the Raji xenografts, and the mean doubling time for the experimental Raji xenografts was 6.3 days (+/-4.5 days), compared to the "historical" control group mean of 5.1 days (+/-3.9 days; p = 0.2). Similarly, the growth rates for the HBT 3477 xenografts were not affected by the Raji xenografts and the pre-radiation needed for this model. Mean doubling time for HBT 3477 xenografts in the presence of Raji xenografts was 9.2 days (+/-17.6 days), compared to a doubling time of 1.4 days (+/-15.2 days; p = 0.55 and 0.94 studies 1 and 2, respectively). Mean HBT 3477 xenograft doubling time for the "historical" control group was 4.4 days (+/-6.0 days). | Chronic rhinosinusitis (CRS) is a common inflammatory disease of the upper airways that is often categorized into subtypes including "with" and "without" nasal polyps. However, the influence of multiple important epidemiologic factors, including race, on CRS has not been investigated. The present study assessed various phenotypic characteristics of CRS in patients, living in the United States, with different racial backgrounds. We performed a large retrospective cohort study of patients with CRS treated at a large urban tertiary care referral center in Chicago. African American (AA) patients with CRS living in Chicago were more likely to report hyposmia as a symptom of CRS. Furthermore, AA patients with CRS who failed medical therapy and required surgical intervention had a significantly higher frequency of nasal polyposis and aspirin-exacerbated respiratory disease, and a higher disease severity index on computed tomography imaging than did white patients with CRS. The increased polyposis in AAs was associated with increased hospitalization for asthma. There were no differences in the prevalence of atopy, asthma, atopic dermatitis, food allergy, duration of disease, or number of surgeries between different races. |
Is synovial fluid level of aggrecan ARGS fragments a more sensitive marker of joint disease than glycosaminoglycan or aggrecan levels : a cross-sectional study? | Aggrecanase cleavage at the 392Glu-393Ala bond in the interglobular domain (IGD) of aggrecan, releasing N-terminal 393ARGS fragments, is an early key event in arthritis and joint injuries. Here, we use a quantitative immunoassay of aggrecan ARGS neoepitope fragments in human synovial fluid to determine if this cleavage-site specific method better identifies joint pathology than previously available less specific aggrecan assays. Synovial fluid (SF) from 26 people with healthy knees (reference) and 269 patients were analyzed in a cross-sectional study. Patient groups were acute inflammatory arthritis, acute knee injury, chronic knee injury and knee osteoarthritis (OA). Aggrecan ARGS fragments were assayed by ELISA using the monoclonal antibody OA-1. Total aggrecan content was analyzed by an ELISA using the monoclonal antibody 1-F21, and sulfated glycosaminoglycan by Alcian blue precipitation. Aggrecan ARGS fragment concentrations in all groups differed from the reference group (P < 0.001). The acute inflammatory arthritis group had the highest median level, 177-fold greater than that of the reference group. Median levels (in pmol ARGS/ml SF) were: reference 0.5, acute inflammatory arthritis 88.5, acute knee injury 53.9, chronic knee injury 0.5 and OA 4.6. In contrast, aggrecan and sulfated glycosaminoglycan concentrations varied much less between groups, and only acute inflammatory arthritis and acute knee injury were found to have a two-fold increase in median levels compared to the reference. | To investigate the effects of non-drug interventions on the sleep quality of patients after mechanical cardiac valve implantation. In this prospective, randomized, controlled trial, 64 patients scheduled for mechanical mitral valve replacement were recruited. Patients underwent cognitive behavioral therapy and wore noise cancelling earplugs and eye mask. Sleep quality was evaluated on the 4th after admission and the 5th days after operation. The primary outcome was the total sleep quality score differences between the 4th day after admission and the 5th day after operation. All patients had been suffering from poor sleep quality for a month before admission. There was no difference between both groups on the 4th day after admission. Overall sleep quality in the intervention group was better than in the control group on the 5th day after operation. The subjective sleep quality of the patients in each group was significantly lower on the 5th day after the operation than on the 4th day after admission (P <0.05). |
Is additional surgical procedure a risk factor for surgical site infections after laparoscopic cholecystectomy? | Surgical site infections (SSI) are associated with increased costs and length of hospital stay, readmission rates, and mortality. The aim of this study was to identify risk factors for SSI in patients undergoing laparoscopic cholecystectomy. Analysis of 35,432 laparoscopic cholecystectomies of a prospective multicenter database was performed. Risk factors for SSI were identified among demographic data, preoperative patients' history, and operative data using multivariate analysis. SSIs after laparoscopic cholecystectomy were seen in 0.8 % (n = 291) of the patients. Multivariate analysis identified the following parameters as risk factors for SSI: additional surgical procedure (odds ratio [OR] 4.0, 95 % confidence interval [CI] 2.2-7.5), age over 55 years (OR 2.4 [1.8-3.2]), conversion to open procedure (OR 2.6 [1.9-3.6]), postoperative hematoma (OR 1.9 [1.2-3.1]), duration of operation >60 min (OR 2.5 [1.7-3.6], cystic stump insufficiency (OR 12.5 [4.2-37.2]), gallbladder perforation (OR 6.2 [2.4-16.1]), gallbladder empyema (OR 1.7 [1.1-2.7]), and surgical revision (OR 15.7 [10.4-23.7]. SSIs were associated with a significantly prolonged hospital stay (p < 0.001), higher postoperative mortality (p < 0.001), and increased rate of surgical revision (p < 0.001). | Preclinical testing of potential therapies for Duchenne muscular dystrophy (DMD) is conducted predominantly of the mdx mouse. But lack of a detailed quantitative description of the pathology of this animal limits our ability to evaluate the effectiveness of putative therapies or their relevance to DMD. Accordingly, we have measured the main cellular components of muscle growth and regeneration over the period of postnatal growth and early pathology in mdx and wild-type (WT) mice; phalloidin binding is used as a measure of fibre size, myonuclear counts and BrdU labelling as records of myogenic activity. We confirm a two-phase postnatal growth pattern in WT muscle: first, increase in myonuclear number over weeks 1 to 3, then expansion of myonuclear domain. Mdx muscle growth lags behind that of WT prior to overt signs of pathology. Fibres are smaller, with fewer myonuclei and smaller myonuclear domains. Moreover, satellite cells are more readily detached from mdx than WT muscle fibres. At 3 weeks, mdx muscles enter a phase of florid myonecrosis, accompanied by concurrent regeneration of an intensity that results in complete replacement of pre-existing muscle over the succeeding 3 to 4 weeks. Both WT and mdx muscles attain maximum size by 12 to 14 weeks, mdx muscle fibres being up to 50% larger than those of WT as they become increasingly branched. Mdx muscle fibres also become hypernucleated, containing twice as many myonuclei per sarcoplasmic volume, as those of WT, the excess corresponding to the number of centrally placed myonuclei. |
Is time of physical exercise practice after injury in cervical spinal cord-injured men related to the increase in insulin sensitivity? | Physical exercise has an important role in reducing body fat, risk of chronic disease and systemic inflammation. The aim of this study was to determine serum leptin and insulin concentrations and their relationship to the time of physical exercise after injury in men with cervical spinal cord injury (c-SCI). c-SCI subjects with lesion level in C5-C7 (n=25) were divided into two groups: physically active (PA, n=13; those who practiced physical exercise for at least 3 months, three times per week or more, for a total minimum of 150 min of physical activity per week) and non-physically active (N-PA, n=9). Body composition was assessed by dual energy X-ray absorptiometry. Blood samples were obtained 12 h after an overnight fast to measure insulin and leptin in serum, and glucose and C-reactive protein (CRP) in plasma, by validated methods. Comparing the PA and N-PA group, the first presented lower: total body mass (-13%), body mass index (-16%), fat mass (kg -39%, FM% -30%), CRP (-23%), serum insulin (-61%), homeostasis model assessment (HOMA, -35%) and serum leptin (-62%; P<0.05). Both serum insulin (r=-0.561; P<0.05) and HOMA (r=-0.591; P<005) were inversely proportional to the time of practice of physical activity after injury. | Taxus chinensis (Pilger) Rehd is widely distributed in China and the northern hemisphere, and the most popular medicinal component isolated from Taxus chinensis is paclitaxel (PTX), which has now become the first-line chemotherapeutic drug for breast cancer and ovarian cancer. Oral administration of pure PTX as a potential anti-cancer agent is compromised by low bioavailability. In the clinical practice of traditional Chinese medicine, drug co-administration in the form of mixtures or formula could achieve pharmacokinetic/pharmacodynamic synergies. In this study, we aimed to investigate whether there exist any 'inherent' phytochemical synergy from Taxus chinensis extract that could improve PTX bioavailability. Pharmacokinetic study of PTX after oral administration of Taxus chinensis extracts or single PTX was performed. In addition, comparative cytotoxic studies were carried out on the MCF-7 breast cancer cell lines. The plasma concentrations of PTX were determined using a validated high performance chromatography tandem mass spectrometry method. The cytotoxicity was compared using the MTT assay. Oral administration of taxane fractions isolated from Taxus chinensis (containing 17.2% PTX) could achieve remarkably higher blood concentration and systemic exposure of PTX in rats, while the retention of PTX was significantly improved. Further tissue distribution analysis revealed that the penetration of PTX into major tissues was drastically increased compared with that of single PTX. In addition, in MCF-7 cells, the co-existing components in taxane mixtures could strengthen the inhibitory effects of PTX on tumor cell proliferation. |
Does swiss tertiary care center experience challenge the age-cohort effect in Helicobacter pylori infection? | The epidemiology of Helicobacter pylori infection reflects the age-characteristics, developmental status and access to health care of the population in a given area. To assess the influence of demographic variables on the prevalence of H. pylori status among patients evaluated in a Swiss university medical center. Demographic data (i.e. age, gender, place of birth), indication for H. pylori testing, history of prior H. pylori eradication therapy, medical field and clinical setting of the referring physician were reviewed from patient's charts. H. pylori status was assessed by the 13C Urea breath test. Patients born in Switzerland had lower rates of positive (13)C Urea breath test results compared to those born outside of the country (12/101 [11.9%] vs. 67/252 [26.6%]; p=0.003). While there were no differences between males and females (p>0.05), patients 50 years and below were more likely to have a positive test result compared to those above the age of 50 years (59/106 [28.6%] vs. 20/147 [13.6%]; p<0.01). There were no major differences in the rate of positive 13C Urea breath tests in patients with previous history of H. pylori eradication and those without. Patients with dyspeptic symptoms and those without had similar rates of positive tests (11/61 [18.0%] vs. 68/292 [23.3%]; p=ns). | Thrombomodulin (TM), a potent anticoagulant, is not detected in quiescent vascular smooth muscle cells (VSMCs). In diseased vessels, VSMC expresses TM, but the mechanisms are unclear. This study examined molecular mechanisms for TM expression in VSMCs. Platelet-derived growth factor-BB (PDGF-BB) induced TM expression in cultured human aortic VSMCs. PDGF-induced TM is functional in activating protein C. TM induction was eliminated by inhibitors of Src kinase, phosphatidylinositol 3-kinase (PI3-kinase), and mammalian target of rapamycin (mTOR) and by expressing dominant-negative Akt while expressing active Akt-stimulated TM expression. PDGF-BB activated the TM promoter, and the deletion of a sequence segment -394/-255 drastically reduced TM promoter activity. Transcription factor E26 transformation-specific sequence-1 (Ets-1) was upregulated by PDGF-BB in a PI3-kinase- and mTOR-dependent manner. RNA interference of Ets-1 inhibited PDGF induction of TM, and overexpressing Ets-1 increased TM expression. Chromatin immunoprecipitation and electrophoretic mobility shift assay detected increased Ets-1 binding to the TM promoter after PDGF treatment. Following carotid artery ligation of C57/BL6 mice, PDGF-BB and TM were co-expressed in the media and neointima. |
Does absence of circulating aldosterone attenuate foreign body reaction around surgical sutures? | Adrenal hormones influence inflammatory and fibrotic activity and thereby are involved in wound-healing process. Any excess as well as any shortage of glucocorticoids leads to a delayed wound healing. Mineralocorticoids like aldosterone have a pro-fibrotic and pro-inflammatory impact; thus, reduction of circulating aldosterone should result in an attenuated inflammatory response to implanted foreign bodies. Eighteen rats were bilaterally adrenalectomized and substituted with dexamethasone (12 microg/kg per day) and 1% salt in their drinking water; 22 rats were sham-operated. The surgical suture material was removed after 3 weeks and analyzed for size of granuloma, ratio of collagen type I/III, apoptotic cells (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling), expression of matrix metalloproteinase (MMP)-2, cyclooxygenase 2, tumor necrosis factor receptor 2 (TNF-R2), cluster of differentiation 68 (CD68), Ki67, and cold shock protein Y box binding protein 1 (YB-1). Cell expression was scored according to Remmele. All animals developed foreign body granulomas around the sutures. Absence of circulating aldosterone after adrenalectomy (ADX) was associated with smaller granuloma size and a reduced ratio of collagen type I/III. Ki67 and MMP-2 showed the strongest expression in cells of the infiltrate around suture. In adrenalectomized rats, we observed significantly less CD68-positive macrophages and less Ki67-positive cells but no significant differences in the expression of YB-1, TNF-R2, or MMP-2. Looking for correlations and co-expressions of proteins, the number of significant Spearman correlations was reduced in the ADX group compared to controls (one and four, respectively). | To investigate whether single nucleotide polymorphisms (SNP) of drug transporter proteins for TDF is a risk factor for TDF-related renal function decrement. This study investigated the association between 3 SNPs (ABCC2-24, 1249, and ABCB1 2677), which are shown to be associated with TDF-induced tubulopathy, and clinically important renal outcomes (>10ml/min/1.73m2 decrement in eGFR relative to baseline, >25% decrement in eGFR, and eGFR <60ml/min/1.73m2) in 703 HIV-1-infected Japanese patients who initiated TDF-containing antiretroviral therapy (ART). Genotyping was performed by allelic discrimination using TaqMan 5'-nuclease assays. 95% of the study patients were males and 66% were treatment-naïve, with median CD4 count of 249/μl, median baseline eGFR of 96ml/min/1.73m2 (IQR 84.6-109.2), and median exposure to TDF of 3.66 years (IQR 1.93-5.59). The frequencies of genotypes at -24, 1249 of ABCC2, and 2677 of ABCB1 were neither different between patients with decrement in eGFR of >10ml/min/1.73m2 and those without such decrement (ABCC2: -24, p = 0.53, 1249, p = 0.68; ABCB1: 2677, p = 0.74), nor between those without and with the other two renal outcomes (>25% decrement: ABCC2: -24, p = 0.83, 1249, p = 0.97, ABCB1: 2677, p = 0.40; eGFR <60ml/min/1.73m2: ABCC2: -24, p = 0.51, 1249, p = 0.81, ABCB1: 2677, p = 0.94). Logistic regression analysis showed that the risk genotype of the three SNPs were not associated with any of the three renal outcomes, respectively. Logistic regression model that applied either dominant, recessive, or additive model yielded the same results. |
Does high-frequency QRS electrocardiogram predict perfusion defects during myocardial perfusion imaging? | Changes in high-frequency (HF) QRS components of the electrocardiogram (ECG) (150-250 Hz) are more sensitive than changes in conventional ST segments for detecting myocardial ischemia. We investigated the accuracy of 12-lead HF QRS ECG in detecting perfusion defects during adenosine tetrofosmin myocardial perfusion imaging (MPI). 12-lead HF QRS ECG recordings were obtained from 45 patients before and during adenosine technetium Tc 99m tetrofosmin MPI tests. Before the adenosine infusions, recordings of HF QRS were analyzed according to a morphologic score that incorporated the number, type, and location of reduced amplitude zones (RAZs) present in the 12 leads. During the adenosine infusions, recordings of HF QRS were analyzed according to the maximum percentage changes (in both the positive and negative directions) that occurred in root mean square voltage amplitudes within the 12 leads. The best set of prospective HF QRS criteria had a sensitivity of 94% and a specificity of 83% for correctly identifying the MPI result. The sensitivity of simultaneous ST-segment changes (18%) was significantly lower than that of any individual HF QRS criterion (P < .001). | The aim of the present study was to investigate to what extent personality and choice of coping predicted self-reported quality of life (QoL) in successfully treated head and neck squamous cell carcinoma (HNSCC) patients. We determined QoL by the European Organization for Research and Treatment of Cancer Quality of life Questionnaire (EORTC-QLQ) C30/H&N35, personality by the Eysenck Personality Inventory and coping by the COPE questionnaire. All patients younger than 80 years who had been diagnosed with HNSCC in Western Norway in the period from 1992 to1997, and who had survived until 1999, were sampled. Ninety-six patients (90% response rate) were included 48+/-2 months after diagnosis. Fifty-five of 58 eligible patients were interviewed a second time 47+/-1 months after the first interview where neuroticism and QoL questionnaires were answered. Numerical T stage was inversely associated with the second QoL scores (CV: 10-24%). High neuroticism generally predicted low secondary QoL scores both directly (common variance: 17-25%) and adjusted by the QoL values measured simultaneously as the neuroticism (CV: 11-25%). Avoidance focused, problem focused, drinking to cope and coping by humor all predicted QoL scores (CV: 8.5-15%). The present association pattern could still be shown when adjusted for gender, age and educational level when studied by multiple regression analyses. |
Is esophageal tumor length independently associated with long-term survival? | Esophageal cancer staging uses tumor depth as the sole criterion for assessment of the primary tumor (pT). To the authors' knowledge the impact of esophageal tumor length on long-term outcome and the esophageal cancer staging system has not been fully evaluated in the current era. All esophageal cancer patients (n = 209) undergoing surgery from 1995 to 2005 who did not receive preoperative chemotherapy or radiotherapy were reviewed. Maximum esophageal tumor length along a craniocaudal axis was determined pathologically after surgical resection. Univariate and multivariate analyses were used to assess the impact of esophageal tumor length (< or = 3 cm vs >3 cm) on long-term survival. Esophageal tumor length was closely associated with long-term survival (hazards ratio [HR] of 6.14 [95% confidence interval (95% CI), 4.1-9.25]; 5-year survival: < or = 3 cm = 68%, >3 cm = 10% [P < .001]). Multivariate Cox regression analyses demonstrated tumor length (HR of 2.13 [95% CI, 1.26-3.63]) was found to be a significant independent predictor of long-term survival even when controlled for sex, age, tumor location, histology, margin positivity, surgical procedure, and current pTNM criteria. The incorporation of tumor length in pTNM staging significantly improves the ability to predict the long-term survival of patients (5-year survival for patients with tumors < or = 3 cm and stages I, IIA, IIB, and III disease = 86%, 62%, 49%, and 22%, respectively; survival for patients with tumors measuring >3 cm and stages I, IIA, IIB, and III disease = 27%, 22%, 0%, and 8%, respectively [P < .1]). | Obese individuals are known to have increased Matrix metalloproteinase (MMP)-9 plasma levels and MMP-9 is reported to play an important role in obesity-associated adipose tissue inflammation. Since in obesity, the levels of circulatory saturated free fatty acid (FFA) palmitate (palimitic acid) are increased and modulate the expression of inflammatory mediators, the role of palmitate in the regulation of MMP-9 remains unclear. Human monocytic cell line THP-1 and primary monocytes were stimulated with palmitate and TNF-α (positive control). MMP-9 expression was assessed with real time RT-PCR and ELISA. Signaling pathways were studied by using THP-1-XBlue™ cells, THP-1-XBlue™-defMyD cells, anti-TLR4 mAb and TLR4 siRNA. Phosphorylation of NF-kB and c-Jun was analyzed by Western blotting. Here, we provide the evidence that palmitate induces MMP-9 expression at both mRNA (THP-1: 6.8 ± 1.2 Fold; P = 0.01; Primary monocytes: 5.9 ± 0.7 Fold; P = 0.0003) and protein (THP1: 1116 ±14 pg/ml; P<0.001; Primary monocytes: 1426 ± 13.8; P = 0.0005) levels in human monocytic cells. Palmitate-induced MMP-9 secretion was markedly suppressed by neutralizing anti-TLR-4 antibody (P < 0.05). Furthermore, genetic silencing of TLR4 by siRNA also significantly abrogated the palmitate-induced up-regulation of MMP-9. Additionally, MyD88-/- THP-1 cells did not express MMP-9 in response to palmitate treatment. Increased NF-κB/AP-1 activity (P<0.05) was also observed in palmitate-treated THP-1 cells. |
Does apolipoprotein E genotype modify the risk of behavior problems after infant cardiac surgery? | The goal was to evaluate polymorphisms of the APOE gene as modifiers of neurobehavioral outcomes for preschool-aged children with congenital heart defects, after cardiac surgery. A prospective observational study with neurodevelopmental evaluation between the fourth and fifth birthdays was performed. Attention and behavioral skills were assessed through parental report. Parents of 380 children completed the neurobehavioral measures. Child Behavior Checklist scores for the pervasive developmental problem scale were in the at-risk or clinically significant range for 15% of the cohort, compared with 9% for the normative data (P < .00001). Attention problem scores were in the at-risk or clinically significant range for 12% of the cohort, compared with 7% for the normative data (P = .0002). The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Preschool Version, was completed for 378 children; 30% scored in the clinically significant range for inattention and 22% for impulsivity. After adjustment for covariates, the APOE epsilon2 allele was significantly associated with higher scores (worse problems) for multiple Child Behavior Checklist indices, including somatic complaints (P = .009), pervasive developmental problems (P = .032), and internalizing problems (P = .009). In each case, the epsilon4 allele was associated with a better outcome. APOE epsilon2 carriers had impaired social skills, compared with epsilon4 carriers (P = .009). | Porphyromonas gingivalis, an important periodontal pathogen, is closely associated with inflammatory alveolar bone resorption. This bacterium exerts its pathogenic effect indirectly through multiple virulence factors, such as lipopolysaccharides, fimbriae, and proteases. Another possible pathogenic path may be through a direct interaction with the host's soft and hard tissues (e.g., alveolar bone), which could lead to periodontitis. The aim of the present study was to investigate the direct effect of live and heat-inactivated P gingivalis on bone resorption, using an in vitro osteoblast culture model. Optical microscopy and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide MTT assay revealed that live P gingivalis induced osteoblast detachment and reduced their proliferation. This effect was specific to live bacteria and was dependent on their concentration. Live P gingivalis increased IL-6 mRNA expression and protein production and downregulated RANKL and OPG mRNA expression. The effect of live P gingivalis on bone resorption was strengthened by an increase in MMP-9 expression and its activity. This increase was accompanied by an increase in TIMP-1 and TIMP-2 mRNA expression and protein production by osteoblasts infected with live P gingivalis. |
Does gray matter atrophy correlate with MS disability progression measured with MSFC but not EDSS? | Gray matter (GM) pathology is an important component of the multiple sclerosis (MS) disease process. Accelerated gray matter atrophy has been observed in MS patients, but its relationship to neurological disability is not defined. This study was done to determine the relationship between whole brain, GM, and white matter (WM) atrophy and MS disability progression. Patients with MS and Clinically Isolated Syndromes (CIS), and age- and gender-matched healthy controls were entered into an observational protocol. Baseline brain parenchymal fraction (BPF), GM fraction, and WM fraction, and change over 4 years were correlated with sustained disability progression over the entire study duration. Disability progression was measured using the Multiple Sclerosis Functional Composite (MSFC) and the Expanded Disability Status Scale (EDSS). Seventy MS and CIS patients and 17 HCs were studied for an average of 6.6 years (range, 3.6-7.8 years). At the final visit, 7 patients were classified as CIS, 36 as relapsing-remitting MS (RRMS), and 27 as secondary progressive MS (SPMS). Baseline whole brain, GM, and WM atrophy predicted EDSS >6.0 at the last study visit. Twenty-one (33%) patients worsened using the EDSS to define disability progression; 29 (46%) worsened using MSFC to define disability progression. Patients with MSFC progression had significantly higher GM atrophy rates compared with patients who were stable on MSFC. White matter atrophy was similar in patients with and without disability progression. Atrophy rates were not different in patients with or without disability progression defined using EDSS. | Mortality from colon cancer is significant with an expected 30,350 colon cancer deaths in 2005 with current treatment(s). Long-acting natriuretic peptide, vessel dilator, kaliuretic peptide, and atrial natriuretic peptide have significant anticancer effects in breast and pancreatic adenocarcinomas. Whether these peptide hormones have anticancer effects in colon adenocarcinoma cells and whether these effects are specifically mediated by cyclic GMP has not been determined. These peptide hormones were evaluated for anticancer effects in human colon adenocarcinoma cells and to determine whether their anticancer effects are specifically mediated by cyclic GMP. There was a 89-97% decrease (p <0.001 for each) in colon adenocarcinoma cells within 24 h with 1 mM of these peptide hormones. There was a significant (p <0.05) decrease in human colon cancer cell number with each 10-fold increase in concentration from 1 to 1,000 microM (i.e., 1 mM) of these four peptide hormones without any proliferation in the 3 d following this decrease. These same hormones decreased DNA synthesis 65-83% (p <0.001). Cyclic GMP antibody inhibited 75- 80% of these peptides' ability to decrease colon adenocarcinoma cell number and inhibited 92-96% of their DNA synthesis effects and 97% of cyclic GMP's effects. Western blots revealed that for the first time natriuretic peptide receptors (NPR) A and C were present in colon adenocarcinoma cells. |
Do par3 and dynein associate to regulate local microtubule dynamics and centrosome orientation during migration? | Centrosome orientation toward the leading edge of migrating cells depends on dynein and microtubules (MTs), as well as a number of signaling factors at the leading edge. However, centrosomes are maintained at the cell center during orientation in fibroblasts, suggesting that factors working at sites other than the leading edge may also be involved. In a search for factors that function with dynein in centrosome orientation, we found that the polarity protein Par3 associated with dynein and that knockdown of Par3 inhibited centrosome orientation by disrupting the position of the centrosome at the cell center; this disrupted centrosome positioning is the same phenotype as that observed with dynein inhibition. Par3 associated with dynein through its N-terminal dimerization and PDZ1 domains and interacted specifically with dynein light intermediate chain 2 (LIC2). siRNA knockdown of LIC2, but not LIC1, or overexpression of LIC2 or the N-terminal domain of Par3, also inhibited centrosome orientation by disrupting centrosome position. In wound-edge fibroblasts, Par3 specifically localized to cell-cell contacts where it overlapped with MT ends and dynein puncta in a LIC2-dependent fashion. Live imaging showed that MTs exhibited increased pausing at cell-cell contacts compared to the leading edge and that this elevated pausing was dependent on Par3 and LIC2. | Many patients with coronary heart disease (CHD) are not managed adequately, and we often fail to reach treatment targets. To investigate if knowledge of risk factors for CHD, measured by a questionnaire, would show any relation to advice to compliance to lifestyle changes to attain treatment goals and adherence to drug therapy. Men and women <71 years who had had a cardiac event were screened consecutively (509) from the medical records. Responders (392) were interviewed, examined and received a questionnaire. Three hundred and forty-seven patients answered the questionnaire regarding their general knowledge of risk factors for CHD, compliance to lifestyle changes to attain treatment goals and adherence to drug therapy. There were statistically significant correlations between general knowledge about risk factors for CHD and compliance to certain lifestyle changes: weight, physical activity, stress management, diet, attainment of lipid level goals and the likelihood of taking prescribed blood pressure-lowering drugs. General knowledge of risk factors had no correlation to blood glucose or blood pressure levels nor on smoking habits or treatment patterns for prescribed lipid- and blood glucose-lowering drugs. |
Are presence and extent of extrapancreatic fluid collections indicators of severe acute pancreatitis? | It has been suggested that early localization of both necrosis and extrapancreatic fluid collections by contrast-enhanced computed tomography (CT) can predict the outcome in severe acute pancreatitis. These two assumptions were evaluated. This study comprises 228 patients with a first attack of acute pancreatitis admitted to our clinic from 1987 to 1995 and for whom the prognostic value of a contrast-enhanced CT obtained within 72 h of admission was prospectively evaluated. These CTs were retrospectively re-evaluated for the localization of pancreatic necrosis and extrapancreatic fluid collections. The indication for dialysis and artificial ventilation, the development of pancreatic pseudocysts, the necessity for surgery (necrosectomy), and mortality were used as clinical parameters. There was a significant correlation between the presence of pancreatic necrosis and extrapancreatic fluid collections versus the clinical parameters. The localization of pancreatic necrosis was of no importance for the outcome of the disease, whereas the increasing amount of extrapancreatic fluid collections paralleled the severity of acute pancreatitis. | Androgens cause regression of human hair follicles in the parietofrontal scalp, but the precise mechanisms by which they do so are unknown. Although many investigators have elucidated the effect of androgens on hair growth by using rodents and other animals, some of the evidence is conflicting. To investigate the effect of androgens on mouse hair regrowth and hair cycle by using androgen receptor knockout (ARKO) mice. Methods We examined the effects of dihydrotestosterone (DHT) on hair regrowth by using ARKO mice and wild-type (WT) littermates, compared the hair cycles in ARKO mice and WT littermates by histology and histomorphometry, and measured hair length and thickness in ARKO mice and WT littermates. DHT inhibited the hair regrowth of WT mice but not that of their ARKO littermates. The anagen phase in the second hair cycle was longer in ARKO mice than in their WT littermates. The hair of ARKO mice was longer and thicker than that of their WT littermates. |
Does distance to Thrombus in Acute Middle Cerebral Artery Occlusion predict Target Mismatch and Ischemic Penumbra? | In patients with occlusion of the middle cerebral artery (MCA) treated by intravenous thrombolysis (IVT), the distance to thrombus (DT) has been proposed as a predictor of outcome. The purpose of the present study was to investigate how DT relates to dynamic susceptibility contrast perfusion metrics. Retrospective analysis was undertaken of patients who were diagnosed with acute MCA occlusion by magnetic resonance imaging and treated with IVT. Volumes of time-to-maximum (Tmax) perfusion deficits and diffusion-weighted imaging (DWI) lesions, diffusion-perfusion mismatch volumes, and the presence of target mismatch were determined. Correlations between the above stoke measures and DT were then calculated. Fifty-five patients were included. DT showed significant inverse correlations with Tmax greater than 4, 6, 8, and 10 seconds, respectively, and mismatch volumes. Using the DT group median (14 mm) as a separator, significant intergroup differences were observed for Tmax greater than 4, 6, and 8 seconds, respectively, and for mismatch volumes. Grouping DT into quartiles showed significant intergroup differences regarding mismatch volumes and Tmax values greater than 4 and 6 seconds. Binary logistic regression identified DT (odds ratio [OR] = .89; 95% confidence interval [CI], .81-.99) and DWI lesion volumes (OR = .92; 95% CI, .86-.97) as independent predictors of target mismatch. A low DT predicted target mismatch with an area under the curve of .69. | The hygiene hypothesis states that children exposed to higher loads of microbes such as farmers' children suffer less from allergies later in life. Several immunological mechanisms underpinning the hygiene hypothesis have been proposed such as a shift in T helper cell balance, T regulatory cell activity, or immune regulatory mechanisms induced by the innate immunity. To investigate whether the proposed immunological mechanisms for the hygiene hypotheses are found in farmers' children. We assessed gene expression levels of 64 essential markers of the innate and adaptive immunity by quantitative real-time PCR in white blood cells in 316 Swiss children of the PARSIFAL study to compare farmers' to non-farmers' expressions and to associate them to the prevalence of asthma and rhinoconjunctivitis, total and allergen-specific IgE in serum, and expression of Cε germ-line transcripts. We found enhanced expression of genes of the innate immunity such as IRAK-4 and RIPK1 and enhanced expression of regulatory molecules such as IL-10, TGF-β, SOCS4, and IRAK-2 in farmers' children. Furthermore, farmers' children expressed less of the TH1 associated cytokine IFN-γ while TH2 associated transcription factor GATA3 was enhanced. No significant associations between the assessed immunological markers and allergic diseases or sensitization to allergens were observed. |
Does peripheral blood stem cell transplantation improve liver functional reserve? | Currently available treatment options for decompensated hepatitis B-induced liver cirrhosis are limited and largely ineffective. Recently, stem cell transplantation has emerged as a promising treatment for cirrhosis. The aim of this study was to determine whether autologous peripheral blood stem cell transplantation can improve liver functional reserve in patients with hepatitis B-induced cirrhosis. In this study, 51 patients with hepatitis B-induced liver cirrhosis were assigned to the treatment group (n=23) or the control group (n=28). The treatment group underwent autologous peripheral blood stem cell transplantation in addition to comprehensive medical treatment, and the control group received comprehensive medical treatment alone. Liver functional reserve was monitored for 48 weeks after autologous peripheral blood stem cell transplantation. After transplantation, most patients showed improvements in symptoms such as fatigue, anorexia, and abdominal distension. The retention rate of indocyanine green at 15 minutes, a common indicator of liver functional reserve, declined from 41.99±4.68 at baseline to 37.79±3.75 by 48 weeks after transplantation, showing significant improvement. | The inhalation anesthetic isoflurane has been shown to open the mitochondrial permeability transition pore (mPTP) and induce caspase activation and apoptosis, which may lead to learning and memory impairment. Cyclosporine A, a blocker of mPTP opening might attenuate the isoflurane-induced mPTP opening, lessening its ripple effects. Magnesium and anesthetic propofol are also mPTP blockers. We therefore set out to determine whether propofol and magnesium can attenuate the isoflurane-induced caspase activation and mPTP opening. We investigated the effects of magnesium sulfate (Mg2+), propofol, and isoflurane on the opening of mPTP and caspase activation in H4 human neuroglioma cells stably transfected to express full-length human amyloid precursor protein (APP) (H4 APP cells) and in six day-old wild-type mice, employing Western blot analysis and flowcytometry. Here we show that Mg2+ and propofol attenuated the isoflurane-induced caspase-3 activation in H4-APP cells and mouse brain tissue. Moreover, Mg2+ and propofol, the blockers of mPTP opening, mitigated the isoflurane-induced mPTP opening in the H4-APP cells. |
Does analysis of mammalian gene batteries reveal both stable ancestral cores and highly dynamic regulatory sequences? | Changes in gene regulation are suspected to comprise one of the driving forces for evolution. To address the extent of cis-regulatory changes and how they impact on gene regulatory networks across eukaryotes, we systematically analyzed the evolutionary dynamics of target gene batteries controlled by 16 different transcription factors. We found that gene batteries show variable conservation within vertebrates, with slow and fast evolving modules. Hence, while a key gene battery associated with the cell cycle is conserved throughout metazoans, the POU5F1 (Oct4) and SOX2 batteries in embryonic stem cells show strong conservation within mammals, with the striking exception of rodents. Within the genes composing a given gene battery, we could identify a conserved core that likely reflects the ancestral function of the corresponding transcription factor. Interestingly, we show that the association between a transcription factor and its target genes is conserved even when we exclude conserved sequence similarities of their promoter regions from our analysis. This supports the idea that turnover, either of the transcription factor binding site or its direct neighboring sequence, is a pervasive feature of proximal regulatory sequences. | We previously reported significant variations in oxidation status and molecular length among sources and lots of human serum albumin (HSA) commercial preparations intended for clinical use. In this report, we investigated what effect the presence of HSA products have on the immune response in vitro. Laboratory study. Trauma research basic science laboratory. Activated human peripheral blood mononuclear cells. Six commercial HSA preparations were tested for their effect on cytokine release from activated human peripheral blood mononuclear cells (PBMCs) and T-lymphocytes. Mass spectrometry analysis of aspartyl-alanyl diketopiperazine (DA-DKP) content of HSA and percentage of HSA having lost its amino terminal dipeptide aspartyl alanyl (HSA-DA) were correlated. Human PBMCs were cultured in the presence of six commercial HSA preparations and activated via the T-cell receptor complex. A cloned T-lymphocyte cell line, activated with specific antigen, was also cultured with both synthetic DA-DKP and small molecular weight extracts from the commercial HSA tested. Supernatants were quantified by enzyme-linked immunosorbent assay for interferon-gamma and tumor necrosis factor-alpha content. DA-DKP was extracted from HSA by centrifugal filters and quantified by anion exchange liquid chromatography coupled to negative electrospray ionization mass spectrometry. HSA species were determined by reverse phase liquid chromatography coupled to positive electrospray ionization, time of flight mass spectrometry. All HSA preparations significantly inhibited the in vitro production of interferon-gamma and tumor necrosis factor-alpha by activated PBMCs. DA-DKP was detected in all HSA sources at concentrations ranging between 42.0 and 79.6 microM. A synthetic form of DA-DKP possessed similar immunosuppressive qualities in a dose-dependent manner on T lymphocytes. |
Do phospholipids prevent enteric bacterial translocation in the early stage of experimental acute liver failure in the rat? | Bacterial infections and bacteremia in acute liver failure may at least partly be attributed to translocation of enteric bacteria. Attempts to prevent or treat such infections by the use of antibiotics may instead result in overgrowth of surviving microbes. In the present study, normal saline (1.5 ml/100 g body weight), phosphatidylcholine (1.5 ml/100 g body weight), and phosphatidylinositol (1.5 ml/100 g body weight) were orally administered by means of a gastric tube both 12 h and 30 min before operation. Effects of enteric administration of phospholipids on the prevention of enteric bacterial translocation, intestinal and mucosal mass, and enterocyte protein contents in acute liver failure induced by subtotal liver resection in the rat were evaluated. The incidence of bacterial translocation increased significantly 2 and 4 h after 90% hepatectomy as compared with sham-operated animals. Enteric administration of phospholipids, however, significantly reduced the incidence of bacterial translocation after 90% hepatectomy. Phospholipid treatment prevented the postoperative decrease in intestinal mucosal mass and enterocyte protein content. | SNP309 polymorphism (T-G) at the promoter region of MDM2 has been reported to cause increased binding affinity of transcriptional activator Sp1 followed by increased MDM2 both in mRNA and protein level. This model was proposed in vitro in the small panel of cell lines that indicated an on average 8-fold higher level of MDM2 mRNA in cells bearing the GG genotype. The incidence of SNP309 was determined in a cohort of 158 breast, 17 endometrium, 13 cervix and 45 ovarian cancer tissues by PCR-RFLP. The expression of p53 and MDM2 protein levels in the cohort was immunohistochemically investigated and statistically correlated with SNP309 polymorphism using Pearson chi(2) and t test. No significant difference was observed in the G allele incidence in breast cancer specimens compared to 149 noncancer controls. Furthermore, no statistically significant association of the G allele frequencies and p53 and MDM2 protein expression levels was observed. |
Does intrathecal morphine reduce the visceromotor response to acute uterine cervical distension in an estrogen-independent manner? | Acute uterine cervical distension (UCD) forms the basis for obstetric and some gynecologic pain. Systemic morphine inhibits the visceromotor response to UCD in rats by an action in the central nervous system, but the effect of morphine is blocked by exposure to estrogen. The purpose of the present study was to determine whether this estrogen blockade of the action of morphine reflects a spinal mechanism. Virgin Sprague-Dawley rats received estrogen or placebo treatment for 1 week after ovariectomy. Rats were then anesthetized, and the electromyographic response in the rectus abdominis muscle to UCD was recorded in the absence and presence of cumulative dosing with intrathecal morphine. Estrogen treatment did not alter the stimulus- response relationship between UCD and reflex muscle contraction. Intrathecal morphine reduced the visceromotor reflex response to UCD in a dose-dependent manner that was unaffected by estrogen treatment. | Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become key therapeutic agents for non-small cell lung cancer (NSCLC) patients with EGFR mutation, little is known about the efficacy of EGFR-TKIs according to different treatment timings. A total of 1,250 patients with NSCLC were screened for EGFR mutations at a single institution between March 2006 and May 2010. The efficacy of EGFR-TKIs in terms of response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared according to the treatment timing. Among the 437 patients (36.1 %) with EGFR mutation, we analyzed 222 patients who received EGFR-TKI treatment. With a median follow-up duration of 27.5 months (range 8.3-69.2), EGFR-TKI was given to 97 (43.7 %), 109 (49.1 %), and 16 (7.2 %) patients as first-line, second-line, and third-line therapy, respectively. All three groups showed similar RR (71.1, 72.5, and 75.0 %, respectively) to EGFR-TKI (p = 0.802). No significant difference was observed according to treatment timing of EGFR-TKI in terms of PFS (median 10.6, 13.0, and 10.4 months; p = 0.670) and OS (median 20.5, 26.2, and 17.1 months; p = 0.142). The treatment timing of EGFR-TKI still showed no association with PFS or OS after adjusting significant prognostic factors including performance, disease status, and EGFR mutation types. |
Does serum Angiopoietin-like Protein 2 improve Preoperative Detection of Lymph Node Metastasis in Colorectal Cancer? | We investigated whether serum markers and clinical factors could be used to preoperatively predict lymph node (LN) metastasis in colorectal cancer (CRC). The present study enrolled 157 curative CRC patients for whom preoperative serum carcinoembryonic antigen (CEA), systemic inflammatory markers (C-reactive protein (CRP) and angiopoietin-like protein 2 (ANGPTL2)) and objective preoperative clinical factors were available as indicators of pathological LN status. Specific clinical factors, including gender, tumor size, histopathology of biopsy sample and tumor morphology, were significantly correlated with LN metastases. Additionally, CEA, CRP and ANGPTL2 levels were also predictive factors for LN status. Multivariate analysis revealed that clinical factors, including gender, histopathology, tumor morphology and ANGPTL2, were identified as independent predictive factors for LN metastases. A combination of clinical factors reached high predictive accuracy of LN metastases and, combined with clinical factors, ANGPTL2 further improved the accuracy. | Nicotinamide adenine dinucleotide (NAD(+)) and its phosphorylated form (NADP(+)) are key molecules in ubiquitous bioenergetic and cellular signaling pathways, regulating cellular metabolism and homeostasis. Thus, supplementation with NAD(+) and NADP(+) precursors emerged as a promising strategy to gain many and multifaceted health benefits. In this proof-of-concept study, we sought to investigate whether chronic nicotinamide riboside administration (an NAD(+) precursor) affects exercise performance. Eighteen Wistar rats were equally divided in two groups that received either saline vehicle or nicotinamide riboside at a dose of 300 mg/kg body weight/day for 21 days via gavage. At the end of the 21-day administration protocol, both groups performed an incremental swimming performance test. The nicotinamide riboside group showed a tendency towards worse physical performance by 35 % compared to the control group at the final 10 % load (94 ± 53 s for the nicotinamide riboside group and 145 ± 59 s for the control group; P = 0.071). |
Does reduced Expression of SMAD4 be Associated with Poor Survival in Colon Cancer? | SMAD4 loss is associated with the development of metastases and poor prognosis. We evaluated expression of SMAD4 protein and its association with tumor characteristics, including biomarkers and outcome in terms of relapse-free survival and overall survival. We used 1,564 stage II/III colon cancer samples from PETACC-3 to evaluate SMAD4 expression by immunohistochemistry. SMAD4 protein expression was validated by assessing mRNA expression using available expression array data. SMAD4 expression was also studied on 34 adenomas and 10 colon cancer liver metastases with their primaries. Loss of SMAD4 immunoreactivity was defined as focal or diffuse. Cases without SMAD4 loss were subdivided into those with strong and weak expression. SMAD4 protein expression was informative in 1,381/1,564 cases. SMAD4 loss was found in 293/1,381 (21%) cases. Of 1,088 cases without SMAD4 loss (79%), 530 showed weak and 558 strong expression. SMAD4 loss occurred also in adenomas, but less extensively than in carcinomas. Liver metastases followed mostly the expression pattern of the primary tumor. SMAD4 loss, including weak expression, identified patients with poor survival in stage II as well as III and in both treatment arms. SMAD4 loss was less frequent in tumors with microsatellite instability and more frequent in those with loss of heterozygosity of 18q. | Ambient temperature has been identified as a risk factor for exercise-induced pulmonary haemorrhage (EIPH) in racing Thoroughbreds. This warranted a more expansive investigation of climatic conditions on the incidence and severity of EIPH. The impact of other variables such as the type of bit used, tongue ties and nonstandard shoes has not been reported and also warrant investigation. To examine the effect of various climatic variables as contributing risk factors for EIPH. Other previously uninvestigated variables as well as standard track and population factors will also be examined. Cross-sectional study. Thoroughbred racehorses competing at metropolitan racetracks in Perth, Western Australia were examined 30-200 min post race with tracheobronchoscopy. Examination took place at 48 race meetings over a 12 month period. Examinations were graded (0-4), independently by two experienced veterinarians. Univariable analyses were performed and variables with a P<0.25 were entered into a multivariable logistic regression analysis. The analysis was performed twice using the presence of blood (EIPH grade 0 vs. grades ≥1) and EIPH grades ≤1 vs. EIPH grades ≥2 as dependent variables. Exercise-induced pulmonary haemorrhage was diagnosed in 56.6% of observations. Lower ambient temperature was significantly associated with EIPH grades ≥1 (OR 0.95; 95% CI 0.93-0.98) and EIPH grades ≥2 (OR 0.97; 95% CI 0.94-1.0). Bar shoes were significantly associated with EIPH grades ≥1 (OR 6.35; 95% CI 2.17-18.54) and EIPH grades ≥2 (OR 2.72; 95% CI 1.3-5.68). Increasing race distance was significantly associated with EIPH grade ≥1 and increasing lifetime starts was significantly associated with EIPH grade ≥2. |
Does genome sequencing reveal novel deletions associated with secondary resistance to pyrazinamide in MDR Mycobacterium tuberculosis? | Detection of pyrazinamide resistance in Mycobacterium tuberculosis isolates presents significant challenges in settings with no dominant clonal lineages, such as Australia. We assessed the utility of WGS versus standard PCR amplification assays for the characterization of pyrazinamide resistance in MDR-TB isolates identified in New South Wales, Australia, over an 8 year period. PCR amplicon sequencing was used to identify molecular markers associated with antibiotic resistance in pyrazinamide-resistant MDR-TB isolates recovered by the New South Wales Mycobacterium Reference Laboratory between 2007 and 2014. WGS was subsequently performed on two isolates for which pncA amplification failed. WGS identified two novel genomic deletions associated with in vitro resistance to pyrazinamide in MDR-TB. One isolate also carried a second deletion involving the genes dfrA and thyA associated with resistance to para-aminosalicylic acid. | The apolipoprotein E mimetic peptide Ac-hE18A-NH(2), capable of reducing plasma cholesterol and possessing anti-inflammatory properties, was compared with the well-studied anti-atherogenic apoA-I mimetic peptide 4F for reducing lesion formation in female apoE null mice with already existing lesions. In initial experiments, Ac-hE18A-NH(2) was administered retro-orbitally two or three times weekly for 6-8 weeks, while peptide 4F was administered intraperitoneally every day for the same period. Age matched controls were injected with saline every day. At the end of the treatment period, plasma cholesterol levels of Ac-hE18A-NH(2) administered mice were significantly lower than in 4F and control mice. However, both 4F and Ac-hE18A-NH(2) showed reduced lesion areas in en face lesion analysis to a similar extent compared to the control group, while paraoxonase-1 (PON-1) activity was increased only in the Ac-hE18A-NH(2) group. In the third experiment, both peptides were administered at the same dose, frequency, and route of administration. The reduction in en face lesions with Ac-hE18A-NH(2) was significantly greater than the 4F and control groups, although lesions in 4F-treated mice were also significantly reduced compared with controls. Both peptide groups had significantly reduced plasma lipid hydroperoxides, but only the Ac-hE18A-NH(2) group had significantly reduced serum amyloid A levels. HDL and plasma inflammatory indices were significantly reduced in both peptide groups compared with controls. |
Are hER1-4 protein concentrations in normal breast tissue from breast cancer patients expressed by the same profile as in the malignant tissue? | The epidermal growth factor receptor HER2 is overexpressed or amplified in 25%-30% of patients with breast cancer. The mechanism behind HER2 amplification is unknown, but may be a patho-physiological phenomenon caused by continuous stimulation and activation of the HER1-4 system. We have mapped the protein concentrations of HER1-4 in breast cancer tissue, autologous reference tissue, normal breast tissue and serum samples, to see whether non-cancer cells from these patients express a protein profile indicating general activation. Tissue samples from malignant and adjacent normal breast tissue (autologous reference tissue) were collected from 118 women consecutively admitted for surgical treatment of breast cancer. In addition, 26 samples of normal breast tissue were collected from healthy women having breast reduction surgery. The tissue samples were homogenized and the proteins extracted. The tissue and serum concentrations of HER1-4 were determined quantitatively using a commercially available enzyme linked immunosorbent assay (ELISA) method. HER1 was down regulated in cancer tissue when compared to autologous reference tissue (p=8 x 10(-6)), while HER2 (p<10(-7)) and HER3 (p=3 x 10(-5)) were up regulated. Comparing autologous reference tissue with normal tissue showed down regulation of HER1 (p=0.122) and up regulation of HER2 (p=10(-6)), HER3 (p<10(-7)) and HER4 (p<10(-7)). Furthermore, we observed that correlations between the receptor combinations HER1-2, HER1-3 and HER1-4 were maintained from normal breast tissue to autologous reference breast tissue, but were lost in cancer tissue. | The list of recommended pediatric preventive services has grown considerably in the past decade, and clinician variability, clinician distribution, and other correlates of provision of these basic preventive services (BPS) are not known. To describe the proportion of high-quality basic pediatric preventive services, exclusive of immunizations, reported by parents and to identify sociodemographic and health system predictors and health service correlates of provision of these services. The study used cross-sectional data on 2041 children, 4 to 35 months of age, in the 2000 National Survey of Early Childhood Health. The BPS measure assesses the receipt of (1) developmental assessment, (2) injury prevention counseling, (3) screening for parental smoking, (4) guidance on reading to the child, and (5) guidance on 14 other topics (assessed as a composite score). The BPS scale categorizes the receipt of services as excellent, good, fair, or poor. Most children received excellent (34.9%) or good (31.5%) care, but many received fair (24.9%) or poor (8.7%) care. Sociodemographic and health care factors such as race/ethnicity, insurance, and practice setting were not associated with BPS levels. Higher BPS scores were associated with parental reports of longer well-child visits, more counseling regarding family and community risk factors, lower rates of delayed or missed care, and greater satisfaction. |
Is synovial T cell hyporesponsiveness to myeloid dendritic cells reversed by preventing PD-1/PD-L1 interactions? | The aim of this study was to investigate PD-1/PD-L1 involvement in the hyporesponsiveness of rheumatoid arthritis (RA) synovial fluid (SF) CD4 T cells upon stimulation by thymic stromal lymphopoietin (TSLP)-primed CD1c myeloid dendritic cells (mDCs). Expression of PD-1 on naïve (Tn), central memory (Tcm) and effector memory (Tem) CD4 T cell subsets was assessed by flow cytometry. PD-L1 expression and its regulation upon TSLP stimulation of mDCs from peripheral blood (PB) and SF of RA patients were investigated by quantitative RT-PCR and flow cytometry. The involvement of PD-1/PD-L1 interactions in SF T cell hyporesponsiveness upon (TSLP-primed) mDC activation was determined by cell culture in the presence of PD-1 blocking antibodies, with or without interleukin 7 (IL-7) as a recognized suppressor of PD-1 expression. PD-1 expression was increased on CD4 T cells derived from SF compared with PB of RA patients. TSLP increased PD-L1 mRNA expression in both PB and SF mDCs. PD-L1 protein expression was increased on SF mDCs compared with PB mDCs and was associated with T cell hyporesponsiveness. Blockade of PD-1, as well as IL-7 stimulation, during cocultures of memory T cells and (TSLP-primed) mDCs from RA patients significantly recovered T cell proliferation. | To describe the case selection, imaging considerations, technique, and results of catheter closure of atrial septal defects (ASD) with deficient inferior vena cava (IVC) rim. Transcatheter closure with Amplatzer septal occluder (ASO) has become standard treatment for most secundum ASDs. Defects with deficient IVC rim continue to be challenging to image and close in the catheterization laboratory. Records of 12 patients with deficient IVC rim (<5 mm), who underwent catheter closure (April 2007 to June 2008) were reviewed. General anesthesia and transesophageal echo (TEE) guidance was used in all. The IVC rim was imaged at 70 degrees-90 degrees with retroflexion of the TEE probe, in addition to the conventional views. Devices 1-4 mm > maximal ASD size were selected. Deployment was accomplished either from the left atrium, left upper or from the right pulmonary veins. The median age was 5.5 (2.5-27) years and median weight was 19.5 (9-65) kg. The defects measured 16-32 mm and 18-36 mm septal occluders were used. The median fluoroscopic time was 13.1 (4.2-32.7) min. Initial device selection was revised in four patients. Two patients had residual flows at IVC margin. The device embolized to right ventricular outflow tract in one patient. This was retrieved, and a larger device was deployed. No other complications were observed immediately or on follow-up (median 6; range 1-14 months). |
Do adult mouse subventricular zones stimulate glioblastoma stem cells specific invasion through CXCL12/CXCR4 signaling? | Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months. This catastrophic survival rate is the consequence of systematic relapses that could arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. We previously demonstrated that GSCs are able to escape the tumor mass and specifically colonize the adult subventricular zones (SVZs) after transplantation. This specific localization, away from the initial injection site, therefore represents a high-quality model of a clinical obstacle to therapy and relapses because GSCs notably retain the ability to form secondary tumors. In this work, we questioned the role of the CXCL12/CXCR4 signaling in the GSC-specific invasion of the SVZs. We demonstrated that both receptor and ligand are respectively expressed by different GBM cell populations and by the SVZ itself. In vitro migration bio-assays highlighted that human U87MG GSCs isolated from the SVZs (U87MG-SVZ) display stronger migratory abilities in response to recombinant CXCL12 and/or SVZ-conditioned medium (SVZ-CM) compared with cancer cells isolated from the tumor mass (U87MG-TM). Moreover, in vitro inhibition of the CXCR4 signaling significantly decreased the U87MG-SVZ cell migration in response to the SVZ-CM. Very interestingly, treating U87MG-xenografted mice with daily doses of AMD3100, a specific CXCR4 antagonist, prevented the specific invasion of the SVZ. Another in vivo experiment, using CXCR4-invalidated GBM cells, displayed similar results. | To investigate the clinical logistics of laboratory routines at primary health care centres (PHCs). Prospective registration was carried out for each PHC using questionnaires during 2-week intervals between the end of November 2001 and mid-January 2002. The study included 9 PHCs in the county of Ostergötland and 4 in the county of Jönköping, Sweden, with different numbers of blood tests analysed using point-of-care testing (POCT). Data for B-glucose, HbA1c, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), thyroid-stimulating hormone (TSH), T4, cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides were collected. Main outcome measures were median time from sampling to available test result (TATa) and median time from sampling to clinical decision (TATd), and the proportion of patients informed of the outcome of the blood test in question during the sampling occasion. A total of 3542 samples were collected. The median TATa showed that B-glucose, ESR and CRP were immediately analysed at all 13 PHCs. For the other tests, TATa varied from immediately to about two days. The median TATd varied from immediately to about a week. When POCT was used, 30% of the patients were informed about the outcome of the test during the sampling occasion. |
Do urinary excretions of lipocalin-type prostaglandin D2 synthase predict the development of proteinuria and renal injury in OLETF rats? | Otsuka Long-Evans Tokushima Fatty (OLETF) rats genetically develop diabetes which is associated with hypertension. In preliminary studies, urinary excretions of L-PGDS (lipocaline-type prostaglandin D synthase) increase before diabetic nephropathy obviously develops, and this may predict progression of renal injury following diabetes. In the present study, we attempted to define whether urinary excretions of L-PGDS behave as the predictor of development of diabetic nephropathy in OLETF rats. We investigated alterations of urinary L-PGDS excretions during the establishment of diabetes and assessed the relationship between the L-PGDS excretions and renal function in OLETF rats. Furthermore, we treated OLETF rats with troglitazone and analysed the effects on L-PGDS metabolisms. Urinary L-PGDS was measured by immunoenzyme assay and the occurrence of L-PGDS and its mRNA in the kidney was assessed by immunohistochemistry and a PCR method. Urinary excretions of L-PGDS were significantly higher in OLETF rats than non-diabetic Long-Evans Tokushima Otsuka (LETO) rats. The excretions age-dependently increased in OLETF and this increase appeared to be due to increased glomerular permeability to L-PGDS. Messenger RNA and antigenicity of L-PGDS were demonstrated in renal tissue; however, the de novo synthesis of L-PGDS mRNA seemingly contributed to urinary L-PGDS excretions much less than glomerular filtration. Multiple regression analysis revealed that urinary L-PGDS was determined by urinary protein excretions, and not by high blood pressure per se. Conversely, urinary proteinuria in the established diabetic nephropathy was predicted by urinary L-PGDS excretions in the early stage of diabetes. | Here we report the results of a randomized study undertaken to test the efficacy of a supplementary, telephone-based nursing intervention in increasing patients' awareness and understanding of the clinical trials in which they are asked to participate. During a 12-month period, 180 cancer patients who were approached to participate in a phase II or III clinical trial were randomized to undergo either of the following: (1) standard informed consent procedures based on verbal explanations from the treating physician plus written information (controls); or (2) standard informed consent procedures plus a supplementary, telephone-based contact with an oncology nurse (intervention). For purposes of evaluation, face-to-face interviews were conducted with all patients approximately 1 week after the informed consent process had been completed. The two groups were comparable with regard to sociodemographic and clinical variables. Both groups had a high level of awareness of the diagnosis and of the nature and objectives of the proposed treatments. The intervention group was significantly (P < .01) better informed about the following: (1) the risks and side effects of treatment; (2) the clinical trial context of the treatment; (3) the objectives of the clinical trial; (4) where relevant, the use of randomization in allocating treatment; (5) the availability of alternative treatments; (6) the voluntary nature of participation; and (7) the right to withdraw from the clinical trial. The intervention did not have any significant effect on patients' anxiety levels or on rates of clinical trial participation. Patients reported high levels of satisfaction with the intervention. |
Does capsular closure affect development of heterotopic ossification after hip arthroscopy? | The purpose of this study was to evaluate the role of capsular closure after hip arthroscopy in reduction of the incidence of heterotopic ossification (HO). One hundred (50 study group, 50 control group) consecutive hip arthroscopy procedures with radiographic follow-up of more than 9 weeks were included in the study. The study group consisted of 50 patients in whom capsular closure with 2 No. 1 polydioxanone (PDS) sutures was performed, and a control group consisted of 50 patients in whom the capsule remained open after capsulotomy. HO was assessed by radiographs using the Brooker classification. Statistical analysis of the data was carried out with the χ-square or Fisher exact test and Student t test, when appropriate, at a significance level of .05. Thirty-six (36%) patients had radiographic evidence of postoperative HO (14 patients in the capsular closure group). No significant difference was found regarding sex, side of operation, age, or HO rate between the study and the control groups (P = .778, P = .123, P = .744, and P = .144, respectively). Furthermore, no significant difference was found in the rate of HO with potential clinical significance (Brooker classification > I) between the control and study groups (P = .764). | The ubiquitin proteasome system (UPS) mediates regulated protein degradation and provides a mechanism for closely controlling protein abundance in spatially restricted domains within cells. We hypothesized that the UPS may acutely determine the local concentration of key regulatory proteins at neuronal synapses as a means for locally modulating synaptic efficacy and the strength of neurotransmission communication. We investigated this hypothesis at the Drosophila neuromuscular synapse by using an array of genetic and pharmacological tools. This study demonstrates that UPS components are present in presynaptic boutons and that the UPS functions locally in the presynaptic compartment to rapidly eliminate a conditional transgenic reporter of proteasome activity. We assayed a panel of synaptic proteins to determine whether the UPS acutely regulates the local abundance of native synaptic targets. Both acute pharmacological inhibition of the proteasome (<1 hr) and targeted genetic perturbation of proteasome function in the presynaptic neuron cause the specific accumulation of the essential synaptic vesicle-priming protein DUNC-13. Most importantly, acute pharmacological inhibition of the proteasome (<1 hr) causes a rapid strengthening of neurotransmission (an approximately 50% increase in evoked amplitude) because of increased presynaptic efficacy. The proteasome-dependent regulation of presynaptic protein abundance, both of the exogenous reporter and native DUNC-13, and the modulation of presynaptic neurotransmitter release occur on an intermediate, rapid (tens of minutes) timescale. |
Is low caregiver health literacy associated with higher pediatric emergency department use and nonurgent visits? | We sought to determine the association between low caregiver health literacy and child emergency department (ED) use, both the number and urgency of ED visits. This year long cross-sectional study utilized the Newest Vital Sign questionnaire to measure the health literacy of caregivers accompanying children to a pediatric ED. Prior ED visits were extracted from a regional database. ED visit urgency was classified by resources utilized during the index ED visit. Regression analyses were used to model 2 outcomes-prior ED visits and ED visit urgency-stratified by chronic illness. Analyses were weighted by triage level. Overall, 503 caregivers completed the study; 55% demonstrated low health literacy. Children of caregivers with low health literacy had more prior ED visits (adjusted incidence rate ratio 1.5; 95% confidence interval 1.2, 1.8) and increased odds of a nonurgent index ED visit (adjusted odds ratio 2.4; 95% confidence interval 1.3, 4.4). Among children without chronic illness, low caregiver health literacy was associated with an increased proportion of nonurgent index ED visits (48% vs. 22%; adjusted odds ratio 3.2; 1.8, 5.7). | The aim of this study was to describe the revascularization process of autogenous bone block grafts placed with or without an expanded polytetrafluoroethylene (e-PTFE) membrane. Thirty Wistar male rats had their mandibles augmented by either an autogenous bone block graft (group A) or an autogenous bone block graft covered with an e-PTFE membrane (group B). The animals were sacrificed by perfusion at baseline, 3, 7, 14, and 21 days after surgery. After 3 days, the presence of vascular sprouts derived from the recipient bed was observed in group A; more discrete sprouts were also observed in group B. After 7 days, revascularization continued, with vessels derived from both the recipient bed and the surrounding connective tissue in group A but only from the recipient bed in group B. At 14 days, group A showed penetration of vessels at the periphery of the graft; the vessels reached varying distances inside it. In group B, revascularization of the graft occurred mainly near its perforation, its borders, and at the recipient bed-graft interface. After 21 days, graft vascular penetration could be observed throughout the extent of the graft in group A but only approximately halfway through the graft in group B. |
Do microvascular free tissue transfer in acute and secondary burn reconstruction? | The mainstay of operative treatment in burns is split skin grafting with free tissue transfer being indicated in a minority of cases. However, free tissue transfer faces a number of challenges in the burns patient. These include; overall cardiovascular and respiratory stability of the patient, availability of suitable vessels for anastomosis, sufficient debridement of devitalised tissue and a potentially increased risk of infection. We carried out a retrospective study in order to determine the indications, timing, principles of flap selection, complications, outcomes and methods of promoting flap survival when free tissue transfer was utilised for burn reconstruction in our unit. All patients who underwent soft tissue reconstruction for burn injuries with microvascular free tissue transfer between May 2002 and September 2014 were identified from our burns database. The records of these patients were then retrospectively reviewed. Data extracted included, age, gender, type of injury, total body surface area involved, indications for free tissue transfer, anatomical location, timing of reconstruction, complications and flap survival. Out of a total of 8776 patients admitted for operative treatment over a 12-year period, 23 patients required 26 free flaps for reconstruction. Out of 26 free flaps, 23 were utilised for acute burn reconstruction while only 3 free flaps were utilised for secondary burn reconstruction. All 26 free flaps survived regardless of timing or burn injury mechanism. Complications included haematomas in 2 flaps and tip necrosis in 4 flaps. Two flaps required debridement and drainage of pus, 1 flap required redo of the venous anastomosis while 1 required redo of the arterial anastomosis with a vein graft. | Ursodeoxycholic acid prevents gallstone formation in selected patients. The aim of this study was to examine whether decreased concentration and nucleation-promoting activity of various proteins contribute to this beneficial effect. Gallbladder bile of 13 patients with cholesterol gallstones treated with ursodeoxycholic acid (10 mg/kg(-1)/day(-1)) and of 13 untreated patients were compared. Total protein concentration in gallbladder bile (2.8 +/- 0.6 vs. 6.7 +/- 1.3 mg/mL; P=0.008) and concanavalin A-binding fraction (0.16 +/- 0.03 vs. 0.42 +/- 0.07 mg/mL; P=0.003) were strongly decreased by ursodeoxycholic acid therapy. Significant decreases were also found for gallbladder bile alpha1-acid glycoprotein, haptoglobin, immunoglobulin (Ig) A, IgG, gamma-glutamyl transpeptidase, and aminopeptidase N but not for IgM, mucin, or beta-glucuronidase. Decreases were most pronounced for proteins of canalicular membrane origin. Gallbladder bile total protein correlated with cholesterol saturation index (r=0.54; P=0.0047) but not with bile salt hydrophobicity index. Crystallization-promoting activity of the concanavalin A-binding fraction (assessed by nephelometry and microscopic examination) was also significantly decreased by ursodeoxycholic acid. |
Is the C609T variant of NQO1 associated with carotid artery plaques in patients with type 2 diabetes? | Atherosclerosis in patients with type 2 diabetes has been linked to oxidative stress. NADP[1]:quinone oxidoreductase 1 (NQO1) plays a key role in cellular antioxidant defense. Recent reports suggest that highly expressed and inducible endogenous NQO1 from cardiovascular cells may act as a potential superoxide scavenger. We examined the relationship between the risk of NQO1 C609T polymorphism and carotid artery atherosclerosis in patients with type 2 diabetes. We recruited 601 (Seoul set) and 233 (Koyang set) unrelated patients with type 2 diabetes from independent groups. The C609T variant of NQO1 was genotyped by Taqman RT-PCR. Mean and maximum carotid intima-media thickness (IMT) and carotid artery plaques were measured by high-resolution ultrasonography. Patients with the T allele exhibited a higher prevalence of atherosclerotic plaques than non-T allele carriers in both sets (Seoul set vs. Koyang set, p=0.021, p=0.023, respectively). After adjusting for age, sex, duration of diabetes, systolic blood pressure, body mass index, current smoking, HDL-cholesterol, LDL-cholesterol and HbA1c, subjects with the T allele had a significantly higher risk of carotid artery plaques (Seoul set vs. Koyang set, OR=1.65, p=0.015; OR=2.00, p=0.037, respectively) than subjects with the CC genotype. | To determine whether systemically administered recombinant human epidermal growth factor (rhEGF) accelerates the recovery of mouse small intestinal mucosa after irradiation. A mouse mucosal damage model was established by administering radiation to male BALB/c mice with a single dose of 15 Gy applied to the abdomen. After irradiation, rhEGF was administered subcutaneously at various doses (0.04, 0.2, 1.0, and 5.0 mg/kg/day) eight times at 2- to 3-day intervals. The evaluation methods included histologic changes of small intestinal mucosa, change in body weight, frequency of diarrhea, and survival rate. The recovery of small intestinal mucosa after irradiation was significantly improved in the mice treated with a high dose of rhEGF. In the mice that underwent irradiation without rhEGF treatment, intestinal mucosal ulceration, mucosal layer damage, and severe inflammation occurred. The regeneration of villi was noticeable in mice treated with more than 0.2 mg/kg rhEGF, and the villi recovered fully in mice given more than 1 mg/kg rhEGF. The frequency of diarrhea persisting for more than 3 days was significantly greater in the radiation control group than in the rhEGF-treated groups. |
Does confocal endomicroscopy show food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome? | We investigated suspected food intolerances in patients with irritable bowel syndrome (IBS) using confocal laser endomicroscopy (CLE) for real-time visualization of structural/functional changes in the intestinal mucosa after food challenge. Patients with functional changes after food challenge (CLE+) were placed on personalized exclusion diets and followed up for long-term symptom relief. Thirty-six IBS patients with suspected food intolerance and 10 patients with Barrett's esophagus (controls) without IBS symptoms were examined by CLE at University Hospital Schleswig-Holstein (Kiel, Germany). Diluted food antigens were administered directly to the duodenal mucosa through the working channel of the endoscope. Epithelial breaks, intervillous spaces, and the number of intraepithelial lymphocytes (IEL) were measured before and after the food challenge. CLE+ patients were placed on exclusion diets, given symptom score questionnaires, and followed up for 1 year; controls resumed their previous diet. CLE showed a real-time response to food antigens in 22 of 36 patients; no responses were observed in 14 of 36 patients (CLE-) or any of the controls. Baseline IELs were significantly higher in CLE+ than CLE- subjects (P = .004); numbers increased significantly after food challenge (P = .0008). Within 5 minutes of exposure of CLE+ patients to food antigens, IELs increased, epithelial leaks/gaps formed, and intervillous spaces widened. Epithelial leaks and intervillous spaces also increased significantly in CLE+ vs baseline (both P < .001). The concordance of IELs measured by CLE and conventional histology was 70.6%; they did not correlate (P = .89; r(2) = 0.027). Symptom scores improved more than 50% in CLE+ patients after a 4-week exclusion diet and increased to 74% at 12 months; symptoms continued in CLE- patients. | Right ventricular failure does not explain all cases of death in patients with chronic pulmonary hypertension. Searching for alternative explanations, we evaluated the prognostic significance of main pulmonary artery (PA) dilatation in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). A retrospective outcome analysis was made of 264 patients (aged 46 ± 17 years; women, 69%; PAH, 82%) who underwent both CT scan measurement of the PA and right-sided heart catheterization (mean PA pressure, 57.6 ± 16.5 mm Hg) at initial evaluation. The diameter of the PA ranged from 28 to 120 mm (mean, 39 ± 8.6 mm; median, 38 mm) and was largest in patients with unrepaired congenital defects (42.6 ± 7.6 mm). Pulmonary pulse pressure (P = .04), lower age (P = .03), and duration of symptoms (P < .001) were independently but weakly related to PA diameter. During follow-up (median, 38 months), 99 patients (37%) died. Of these 99 deaths, 73 (74%) were due to heart failure or comorbidities, and 26 (26%) were unexpected deaths (UE-Ds). PA diameter (hazard ratio [HR], 1.06 per 1 mm; 95% CI, 1.03-1.08), heart rate (HR, 1.30 per 10 beats/min; 95% CI, 1.01-1.66), and systolic pulmonary arterial pressure (HR, 1.02 per 1 mm Hg; 95% CI, 1.01-1.04) were the only independent predictors of UE-D and differed from the usual predictors found in the study group for all-cause mortality. PA diameter ≥ 48 mm had 95% specificity and 39% sensitivity and carried 7.5 times higher risk of UE-D (95% CI, 3.4-16.5; P < .0001) during follow-up. |
Is round block technique a useful oncoplastic procedure for multicentric fibroadenomas? | Multicentric fibroadenomas, defined as multiple fibroadenomas located at different quadrants of the breast, occur in 10-20% of women with fibroadenoma. The surgical management of multicentric fibroadenomas may be troublesome for surgeons and patients. In this study, we report our preliminary experience using the "round block technique" in the management of women with multicentric fibroadenomas of the breast. Records of patients with breast diseases managed with the round block technique were searched for in the Changhua Christian Hospital oncoplastic breast surgery database. The patients' clinicopathologic characteristics, type of surgery, operation time, blood loss, and complications were recorded. The cosmetic outcome was evaluated by the patient and operating surgeon two months after the surgery. Twenty patients with multicentric fibroadenomas managed by the round block technique comprised the current study cohort. The mean age of the subjects was 36.5 ± 10.4 years. Twelve (60%) patients had tumors on one side of the breast, and eight (40%) had bilateral breast lesions. The average number of tumors removed was 3.3 ± 1.2 (range 2-6) per breast, and mean tumor size was 2.2 ± 0.5 cm. Three (15%) patients developed mild ecchymosis of the breast undergoing operation, which resolved spontaneously. One (5%) patient had partial nipple ischemia/necrosis due to 2 tumors excised near the nipple-areolar complex. The aesthetic results were evaluated as good in 19 (95%) patients and fair in 1 (5%). | HIV-1-infected and/or immune-activated microglia and macrophages are pivotal in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). Glutaminase, a metabolic enzyme that facilitates glutamate generation, is upregulated and may play a pathogenic role in HAND. Our previous studies have demonstrated that glutaminase is released to the extracellular fluid during HIV-1 infection and neuroinflammation. However, key molecular mechanisms that regulate glutaminase release remain unknown. Recent advances in understanding intercellular trafficking have identified microvesicles (MVs) as a novel means of shedding cellular contents. We posit that during HIV-1 infection and immune activation, microvesicles may mediate glutaminase release, generating excessive and neurotoxic levels of glutamate. MVs isolated through differential centrifugation from cell-free supernatants of monocyte-derived macrophages (MDM) and BV2 microglia cell lines were first confirmed in electron microscopy and immunoblotting. As expected, we found elevated number of MVs, glutaminase immunoreactivities, as well as glutaminase enzyme activity in the supernatants of HIV-1 infected MDM and lipopolysaccharide (LPS)-activated microglia when compared with controls. The elevated glutaminase was blocked by GW4869, a neutral sphingomyelinase inhibitor known to inhibit MVs release, suggesting a critical role of MVs in mediating glutaminase release. More importantly, MVs from HIV-1-infected MDM and LPS-activated microglia induced significant neuronal injury in rat cortical neuron cultures. The MV neurotoxicity was blocked by a glutaminase inhibitor or GW4869, suggesting that the neurotoxic potential of HIV-1-infected MDM and LPS-activated microglia is dependent on the glutaminase-containing MVs. |
Does luteolin alleviate bronchoconstriction and airway hyperreactivity in ovalbumin sensitized mice? | Asthma is an inflammatory disease of the airways and the current focus in managing asthma is the control of inflammation. In this study, we attempted to investigate the anti-asthmatic potential of a plant derived natural compound, luteolin. We used a murine model of airway hyperreactivity, which mimicked some of the characteristic features of asthma. Male BALB/c mice (8-9 weeks) were used for this study. Mice (n = 6) were sensitized by intraperitoneal (i. p.) injection of 10 mg of ovalbumin (OVA) on days 0, 7 and 14 followed by aerosol inhalation (5% OVA) treatments daily beginning from day 19 to day 23. To study its preventive effect, luteolin (0.1, 1.0, and 10 mg/kg body weight; daily) was administered orally during the entire period (0 to 23 day) of sensitization. To study its curative effect, mice were first sensitized and then luteolin (1.0 mg/kg body weight daily) was given orally from day 26 to 32. The airway hyperreactivity, immunoglobulin E (IgE) in the sera, and cytokines (IFN-gamma, IL-4 and IL-5) in the bronchoalveolar lavage fluid (BALF) were measured. Both during sensitization and after sensitization, luteolin, at a dose of 0.1 mg/kg body weight, significantly modulated OVA-induced airway bronchoconstriction and bronchial hyperreactivity (p < 0.05). Luteolin also reduced OVA-specific IgE levels in the sera, increased interferon gamma (IFN-gamma) levels and decreased the interleukin-4 (IL-4) and interleukin-5 (IL-5) levels in the BALF. | We hypothesised that in blunt trauma patients with haemodynamic instability and haemoperitoneum on hospital admission, the haemorrhagic source may not be confined to the peritoneum. The purpose of this study was to describe the incidence and location of bleeding source in this population. The charts of trauma patients admitted consecutively between January 2005 and January 2010 to our level I Regional Trauma Centre were reviewed retrospectively. All hypotensive patients presenting a haemoperitoneum on admission were included. Hypotension was defined by a systolic blood pressure ≤ 90 mmHg. The haemoperitoneum was quantified on CT images or from operative reports as moderate (Federle score<3 or between 200 and 500 ml) or large (Federle score ≥ 3 or >500 ml). Active bleeding (AB) was defined as injury requiring a surgical or radiologic haemostatic procedure, regardless of origin (peritoneal (PAB) or extraperitoneal (EPAB)). Of 1079 patients admitted for severe trauma, 110 patients met the inclusion criteria. Seventy-eight (71%) were male, mean age 35.3 (SD 19) years and mean ISS 36.5 (SD 20.5). Among the 91 patients who had AB, 37 patients (41%) had PAB, 34 (37%) had EPAB and 20 had both (22%). Forty-eight (53%) of them had moderate haemoperitoneum and 43 (47%) had large haemoperitoneum. A large haemoperitoneum had positive predictive value for PAB of 88% (95% CI 75-95%) and negative predictive value of 65% (95% CI 49-79%). The corresponding values in the subgroup of patients with EPAB were 65% (95% CI 38-86%) and 76% (95% CI 59-88%). |
Does decrease in adiponectin levels correlate to growth response in growth hormone-treated children? | Adiponectin is secreted by adipose tissue and circulates in human plasma at high levels. Decreased adiponectin levels are associated with insulin resistance and obesity. The aim of this study was to investigate whether changes in serum adiponectin levels are related to the growth response, insulin levels and insulin resistance during growth hormone (GH) treatment. The study included 94 short prepubertal children (19 girls and 75 boys). The mean age at the start of daily GH injections was 9.04 +/- 2.38 years. Adiponectin levels in serum were measured using an ELISA. At baseline, adiponectin correlated with the first-year growth response (r = 0.26, p = 0.012). Adiponectin decreased significantly after 1 week, 3 months and 1 year from 14.5 +/- 5.71 to 13.1 +/- 5.22 (p < 0.0001), 10.3 +/- 4.82 (p < 0.0001) and 12.5 +/- 5.34 microg/ml (p < 0.0001), respectively. There were significant correlations between the first-year growth response and the decrease in adiponectin levels after 3 months and 1 year (r = -0.38, p < 0.0001 and r = -0.47, p < 0.0001, respectively). No correlations between adiponectin, insulin and the homeostasis model assessment of insulin resistance were seen. | Retinal ischemia/reperfusion (IR) is common in eye disorders. Pattern-recognition receptors (PRRs) are reported to initiate sterile inflammatory response. The role of PRRs in retinal IR injury is currently unknown. Thus, we investigated the expression and function of membrane and cytoplasmic PRRs during retinal IR. Retinal IR was induced in adult Brown Norway rats by clipping the retinal vessels for 30 minutes. RNA and proteins were extracted during the course of reperfusion, and the expression levels of the following proteins were determined: Toll-like receptor 2 (TLR2), TLR4, myeloid differentiation factor 88 (MyD88), TNF receptor-associated factor 6 (TRAF6), nuclear factor-κB (NF-κB), nucleotide-binding oligomerization domain-like receptor with pyrin domain protein 1 (NLRP1), NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, IL-1β, and IL-18. TLR4 expression in the retina was studied using immunohistochemistry. In addition, a TLR4 inhibitor was injected into the vitreous body as a therapeutic agent. After the treatment of TLR4 inhibitors, the levels of the above factors were evaluated, the apoptosis of cells in the retina, expression of cleaved-caspase-3 (c-casp-3), death of retinal ganglion cells, and the retina electroretinography was assessed. After releasing the artery clamp, the retinal vessels were reperfused in 5 minutes. During the reperfusion, TLR4, MyD88, TRAF6, NF-κB, NLRP1, NLRP3, mature IL-1β, and IL-18 were upregulated, but not TLR2. In the IR model, TLR4 was highly expressed in ganglion cell and glia cell. Additionally, the inhibition of TLR4 significantly downregulated the activation of NLRP3, but not NLRP1, and the secretion of mature IL-1β and IL-18 also were inhibited. Moreover, the TLR4 inhibitor partially attenuated the injury of the retina, including alleviated retina apoptosis, downregulated c-casp-3 expression, rescued retinal ganglion cells death, and restored retina function. |
Does cXC chemokine receptor CXCR4 expression enhance tumorigenesis and angiogenesis of basal cell carcinoma? | Chemokines and their receptors, well known for their ability to attract leucocytes, also play important roles for tumour progression. To investigate the possible involvement of chemokine receptors in the pathogenesis of cutaneous basal cell carcinoma (BCC). We performed an expression analysis of chemokine receptors using a well-characterized human BCC cell line. Upon the finding of CXCR4 expression by BCC, retroviral transduction of BCC cells with the CXCR4 gene was employed to address its functional significance for BCC in vitro and in vivo. We found expression of the CXC chemokine receptor CXCR4 by a human cell line and a subset of tissue samples from BCC, especially in noduloulcerative and sclerosing types. Following treatment with CXCL12, the ligand for CXCR4, CXCR4-transduced BCC cells (CXCR4-BCC) showed increased proliferation under low serum concentration and resistance to apoptosis induced by ultraviolet B irradiation in vitro. Conditioned media from CXCR4-BCC preincubated with CXCL12 enhanced tubule formation of human endothelial cells in vitro. These responses of CXCR4-BCC were negated by cotreatment with either neutralizing antibodies or specific blocking peptides for CXCR4 in vitro. Moreover, xenograft tumour transplants produced by injection of CXCR4-BCC yielded significant tumour progression in nude mice, whereas additional serial injections of CXCR4-blocking peptides resulted in tumour regression. | Nonalcoholic steatohepatitis (NASH) is associated with dyslipidemia and cardiovascular disease (CVD). To determine the relationship between resolution of NASH and dyslipidemia. Individuals in the Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial with paired liver biopsies and fasting lipid levels were included (N = 222). In the PIVENS trial individuals were randomised to pioglitazone 30 mg, vitamin E 800 IU or placebo for 96 weeks. Change in lipid levels at 96 weeks was compared between those with and without NASH resolution. Dyslipidemia at baseline was frequent, with low high-density lipoprotein (HDL) (<40 mg/dL in men or <50 mg/dL in women) in 63%, hypertriglyceridaemia (≥150 mg/dL) in 46%, hypercholesterolaemia (≥200 mg/dL) in 47% and triglycerides (TG)/HDL >5.0 in 25%. Low-density lipoprotein (LD) ≥160 mg/dL was found in 16% and elevated non-HDL cholesterol (non-HDL-C) (≥130 mg/dL) in 73%. HDL increased with NASH resolution but decreased in those without resolution (2.9 mg/dL vs. -2.5 mg/dL, P < 0.001). NASH resolution was associated with significant decreases in TG and TG/HDL ratio compared to those without resolution (TG: -21.1 vs. -2.3 mg/dL, P = 0.03 and TG/HDL: -0.7 vs. 0.1, P = 0.003). Non-HDL-C, LDL and cholesterol decreased over 96 weeks in both groups, but there was no significant difference between groups. Treatment group did not impact lipids. |
Does genomic mid-range inhomogeneity correlate with an abundance of RNA secondary structures? | Genomes possess different levels of non-randomness, in particular, an inhomogeneity in their nucleotide composition. Inhomogeneity is manifest from the short-range where neighboring nucleotides influence the choice of base at a site, to the long-range, commonly known as isochores, where a particular base composition can span millions of nucleotides. A separate genomic issue that has yet to be thoroughly elucidated is the role that RNA secondary structure (SS) plays in gene expression. We present novel data and approaches that show that a mid-range inhomogeneity (~30 to 1000 nt) not only exists in mammalian genomes but is also significantly associated with strong RNA SS. A whole-genome bioinformatics investigation of local SS in a set of 11,315 non-redundant human pre-mRNA sequences has been carried out. Four distinct components of these molecules (5'-UTRs, exons, introns and 3'-UTRs) were considered separately, since they differ in overall nucleotide composition, sequence motifs and periodicities. For each pre-mRNA component, the abundance of strong local SS (< -25 kcal/mol) was a factor of two to ten greater than a random expectation model. The randomization process preserves the short-range inhomogeneity of the corresponding natural sequences, thus, eliminating short-range signals as possible contributors to any observed phenomena. | Patch closure after carotid endarterectomy (CEA) improves clinical outcome compared with primary closure. Whether there are differences in outcome between various patch materials is still not clear. The objective of this retrospective study was to investigate whether a relationship exists between the patch type and the number of microemboli as registered during CEA by transcranial Doppler imaging, the clinical outcome (transient ischemic attack and cerebrovascular accident), and the occurrence of restenosis. We included 319 patients who underwent CEA. Intraoperative microembolus registration was performed in 205 procedures. Microembolization was recorded during four different periods: dissection, shunting, clamp release, and wound closure. The decision to perform primary closure or to use a patch for the closure of the arteriotomy was made by the surgeon, and Dacron patches were used when venous material was insufficient. Cerebral events were recorded within the first month after CEA, and duplex scanning was performed at 3 months (n = 319) and 1 year (n = 166) after CEA. A diameter reduction of more than 70% was defined as restenosis. Primary, venous, and Dacron patch closures were performed in 83 (26.0%), 171 (53.6%), and 65 (20.4%) patients, respectively. Primary closure was significantly related to sex (Dacron patch, 35 men and 30 women; venous patch, 108 men and 63 women; primary closure, 72 men and 11 women; P < .001). The occurrence of microemboli during wound closure was also related to sex (women, 2.5 +/- 0.6; men, 1.0 +/- 0.2; P = .01). Additionally, during clamp release, Dacron patches were associated with significantly more microemboli than venous patches (11.1 +/- 3.4 vs 4.0 +/- 0.9; P < .01), and this difference was also noted during wound closure (3.1 +/- 0.9 vs 1.4 +/- 0.4; P < .05). Transient ischemic attacks and minor strokes after CEA occurred in 5 (2.4%) of 205 and 6 (2.9%) of 205 procedures, respectively, and the degree of microembolization during dissection was related to adverse cerebral events (P = .003). In contrast, the type of closure was not related to immediate clinical adverse events. However, primary closure and Dacron patches were associated with an increase in the restenosis rate compared with venous patches: after 400 days, the restenosis rate for Primary closure was 11%, Dacron patch 16%, and venous patch 7% (P = .05; Kaplan-Meier estimates). |
Is guideline-concordant administration of prothrombin complex concentrate and vitamin K associated with decreased mortality in patients with severe bleeding under vitamin K antagonist treatment ( EPAHK study )? | In vitamin K antagonist (VKA)-treated patients with severe hemorrhage, guidelines recommend prompt VKA reversal with prothrombin complex concentrate (PCC) and vitamin K. The aim of this observational cohort study was to evaluate the impact of guideline concordant administration of PCC and vitamin K on seven-day mortality. Data from consecutive patients treated with PCC were prospectively collected in 44 emergency departments. Type of hemorrhage, coagulation parameters, type of treatment and seven-day mortality mortality were recorded. Guideline-concordant administration of PCC and vitamin K (GC-PCC-K) were defined by at least 20 IU/kg factor IX equivalent PCC and at least 5 mg of vitamin K performed within a predefined time frame of eight hours after admission. Multivariate analysis was used to assess the effect of appropriate reversal on seven-day mortality in all patients and in those with intracranial hemorrhage (ICH). Data from 822 VKA-treated patients with severe hemorrhage were collected over 14 months. Bleeding was gastrointestinal (32%), intracranial (32%), muscular (13%), and "other" (23%). In the whole cohort, seven-day mortality was 13% and 33% in patients with ICH. GC-PCC-K was performed in 38% of all patients and 44% of ICH patients. Multivariate analysis showed a two-fold decrease in seven-day mortality in patients with GC-PCC-K (odds ratio (OR) = 2.15 (1.20 to 3.88); P = 0.011); this mortality reduction was also observed when only ICH was considered (OR = 3.23 (1.53 to 6.79); P = 0.002). | The airways of people with cystic fibrosis (CF) are chronically infected with a variety of bacterial species. Although routine culture methods are usually used to diagnose these infections, culture-independent, DNA-based methods have identified many bacterial species in CF respiratory secretions that are not routinely cultured. Many prior culture-independent studies focused either on microbiota in explanted CF lungs, reflecting end-stage disease, or those in oropharyngeal swabs, which likely sample areas in addition to the lower airways. Therefore, it was unknown whether the lower airways of children with CF, well before end-stage but with symptomatic lung disease, truly contained diverse microbiota. To define the microbiota in the diseased lung tissue of a child who underwent lobectomy for severe, localized CF lung disease. After pathologic examination verified that this child's lung tissue reflected CF lung disease, we used bacterial ribosomal RNA gene pyrosequencing and computational phylogenetic analysis to identify the microbiota in serial sections of the tissue. This analysis identified diverse, and anatomically heterogeneous, bacterial populations in the lung tissue that contained both culturable and nonculturable species, including abundant Haemophilus, Ralstonia, and Propionibacterium species. Routine clinical cultures identified only Staphylococcus aureus, which represented only a small fraction of the microbiota found by sequencing. Microbiota analysis of an intraoperative oropharyngeal swab identified predominantly Streptococcus species. The oropharyngeal findings therefore represented the lung tissue microbiota poorly, in agreement with findings from earlier studies of oropharyngeal swabs in end-stage disease. |
Does analysis of pulmonary function test result in a health check-up population? | To explore the incidences of chronic obstructive pulmonary disease (COPD), obstructive ventilatory dysfunction, and obstructive small airway disease and their risk factors in a health check-up population, with an attempt to inform the early diagnosis and treatment of COPD. Subjects who aged 20 years and older and received health check-up in the Health Management Center, Third Xiangya Hospital, Central South University from June 2013 to June 2015 were enrolled in this study. The results of detection and survey for COPD, obstructive ventilatory dysfunction, and obstructive small airway disease were analyzed. Among 6,811 subjects enrolled in this study, the detection rate of COPD, obstructive ventilator dysfunction, and obstructive small airway disease was 0.8%, 2.6%, and 4.0%, respectively, which showed a positive correlation with male gender, age, and smoking index. | Neuroblastoma is a common pediatric solid tumor with poor outcome for metastatic disease. Thus, novel therapeutic options are of main interest. The anti-neoplastic properties of taurolidine have been demonstrated on a variety of human cancer cells. However, data on neuroblastoma is lacking. Therefore, our aim was to evaluate the effect of taurolidine on growth of neuroblastoma cell lines. Neuroblastoma SK-N-BE(2)-M17 and SK-N-SH cells and nonmalignant human umbilical vein endothelial cells as controls were incubated with increasing concentrations of taurolidine (100, 250, 500 µM). Cell growth was examined after 12, 24, and 48 hours of exposure. Inhibition of cell growth by taurolidine was seen in both malignant cell lines. When compared with human umbilical vein endothelial cells, the neuroblastoma cell lines were significantly more responsive to taurolidine. |
Does liver damage in the rat induce hepatocyte stem cells from biliary epithelial cells? | When rat hepatocyte regeneration after partial hepatectomy is blocked by 2-acetylaminofluorene, a proliferation of biliary epithelia sends out ductules into the parenchyma. The ability of these neoductules to act as a significant progenitor compartment for hepatocytes is in dispute. This study aims to resolve this question by varying the amount of 2-acetylaminofluorene administered. Rats were fed 2-acetylaminofluorene fr 6 days before and up to 7 days after partial hepatectomy was performed at a dose of either 2.5 (low) or 5 (high) mg/kg(-1)/day(-1). The response was monitored by the immunohistochemical expression of intermediate filaments and cytochrome P450 enzymes. No regeneration by mature hepatocytes occurred with either dose, and new ductules expressed the biliary cytokeratins 7, 8, 18, and 19 and, in addition, vimentin. At the high dose, hepatocytic differentiation was infrequent, whereas apoptosis and intestinal differentiation were common. At the low dose, almost all ductules differentiated into hepatocytes within 14 days of hepatectomy. | The adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory. This study tested the hypothesis that serum DHEA and DHEA-S are predictors of major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events in a large cohort of elderly men. We used gas and liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based Osteoporotic Fractures in Men study in Sweden (2,416 men, ages 69 to 81 years). Complete cardiovascular clinical outcomes were available from national Swedish registers. During the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality. |
Is sensitivity of apoptosis-resistant colon cancer cells to tanshinones mediated by autophagic cell death and p53-independent cytotoxicity? | Multidrug resistance (MDR) develops in nearly all patients with colon cancer. The reversal of MDR plays an important role in the success of colon cancer chemotherapy. One of the commonest mechanisms conferring MDR is the suppression of apoptosis in cancer cells. This study investigated the sensitivity of cryptotanshinone (CTS) and dihydrotanshinone (DTS), two lipophilic tanshinones from a traditional Chinese medicine Salvia miltiorrhiza, in apoptosis-resistant colon cancer cells. Cell viability was measured by MTT assay. Cell cycle distribution and apoptosis were determined by flow cytometry. Protein levels were analyzed by western blot analysis. The formation of acidic vesicular organelles was visualized by acridine orange staining. Experimental results showed that multidrug-resistant colon cancer cells SW620 Ad300 were sensitive to both CTS and DTS in terms of cell death, but with less induction of apoptosis when compared with the parental cells SW620, suggesting that other types of cell death such as autophagy could occur. Indeed, the two tanshinones induced more LC3B-II accumulation in SW620 Ad300 cells with increased autophagic flux. More importantly, cell viability was increased after autophagy inhibition, indicating that autophagy induced by the two tanshinones was pro-cell death. Besides, the cytotoxic actions of the two tanshinones were p53-independent, which could be useful in inhibiting the growth of apoptosis-resistant cancer cells with p53 defects. | Frozen Shoulder Syndrome is a fibrosis of the shoulder joint capsule that is clinically associated with Dupuytren's disease, a fibrosis of the palmar fascia. Little is known about any commonalities in the pathophysiology of these connective tissue fibroses. β-catenin, a protein that transactivates gene expression, and levels of IGF2 mRNA, encoding insulin-like growth factor-II, are elevated in Dupuytren's disease. The aim of this study was to determine if correlating changes in β-catenin levels and IGF2 expression are evident in Frozen Shoulder Syndrome. Tissue from patients with Frozen Shoulder Syndrome and rotator cuff tear were obtained during shoulder arthroscopies. Total protein extracts were prepared from tissue aliquots and β-catenin immunoreactivity was assessed by Western immunoblotting. In parallel, primary fibroblasts were derived from these tissues and assessed for IGF2 expression by quantitative PCR. β-catenin levels were significantly increased in Frozen Shoulder Syndrome relative to rotator cuff tear when assessed by Western immunoblotting analyses. IGF2 mRNA levels were significantly increased in primary fibroblasts derived from frozen shoulder syndrome tissues relative to fibroblasts derived from rotator cuff tissues. |
Is the mechanical fibrillation pattern of the atrial myocardium associated with acute and long-term success of electrical cardioversion in patients with persistent atrial fibrillation? | Electrophysiological studies demonstrate that a short atrial fibrillation cycle length (AFCL) is related with poor outcome of electrical cardioversion (ECV) of atrial fibrillation (AF). We found previously that the mechanical AFCL (AFCL-tvi) and atrial fibrillatory velocity (AFV-tvi) may be determined noninvasively using color tissue velocity imaging (TVI) and closely relates to the electrophysiological AFCL. To evaluate the relation between AFCL-tvi, AFV-tvi, and success of ECV in patients with AF. We prospectively studied 133 patients with persistent AF by performing echocardiography before ECV and measured the AFCL-tvi and AFV-tvi in the right atrium and left atrium. Recurrent AF was monitored. Nineteen (14%) patients had failure of ECV, 42 (32%) remained in sinus rhythm after 1-year follow-up, and 72 (54%) had a recurrence of persistent AF. Patients with immediate ECV failure had a lower median AFV-tvi measured in the right atrium than did patients with a successful ECV: 0.7 cm/s (0.2-1.0 cm/s) vs. 1.7 cm/s (0.9-2.8 cm/s) (P = .008). Patients with maintenance of sinus rhythm after 1 year had a longer AFCL-tvi measured in the left atrium than did patients with recurrence of AF (150 ms vs 137 ms; P = .017) and had a higher AFV-tvi in both atria (1.4 vs. 0.9 cm/s in the left atrium; P = .013 and 2.2 vs 1.4 cm/s in the right atrium; P = .011). Multivariate analyses showed that all atrial TVI parameters were independently associated with the maintenance of sinus rhythm after 1 year. | Sex differences in response to microbial infections, especially viral ones, may be associated with Toll-like receptor (TLR)-mediated responses by plasmacytoid dendritic cells (pDCs). In this study, we identified sex differences in human infant pDC interferon-α production following challenge with the TLR7/8 agonist R-848. Male pDC responses were significantly lower than those of females during early infancy. This difference may be attributed to the androgen surge experienced by males during the early infancy period. Pretreatment of human pDCs with dihydrotestosterone produced a significant reduction in interferon-α production following R-848 challenge. |
Does echogenicity of medium-to-large carotid plaques predict future vascular events? | Although the echolucent plaque in carotid stenosis is associated with future ischemic stroke, the predictive value of echogenicity in small and medium size carotid plaques on vascular events has not been thoroughly examined. Thus, we prospectively tested the hypothesis that plaque echogenicity of carotid atheroma can predict the future total cardiovascular events in patients with vascular risk factors. Ultrasound assessment of carotid intima-media complex thickness (IMT) and plaque echogenicity using integrated backscatter (IBS) analysis was performed in 596 patients aged 40 or more, with any history of vascular events or with at least 1 risk factor, who were enrolled between 2001 and 2006 in the Osaka Follow-up Study for Carotid Atherosclerosis, part 2 (OSACA2). We followed the incidence of total cardiovascular events including cerebrovascular events, coronary heart disease (CHD), and peripheral artery disease (PAD) for 6.4 years. We divided the patients into two groups according to the IBS index above (echorich plaques) and under (echolucent plaque) the median value, and calculated the hazard ratios (HR) of the echolucent group compared with the echogenic group in the risk of cardiovascular events. Among 596 patients, carotid stenosis was found only in 87 patients. During the follow-up period, we observed 121 cardiovascular events including 63 cerebrovascular events, 45 CHD cases, and 13 PAD cases. The patients with incident cardiovascular events had larger plaque thickness and lower IBS index than those without incident vascular events. The relative risk of vascular events for echolucent versus echorich plaques was 1.45 (95% confidence interval [CI] 0.99-2.13, p = 0.058) after adjustment for risk factors and plaque thickness. In patients with plaque size above the median value (>2.1 mm), the relative risk of vascular events for echolucent plaques was 1.72 (95% CI 1.06-2.85, p = 0.029), but this association was not observed in patients with plaque size <2.0 mm. | Classical strains of Salmonella enterica serovar Typhimurium (Typhimurium) predominantly cause a self-limiting diarrheal illness in humans and a systemic disease in mice. In this study, we report the characterization of a strain isolated from a blood-culture taken from a 15-year old woman suffering from invasive severe salmonellosis, refractory to conventional therapy with extended-spectrum cephalosporin (ESC). The strain, named 33676, was characterized as multidrug-resistant Salmonella serogroup A by biochemical, antimicrobial and serological tests. Multilocus sequence typing (MLST) and XbaI macrorestrictions (PFGE) showed that strain 33676 belonged to the Typhimurium ST213 genotype, previously described for other Mexican Typhimurium strains. PCR analyses revealed the presence of IncA/C, IncFIIA and ColE1-like plasmids and the absence of the Salmonella virulence plasmid (pSTV). Conjugation assays showed that the ESC-resistance gene bla CMY-2 was carried on the conjugative IncF plasmid, instead of the IncA/C plasmid, as found in previously studied ST213 strains. Although the IncA/C plasmid conferred most of the observed antimicrobial resistances it was not self-conjugative; it was rather able to conjugate by co-integrating with the IncF plasmid. Strain 33676 was fully attenuated for virulence in BALB/c mice infections. Both type-three secretion system (T3SS), encoded in Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2), were functional in the 33676 strain and, interestingly, this strain produced the H2 FljB flagellin instead of the H1 FliC flagellin commonly expressed by S. enterica strains. |
Do amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease? | To compare the temporal and spatial expression patterns of amyloid precursor protein (APP), amyloid-beta deposits, inflammatory chemokines, and apoptosis in the retina of a mouse model of Alzheimer disease (AD). Retinas of transgenic mice harboring a mutant presenilin (PS1) and a mutant APP gene were processed for TUNEL and immunohistochemistry with antibodies against APP, amyloid-beta, monocyte chemotactic protein (MCP)-1, and F4/80. Comparisons were made between age groups and between transgenic and wild-type congeners. The neuroretina demonstrated age-dependent increases in APP in the ganglion cells (RGCs) and in neurons of the inner nuclear layer (INL). Amyloid-beta demonstrated significant age-dependent deposition in the nerve fiber layer (NFL). TUNEL-positive RGC increased in an age-dependent fashion and in transgenic compared with wild-type congeners. Concomitant overexpression of MCP-1 and intense immunoreactivity for F4/80 suggested that RGCs upregulate MCP-1 in response to amyloid-beta. Activated microglia proliferated in response to MCP-1. In the outer retina, retinal pigment epithelium (RPE) demonstrated moderate age-dependent APP immunoreactivity, but nearby drusenlike deposits were not present. Amyloid-beta was observed in the choriocapillaris of the older animals. | To analyze the effect of allogeneic blood transfusion on clinical outcome in 119 patients with stage IIB cervical cancer who were treated with radiotherapy +/- chemotherapy. Medical records were examined for hemoglobin levels before and during radiotherapy, history of allogeneic blood transfusions and the time point when transfusions were given. These factors were retrospectively analyzed along with other clinical risk factors for influences on the patients' clinical outcomes. Thirty-two patients (26.9%) received packed red blood cell transfusion (mean, 3.4 units; range, 1-12 units) before or during radiotherapy. Median follow-up period was 39.3 months (range, 7.6-58.4 months). Patients with history of transfusion showed poorer metastasis-free survival and a trend toward poorer overall survival than non-transfused patients. When patients who received transfusions were sub-divided by the time of transfusion, those who received transfusions before radiotherapy had significantly poorer clinical outcome than those who received transfusions during radiotherapy. In a multivariable analysis, patients with pretreatment transfusion showed a higher risk of distant metastasis (HR = 3.75, 95% CI: 1.28-12.15, p = 0.017) and decreased overall survival rates (HR = 4.62, 95% CI: 1.15-18.54, p = 0.031) compared with those of other patients. |
Does sulfasalazine prevent apoptosis in spermatogenic cells after experimental testicular torsion/detorsion? | To determine whether sulfasalazine can prevent apoptosis in spermatogenic cells by preventing the activation of NF-kappaB in spermatogenic epithelium in experimental testicular torsion. Thirty-two adult male Sprague-Dawley rats were subjected to unilateral 720 degree testicular torsion for durations of 0 h and 2 h, then the torsion was relieved. The ischemic/reperfused testes were collected for the detection of NF-kappaB expression with Western blotting and immunohistochemistry techniques, and detection of apoptosis with TUNEL techniques. The NF-kappaB coefficient of spermatogenic epithelium and the apoptosis index of spermatogenic cells were significantly different in the operation and the sham-operation groups after experimental testicular torsion (P<0.01). | Intima-media thickness (IMT) is a valid marker for generalized vascular disease whose main risk factors are associated with food habits and lifestyle. A Mediterranean food pattern may have a protective effect on cardiovascular mortality. To assess the relationship between carotid IMT and olive oil consumption. One hundred and ninety nine patients were randomly extracted from 1055 asymptomatic high cardiovascular risk participants at the AP-UNAV recruitment center of the PREDIMED (PREvención con DIeta MEDiterránea) project. Demographic and clinical variables were collected, and a validated semiquantitative food frequency questionnaire (137 items) was administered at the inclusion interview. A B-mode ultrasound imaging technique was used to measure the mean common carotid IMT. The mean age was 67.3 years and 53.3% were women. Energy-adjusted olive oil consumption quintiles were assessed as the main exposure after adjusting for potential dietary and non-dietary confounders. Using continuous carotid IMT as the outcome in an ANCOVA analysis, the adjusted IMT means throughout quintiles showed an inverse association with a plateau after the second quintile, with statistical differences when the adjusted IMT mean of the merged four upper quintiles were compared with the lowest quintile (p<0.05). The averaged (both sides) mean IMT of the common carotid was dichotomised and values above the median (0.804 mm) were used to identify carotid atherosclerotic damage. We also found an inverse association of olive oil consumption with high IMT, throughout the second to the fifth quintile as compared with the lowest quintile. The adjusted OR was of 0.08 (95% confidence interval, CI, of 0.02-0.37; p=0.001) after merging the four upper quintiles. |
Is methadone superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer? | Cancer pain is still inadequately treated in up to 60% of cancer patients. Based on the additional effect on the N-Methyl-d-Aspartate receptor, we expected that methadone (Met) could provide better pain relief than fentanyl (Fen) in cancer pain with a neuropathic pain component. A randomised controlled trial was performed with 52 strong opioids naive patients with head-and-neck cancer with substantial pain (pain Numerical Rating Scale [NRS] > 4) and a neuropathic pain component (Douleur Neuropathique [DN4] > 4). Twenty-six patients were treated with Met and 26 with Fen. Patients were evaluated at 1, 3 and 5 weeks. The primary outcomes were reduction in average pain, clinical success (defined as 50% average pain decrease) and reduction in pain interference. Secondary outcomes were global perceived effect (GPE) and side-effects. Reduction in NRS was higher with the use of Met at 1, 3 and 5 weeks (pain change 2.9, 3.1 and 3.1) compared to Fen (1.4, 1.7 and 2.0). This difference was significant at 1 (p = 0.011) and at 3 weeks (p = 0.03). Clinical success (>50% improvement) was higher with Met at 1 week (15% versus 50%, p = 0.012). The change in pain interference, the GPE and side-effect profile were not significantly different between the groups. | To assist in the development of preventive strategies, we studied whether the neighbourhood environment or modifiable behavioural parameters, including cardiorespiratory fitness (CRF) and physical activity (PA), are independently associated with obesity and metabolic risk markers in children. We carried out a cross-sectional analysis of 502 randomly selected first and fifth grade urban and rural Swiss schoolchildren with regard to CRF, PA and the neighbourhood (rural vs urban) environment. Outcome measures included BMI, sum of four skinfold thicknesses, homeostasis model assessment of insulin resistance (HOMA-IR) and a standardised clustered metabolic risk score. CRF and PA (especially total PA, but also the time spent engaged in light and in moderate and vigorous intensity PA) were inversely associated with measures of obesity, HOMA-IR and the metabolic risk score, independently of each other, and of sociodemographic and nutritional parameters, media use, sleep duration, BMI and the neighbourhood environment (all p < 0.05). Children living in a rural environment were more physically active and had higher CRF values and reduced HOMA-IR and metabolic risk scores compared with children living in an urban environment (all p < 0.05). These differences in cardiovascular risk factors persisted after adjustment for CRF, total PA and BMI. |
Does methylphenidate improve aspects of executive function in African American children with ADHD? | The undertreatment of ethnic minority children with ADHD prompted a study on the effects of methylphenidate (MPH) on the executive functions of African American children with ADHD. Nineteen African American children with ADHD are tested on the Tower of Hanoi (TOH) and the Paired Associates Learning Task (PAL) in a double-blind crossover acute challenge of MPH and placebo. Under MPH, TOH rule breaks decrease, especially in the second testing session, and TOH planning time increases, particularly for incorrect solutions; PAL recall in the final learning trial improves with MPH. | It has previously been shown that heparanase-1 (HPR1), an endoglycosidase, is up-regulated in pancreatic carcinoma. The purpose of this study was to test whether serum HPR1 levels in pancreatic carcinoma patients are elevated, and whether higher serum HPR1 levels are associated with a shortened survival. Serum HPR1 levels in 40 healthy donors, 31 pancreatic carcinoma patients, and 11 patients treated with gemcitabine were measured by a novel enzyme-linked immunoadsorbent assay. HPR1 expression in tumors was analyzed by immunohistochemical staining. Patient overall survival time was determined according to the Kaplan-Meier method, and their difference was evaluated by the log-rank test. A P value<0.05 was considered statistically significant. The mean serum HPR1 activity in pancreatic carcinoma patients was 439+/-14 units/mL, compared with 190+/-4 units/mL in the control serum samples from healthy donors. Serum HPR1 levels were significantly higher in patients with HPR1-positive tumors (660+/-62 units/mL) compared with those with HPR1-negative tumors (241+/-14 units/mL). The mean survival of 19 pancreatic carcinoma patients with serum HPR1 activity>300 units/mL was 7.9+/-0.2 months, whereas the mean survival of 12 patients with serum HPR1 activity<300 units/mL was 13.3+/-0.6 months. A Kaplan-Meier plot of the patient survival curve followed by log-rank test revealed that patients in the high serum HPR1 group had a significantly shorter survival compared with those in the low serum HPR1 group. Mean serum HPR1 activity decreased by 64% in 11 pancreatic carcinoma patients after 2 weeks of treatment with gemcitabine. |
Does aliskiren inhibit prorenin-induced human aortic smooth muscle cell migration? | In the present study, we investigated the potential effect of aliskiren on smooth muscle cell (SMC) migration in response to prorenin. Cultured human SMCs were incubated with angiotensinogen (ANG) (1.5 × 10(-7)M) and increasing concentrations of aliskiren (10(-6)-10(-5)M). After 24 h, SMC migration was assessed by Boyden's chamber chemotactic assay using prorenin as chemotactic factor (10(-8)M). The effect of aliskiren on RhoA and Rac activity was also determined by G-LISA assay and the lamellipodia formation by rhodamine-phalloidin staining. Changes in cell morphology were recorded in real-time using the iCelligence system. Aliskiren determined, at 10(-5)M, a significant inhibition of SMC migration induced by prorenin (-66.4 ± 18.1%; p < 0.05), while no significant effect was observed when PDGF-BB was utilized as chemotactic agent. Aliskiren also reduced Rac-GTP levels in response to prorenin (-54.2 ± 5.4%) without affecting the RhoA-GTP levels. Finally, aliskiren inhibited both the lamellipodia formation and morphological changes induced by prorenin with no significant effect on PDGF-BB activity. | Stigma has been suggested as a possible contributor to the high rates of treatment attrition in substance-dependent individuals, but no published empirical studies have examined this association. The present paper assessed the relationship between baseline stigma variables and length of treatment stay in a sample of patients in a residential addictions treatment unit. The relationship between baseline stigma variables (self-stigma, enacted stigma, and shame) and length of stay for participants (n=103) in a residential addictions treatment unit was examined. Higher self-stigma predicted longer stay in residential addictions treatment, even after controlling for age, marital status, race, overall mental health, social support, enacted stigma, and internalized shame. However, other stigma variables (i.e. internalized shame, stigma-related rejection) did not reliably predict length of treatment stay. |
Does peripherally administered oxytocin modulate latent inhibition in a manner consistent with antipsychotic drugs? | Peripherally administered oxytocin (OT) has produced antipsychotic drug (APD)-like effects in animal tests that are predictive of APD efficacy. However, these effects have mainly been demonstrated using animal models of schizophrenia-like deficits in prepulse inhibition (PPI) of the startle reflex. Another schizophrenia-relevant abnormality that is the basis of a predictive animal test for APD efficacy is deficient latent inhibition (LI). LI is the normal suppression of a classically conditioned response when the subject is pre-exposed to the conditioned stimulus (CS) before it is paired with the unconditioned stimulus (UCS). Conditioned taste aversion (CTA), the normal avoidance of ingesting a food or liquid by animals when its taste is associated with an aversive experience, was used to test whether OT facilitates LI consistent with APDs. Brown Norway rats, known to naturally display attenuated LI, were aversively conditioned on two consecutive exposures to flavored drinking water (0.1% saccharin) by pairing it with malaise-inducing lithium chloride injections. Concurrent with conditioning, rats received subcutaneous OT (0.02, 0.1, 0.5mg/kg) or saline. Some rats were pre-exposed to the flavored water prior to its aversive conditioning (pre-exposed) while others were not (non pre-exposed). Two days after aversive conditioning the amount of flavored water consumed during a 20-min session was recorded. As expected, LI, defined as greater consumption by pre-exposed vs. non pre-exposed rats was only weakly exhibited in Brown Norway rats and OT enhanced LI by reducing CTA in pre-exposed rats in a dose-dependent manner, with the 0.02 mg/kg dose producing the strongest effect. | Mechanical support leads to an increased risk of both bleeding and thrombotic events, but little is known about the risk of device support in patients with a baseline predisposition to these events. The aim of this study was to examine outcomes among patients with baseline hematologic conditions who underwent continuous-flow LVAD implantation (CF-LVAD). We retrospectively reviewed records of 286 patients who underwent CF-LVAD implantation at the Columbia University Medical Center between April 2008 and December 2013. Patients diagnosed with the following hematologic conditions were enrolled: idiopathic thrombocytopenic purpura (ITP); Factor V Leiden; elevated Factor VIII; heparin-induced thrombocytopenia (HIT); or undefined hypercoagulable state. Of the 286 CF-LVAD patients implanted during the study period, 12 were considered to have a significant hematologic condition predisposing them to either bleeding or thrombotic events. The study included 5 patients with ITP, 1 with Factor V Leiden, 1 with elevated Factor VIII, 2 with HIT and 3 patients with undefined hypercoagulable state. Patients were supported for a total of 168.46 months, with a median of 10.76 months (IQR 4.78 to 21.36 months). There was a high frequency of thrombotic (0.57 event per patient-year), neurologic (0.36 event per patient-year) and bleeding (0.64 event per patient-year). Actuarial survival rates at 6 and 12 months were 81.8%, but fell to 49% at 2 years. |
Do oxygen debt criteria quantify the effectiveness of early partial resuscitation after hypovolemic hemorrhagic shock? | The effectiveness of partial resuscitation after hypovolemic hemorrhagic shock with deferment of full resuscitation is critical to successful hypotensive resuscitation. To quantitatively address this issue, 40 canines were bled under anesthesia to a mean oxygen debt (O(2)D) of 104 +/- 7.6 mL/kg over 60 minutes (mortality, 40%). Animals surviving the shock were then immediately resuscitated with 0%, 8.4%, 15%, 30%, or 120% (full resuscitation) of shed volume as 5% albumin and held for 2 hours postshock, when the remaining portion of full resuscitation volume was given. Animals were followed for 7 days postshock with hepatic and renal function studies, and then, under anesthesia, cardiac output and organ biopsy specimens were taken before the animals were killed. By 2 hours postshock, 0% immediate resuscitation had an O(2)D increase of 80 mL/kg above end of shock, but O(2)D at 8.4% immediate resuscitation decreased -30 mL/kg, 15% immediate resuscitation fell -65 mL/kg, 30% immediate resuscitation decreased -80 mL/kg below end of shock, and O(2)D with 120% full resuscitation fell to preshock levels. All decreases in O(2)D were significantly (p < 0.05) below end of shock, but both 15% and 30% immediate resuscitation exceeded the 8.4% immediate resuscitation rate (p < 0.05) throughout the resuscitation, and 120% full resuscitation exceeded these (p < 0.05). The immediate resuscitation O(2)D response correlated significantly (p < 0.001) with base deficit and lactate, but blood pressure was not a significant discriminator. Seven-day biopsies showed return of bowel mucosa but a pattern of cellular injury in heart, liver, and kidney that improved from 8.4% < 15% < 30 < 120% immediate resuscitation. | To explore the prevalence of work disability (WD) and to identify bio-psychological factors that predicts future WD in rheumatoid arthritis (RA) over a 7-year period. Patients were selected from the Oslo RA register. The prevalence of WD was studied cross-sectionally among respondents <67 years (n = 526) in a postal survey. Mean age (SD) was 51.1 (11.9) years, mean disease duration 11.3 (9.4) years, and 49% of patients were RF-positive. The patients studied for predictive factors for WD were respondents in postal surveys both at baseline and at the 7-year follow-up, in work at baseline and still in working age (<67 years) at follow-up (n = 159). Mean age at baseline (SD) was 44.5 (9.7) years, mean disease duration 8.4 (6.6) years, mean years of formal education 12.7 (3.1) years, 48% were RF-positive. Assessments included socio-demographic variables and health status measures (MHAQ, AIMS2, SF-36, fatigue and pain on VAS 0-100 mm, self efficacy, and RAI as a measure for helplessness). Among the 526 respondents at baseline <67 years, the prevalence of WD was 40%. A high level of education was a predictor of reduced risk of work disability [odds ratio (OR) = 0.4, 95% confidence interval (CI) 0.1; 0.9], while female gender (OR 3.0, 95% CI 1.1; 8.0), physical disability (MHAQ-score) (OR = 3.9, 95% CI 1.2; 12.5) and helplessness over median RAI-score (OR = 3.0, 95% CI 1.4; 6.7) were independent predictors of increased risk for new work disability over 7 years. |
Are serum C-reactive protein and plasma homocysteine levels associated with hormone therapy use and other factors : a population-based study of middle-aged Australian-born women? | To investigate the associations between C-reactive protein (CRP), homocysteine levels, use of hormone therapy (HT) and other factors. A 12-year prospective study of 438 Australian-born women (Melbourne Women's Midlife Health Project), who at baseline were aged 45-55 years, had menstruated in the previous 3 months and were not taking HT. Fasting blood was collected in the 11th follow-up year for CRP, homocysteine, estradiol and follicle stimulating hormone (FSH) levels. Physical measurements and face-to-face interviews obtained information on health and lifestyle variables. A total of 258 women (mean age 60 years) participated in the 11th follow-up year. Multiple regression analysis found that CRP levels were positively associated with body mass index (p < 0.001), HT use (p < 0.01), and negatively associated with statin use (p < 0.005) and exercising (p < 0.05). In postmenopausal women currently not using HT (n = 173) and after adjusting for body mass index, exercise and smoking, CRP was negatively associated with FSH levels (beta = -0.32, p < 0.05). Homocysteine levels were positively associated with smoking (p < 0.001) and negatively associated with HT use (p < 0.05). | Intrathecal magnesium sulfate coinfusion with morphine increases antinociception in normal rats; however, because magnesium also delays the onset of tolerance, it is not clear whether this additional antinociception is a result of potentiated analgesia or tolerance abatement. We examined the antinociceptive interaction of intrathecal (IT) bolus magnesium sulfate and morphine in morphine naive rats and those with mechanical allodynia after a surgical incision. After intrathecal catheter implantation, rats were given preinjections of magnesium or saline, followed by injections of morphine or saline. In morphine naïve rats, IT bolus magnesium sulfate 281 and 375 microg followed by IT morphine 0.25 or 0.5 nmol enhanced peak antinociception and area under the response versus time curve two-to-three-fold in the tail-flick test as compared with morphine alone. Likewise, in rats with incisional pain, IT bolus magnesium sulfate 188 and 375 microg followed by morphine 0.5 nmol reduced mechanical allodynia, whereas morphine 0.5 nmol alone did not. This study suggests that IT magnesium sulfate potentiates morphine at a spinal site of action. |
Does niclosamide suppress cell migration and invasion in enzalutamide resistant prostate cancer cells via Stat3-AR axis inhibition? | It is known that over expression of IL6 in prostate cancer cells confer enzalutamide resistance and that this may occur through constitutive Stat3 activation. Additionally, recent pre-clinical studies suggested enzalutamide might have the potential adverse effect of inducing metastasis of prostate cancer cells via Stat3 activation. This study is aimed to target Stat3 activation and improve enzalutamide therapy. Sensitivity of prostate cancer cells to enzalutamide was tested using cell growth assays and clonogenic assays. Wound healing and invasion assays were performed to determine cell migration and invasion in vitro. Quantitative reverse transcription-PCR, ELISA and Western blotting were performed to detect expression levels of PSA, c-Myc, survivin, Stat3, and AR. ChIP assay was performed to examine recruitment of AR to the PSA promoter. In the present study, we found niclosamide, a previously identified novel inhibitor of androgen receptor variant (AR-V7), inhibited Stat3 phosphorylation, and expression of downstream target genes. Niclosamide synergistically reversed enzalutamide resistance in prostate cancer cells and combination treatment of niclosamide with enzalutamide significantly induced cell apoptosis and inhibited cell growth, colony formation, cell migration and invasion. Knock down of Stat3 abrogated enzalutamide resistance resulting in reduced recruitment of AR to the PSA promoter in prostate cancer cells expressing IL6. Moreover, niclosamide reversed enzalutamide resistance by down-regulating Stat3 target gene expression Stat3and abrogating recruitment of AR to PSA promoter resulting in PSA inhibition. | Extracellular hemoglobin and cell-free heme are toxic breakdown products of hemolyzed erythrocytes. Mammals synthesize the scavenger proteins haptoglobin and hemopexin, which bind extracellular hemoglobin and heme, respectively. Transfusion of packed red blood cells is a lifesaving therapy for patients with hemorrhagic shock. Because erythrocytes undergo progressive deleterious morphological and biochemical changes during storage, transfusion of packed red blood cells that have been stored for prolonged intervals (SRBCs; stored for 35-40 days in humans or 14 days in mice) increases plasma levels of cell-free hemoglobin and heme. Therefore, in patients with hemorrhagic shock, perfusion-sensitive organs such as the kidneys are challenged not only by hypoperfusion but also by the high concentrations of plasma hemoglobin and heme that are associated with the transfusion of SRBCs. To test whether treatment with exogenous human haptoglobin or hemopexin can ameliorate adverse effects of resuscitation with SRBCs after 2 hours of hemorrhagic shock, mice that received SRBCs were given a coinfusion of haptoglobin, hemopexin, or albumin. Treatment with haptoglobin or hemopexin but not albumin improved the survival rate and attenuated SRBC-induced inflammation. Treatment with haptoglobin retained free hemoglobin in the plasma and prevented SRBC-induced hemoglobinuria and kidney injury. In mice resuscitated with fresh packed red blood cells, treatment with haptoglobin, hemopexin, or albumin did not cause harmful effects. |
Does severe Obesity in Adolescents and Young Adults be Associated With Subclinical Cardiac and Vascular Changes? | Severe obesity is the fastest growing subgroup of obesity in youth. We sought to explore the association between severe obesity and subclinical measures of cardiac and vascular structure and function in adolescents and young adults. This was a cross-sectional comparison of 265 adolescents and young adults with severe obesity (defined as body mass index [BMI] ≥120% of the 95th percentile) to 182 adolescents and young adults with obesity (defined as BMI ≥100-119th of the 95th percentile) at tertiary medical center. Noninvasive measures of cardiac and vascular structure and function were assessed. Participants were a mean age of 17.9 years, 62% were non-Caucasian, and 68% were female. Systolic blood pressure, fasting insulin, C-reactive protein, IL-6, and frequency of type 2 diabetes were higher in participants with severe obesity (all P < .05). Arterial thickness and stiffness, cardiac structure, and diastolic function were also significantly worse in youth with severe obesity as measured by higher left ventricular mass index, worse diastolic function, higher carotid intima media thickness, and pulse wave velocity and lower brachial distensibility (all P < .05). Regression modeling showed that severe obesity (compared with obesity) was independently associated with each of the above outcomes after adjustment for age, race, sex, blood pressure, lipids, and inflammatory markers (P < .05). | Recent studies have showed podoplanin expression in several tumors, which has been associated with lymph node metastasis and poor prognosis. Podoplanin expression in cancer-associated fibroblasts also correlates with tumor progression. However, the association of podoplanin expression with melanomas remains unclear. To clarify the prognostic significance of podoplanin in melanoma, podoplanin expression in tumor cells and cancer-associated fibroblasts was examined by immunohistochemistry in tissue samples collected from 55 melanoma patients. Podoplanin expression in tumor cells was identified in 38 patients (69.1%) but did not show correlation with characteristics of tumor progression such as tumor thickness (p = 0.52) and sentinel lymph node (SLN) metastasis (p = 0.79). Podoplanin expression in cancer-associated fibroblasts was observed in 25 patients (45.5%), 11 of whom (44.0%) had SLN metastasis. In contrast, only 4 of 30 patients (13.3%) with podoplanin-negative cancer-associated fibroblasts exhibited SLN metastasis. Podoplanin-positive cancer-associated fibroblasts were associated with increased tumor thickness and SLN metastasis. Furthermore, patients with podoplanin-positive cancer-associated fibroblasts had poorer survival than those with podoplanin-negative cancer-associated fibroblasts (p = 0.0148). |
Do hDL-C levels modify the association between C-reactive protein and coronary artery calcium score? | C-reactive protein (CRP) levels predict incident and recurrent cardiovascular disease (CVD) events; however, associations between CRP and pre-clinical atherosclerosis is less certain. Since high concentrations of high-density lipoprotein cholesterol (HDL-C) are inversely associated with CVD risk, we investigated whether HDL-C modified the association between CRP concentration and measures of preclinical atherosclerosis. Data were analyzed from a Korean occupational cohort of 12,030 male subjects who underwent a cardiac computed tomography (CT) estimation of coronary artery calcification (CAC) score and an assessment of CVD risk factors. Logistic regression was used to describe associations between CRP and measures of pre-clinical atherosclerosis, such as CAC scores >0. As many as 1351 (11.2%) participants had a CAC score>0. CRP was stratified into 3 groups based on clinical category: <1 mg/L, 1 to <2 mg/L, and ≥ 2 mg/dL. In the bottom CRP group, 907/8697 (10.4%) of subjects had a CAC score >0, compared with 242/1943 (12.5%) in the middle group and 202/1396 (14.5%) in the top CRP group (p < 0.0001). After adjustment for multiple CVD risk factors, there was a positive association between CRP and CAC score>0 (OR between top and bottom CRP groups, 1.41 [1.04, 1.90], p = 0.027) in the lowest HDL-C quartile but not in the highest HDL-C (OR between top and bottom CRP group, 0.80 [0.46, 1.39], p = 0.425). | Studies on the use of intradetrusor botulinum toxin A injection for children with neuropathic bladders are insufficient and the results are controversial. The aim of the present study was to evaluate the effect of intradetrusor botulinum toxin A injection for children with neuropathic bladders that are resistant to anticholinergic treatment, and to reveal any criteria indicating treatment success. Hospital records were reviewed of 16 children with neuropathic bladders due to myelomeningocele, and who had botulinum toxin A injections between 2007 and 2010. Botulinum toxin A (10 units/kg) was injected endoscopically into various sites of the detrusor, except the trigone. The success was defined as complete dryness between clean intermittent catheterizations. Urodynamic studies before and after the application were evaluated and parameters, including bladder capacity (measured/expected) and compliance, were also analyzed. Reviewing the results, patients were then classified into two groups: as having fibrotic bladders (noncompliant, acontractile bladders with high pressures) or overactive bladders. Urodynamic findings and therapy success were then compared between the groups. A total of 19 injections, including repeat injections in three patients, were performed. Results of the 16 initial injections were evaluated. Nine patients had detrusor overactivity, and five out of nine (56%) applications in this group resulted in complete dryness between clean intermittent catheterizations. In bladders with typical detrusor overactivity, there was a significant increase in both the capacity (from 0.53 to 0.74) and compliance (from 4.7 to 8.6 ml/cm H2O). Looking at the seven patients that displayed fibrotic bladders with very low compliance and no contraction at all, none of them presented with notable clinical improvement from injections. Comparing the urodynamic findings, there was no significant difference in compliance (3.1 ml/cm H2O before and 3.5 ml/cm H2O after) and bladder capacity (0.58 before and 0.52 after the treatment) in the fibrotic bladders. |
Does hypoperfusion intensity ratio predict infarct progression and functional outcome in the DEFUSE 2 Cohort? | We evaluate associations between the severity of magnetic resonance perfusion-weighted imaging abnormalities, as assessed by the hypoperfusion intensity ratio (HIR), on infarct progression and functional outcome in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2). Diffusion-weighted magnetic resonance imaging and perfusion-weighted imaging lesion volumes were determined with the RAPID software program. HIR was defined as the proportion of TMax >6 s lesion volume with a Tmax >10 s delay and was dichotomized based on its median value (0.4) into low versus high subgroups as well as quartiles. Final infarct volumes were assessed at day 5. Initial infarct growth velocity was calculated as the baseline diffusion-weighted imaging (DWI) lesion volume divided by the delay from symptom onset to baseline magnetic resonance imaging. Total Infarct growth was determined by the difference between final infarct and baseline DWI volumes. Collateral flow was assessed on conventional angiography and dichotomized into good and poor flow. Good functional outcome was defined as modified Rankin Scale ≤2 at 90 days. Ninety-nine patients were included; baseline DWI, perfusion-weighted imaging, and final infarct volumes increased with HIR quartiles (P<0.01). A high HIR predicted poor collaterals with an area under the curve of 0.73. Initial infarct growth velocity and total infarct growth were greater among patients with a high HIR (P<0.001). After adjustment for age, DWI volume, and reperfusion, a low HIR was associated with good functional outcome: odds ratio=4.4 (95% CI, 1.3-14.3); P=0.014. | Guanylin activates an intestinal guanylate cyclase (GCC) and stimulates electrolyte movement across the gut epithelium. Cells expressing guanylin messenger RNA have been localized to the epithelial cell layer of the intestine; however, the identity of the guanylin-producing cells has not been determined. The aim of this study was to identify cells that express guanylin in the rat intestine. Antibodies were raised against defined proguanylin epitopes, evaluated by Western blotting, and used for immunoperoxidase histochemistry. Guanylin-like immunoreactivity was localized to a subset of goblet cells. In the small intestine, most, perhaps all, goblet cells in the villi were immunopositive, as were some goblet cells in upper crypts; however, goblet cells deep within crypts were unlabeled. In the colon, goblet cells clustered in the necks and around the openings of crypts were immunopositive, whereas (as in the small intestine) goblet cells in deeper crypt regions were unlabeled. In some animals, immunoreactive columnar epithelial cells were also observed in the colon (although such cells were not apparent in the small intestine). Relative labeling of columnar cells varied from animal to animal. |
Does cyclosporine withdrawal improve long-term graft survival in renal transplantation? | The reduction in renal transplant rejection rates achieved over the last 20 years have not translated into a commensurate improvement in long-term graft survival. Cyclosporine has been central to immunosuppressive regimens throughout this period but its effect on long-term transplant outcomes remains unclear. This randomized controlled trial allocated first cadaveric renal transplant recipients in seven centers around Australia to three immunosuppressive regimens: azathioprine and prednisolone (AP), long-term cyclosporine alone (Cy), or cyclosporine initiation followed by withdrawal at 3 months and azathioprine and prednisolone replacement (WDL). Between 1983 and 1986, 489 patients were randomized with 98% follow-up to a median of 20.6 years. Mean graft survival (censoring deaths) was superior in the WDL group (14.8 years) when compared with both AP (12.4 years, P=0.01 log-rank test) and Cy (12.5 years, P=0.01 log-rank test) groups by intention-to-treat. Without death censoring, graft survival with WDL was superior to AP (9.5 years vs. 6.7 years, P=0.04) and of borderline superiority to Cy (9.5 years vs. 8.5 years, P=0.06). Patient survival was not different between the three groups. Renal function was superior in AP (at 1, 10, and 15 years posttransplant) and WDL (at 1, 5, 10, 15, and 20 years) groups when compared with Cy. | Affinity purification followed by mass spectrometry (AP/MS) is a widely used approach to identify protein interactions and complexes. In multicellular organisms, the accurate identification of protein complexes by AP/MS is complicated by the potential heterogeneity of complexes in different tissues. Here, we present an in vivo biotinylation-based approach for the tissue-specific purification of protein complexes from Caenorhabditis elegans. Tissue-specific biotinylation is achieved by the expression in select tissues of the bacterial biotin ligase BirA, which biotinylates proteins tagged with the Avi peptide. We generated N- and C-terminal tags combining GFP with the Avi peptide sequence, as well as four BirA driver lines expressing BirA ubiquitously and specifically in the seam and hyp7 epidermal cells, intestine, or neurons. We validated the ability of our approach to identify bona fide protein interactions by identifying the known LGL-1 interaction partners PAR-6 and PKC-3. Purification of the Discs large protein DLG-1 identified several candidate interaction partners, including the AAA-type ATPase ATAD-3 and the uncharacterized protein MAPH-1.1. We have identified the domains that mediate the DLG-1/ATAD-3 interaction, and show that this interaction contributes to C. elegans development. MAPH-1.1 co-purified specifically with DLG-1 purified from neurons, and shared limited homology with the microtubule-associated protein MAP1A, a known neuronal interaction partner of mammalian DLG4/PSD95. A CRISPR/Cas9-engineered GFP::MAPH-1.1 fusion was broadly expressed and co-localized with microtubules. |
Is a rare RET gene exon 8 mutation found in two Greek kindreds with familial medullary thyroid carcinoma : implications for screening? | Familial medullary thyroid carcinoma (FMTC) is caused by germ-line mutations in the RET proto-oncogene. These mutations concern mainly cysteine residues in exons 10 and 11, whereas noncysteine mutations in exons 13-16 are rare. Mutations in other exons have been reported only in isolated families. In this study we have analysed the RET gene in two FMTC families negative for mutations in the above exons. We have analysed exons 7-19 and 21 in one index patient from each family using DNA sequencing. Twenty-eight subjects from both families were clinically assessed and subsequently molecularly analysed for the presence of RET gene mutations. We have found the mutation c.1597G-->T (Gly533Cys) in two Greek families with FMTC. The mutation was detected in all seven MTC patients of both families as well as in 13 asymptomatic relatives in the heterozygote state, although one of the patients was also a homozygote due to consanguinity. The mutation shows a wide clinical heterogeneity, as there are carrier patients with age of diagnosis ranging from 23 to 88 years. | Adult respiratory distress syndrome remains a major cause of morbidity and mortality. We investigated the role of thromboxane receptor antagonism in an experimental model of acute lung injury that mimics adult respiratory distress syndrome. Three groups of rabbit heart-lung preparations were studied for 30 minutes in an ex vivo blood perfusion/ventilation system. Saline control (SC) lungs received saline solution during the first 20 minutes of study. Injury control (IC) lungs received an oleic acid-ethanol solution during the first 20 minutes. Thromboxane receptor blockade (TRB) lungs received the same injury as IC lungs, but a thromboxane receptor antagonist (SQ30741) was added to the blood perfusate just prior to study. Blood gases were obtained at 10-minute intervals, and tidal volume, pulmonary artery pressure, and lung weight were continuously recorded. Oxygenation was assessed by measuring the percent change in oxygen tension over the 30-minute study period. Tissue samples were collected from all lungs for histologic evaluation. Significant differences were found between SC and IC lungs as well as TRB and IC lungs when comparing pulmonary artery pressure (SC = 33.1 +/- 2.2 mm Hg, TRB = 35.4 +/- 2.1 mm Hg, IC = 60.4 +/- 11.1 mm Hg; p < 0.02) and percent change in oxygenation (SC = -20.6% +/- 10.3%, TRB = -24.2% +/- 9.5%, IC = -57.1% +/- 6.2%; p < 0.03). None of the other variables demonstrated significant differences. |
Do large deletions play a minor but essential role in congenital coagulation factor VII and X deficiencies? | Congenital factor VII (FVII) and factor X (FX) deficiencies belong to the group of rare bleeding disorders which may occur in separate or combined forms since both the F7 and F10 genes are located in close proximity on the distal long arm of chromosome 13 (13q34). We here present data of 192 consecutive index cases with FVII and/or FX deficiency. 10 novel and 53 recurrent sequence alterations were identified in the F7 gene and 5 novel as well as 11 recurrent in the F10 gene including one homozygous 4.35 kb deletion within F7 (c.64+430_131-6delinsTCGTAA) and three large heterozygous deletions involving both the F7 and F10 genes. One of the latter proved to be cytogenetically visible as a chromosome 13q34 deletion and associated with agenesis of the corpus callosum and psychomotor retardation. | Hyperglycemia is a risk factor for nosocomial infections with known host effects. Increased glucose levels also increase pathogenicity of infecting microbes through greater biofilm formation. The dose response of biofilm formation to glucose concentration is not known. We asked: What is the relationship between the amount of biofilm formed by Staphylococcus epidermidis and Staphylococcus aureus and change in glucose concentration in the clinically important range of 20 to 300 mg/dL? This experiment studied biofilm formation by S epidermidis and S aureus in Lennox broth medium supplemented with increasing glucose concentrations from 0 to 320 mg/dL in 20 mg/dL intervals. Biofilm was grown for 24 hours for S epidermidis and 48 hours for S aureus. Biofilms were heat fixed, stained with 0.1% crystal violet, and washed with deionized water. The dye was then extracted with 30% acetic acid. Visual light absorption of the extracted crystal violet dye at 600 nm was used to quantify the biofilm biomass. The effect of glucose concentration on the amount of biofilm mass produced was analyzed using ANOVA and Tukey's test. Biofilm mass was increased at higher glucose concentration for both species with a threshold response at 0 to 20 and 160 to 200 mg/dL for S epidermidis and 200 to 240 mg/dL for S aureus. |
Is the 17-mm St. Jude Medical Regent valve a valid option for patients with a small aortic annulus? | When aortic valve replacement is performed in patients with a small aortic annulus, prosthesis-patient mismatch is of concern. Such prosthesis-patient mismatch may affect postoperative clinical status and survival. We investigated the outcomes of isolated aortic valve replacement performed with a 17-mm mechanical prosthesis in patients with aortic stenosis. Twenty-three patients with aortic stenosis (mean age, 74.6 +/- 6.3 years) underwent isolated aortic valve replacement with a 17-mm St. Jude Medical Regent prosthesis. Mean body surface area was 1.41 +/- 0.13 m(2). Preoperative echocardiography yielded a mean aortic valve area of 0.36 +/- 0.10 cm(2)/m(2), a mean left ventricular-aortic pressure gradient of 68.4 +/- 25.3 mm Hg, and a mean left ventricular mass index of 200 +/- 69 g/m(2). There was no operative mortality, and there were no valve-related events. Echocardiography at 14.0 +/- 10.0 months after aortic valve replacement showed a significant increase in the mean effective orifice area index (0.95 +/- 0.24 cm(2)/m(2)), decrease in the mean left ventricular-aortic pressure gradient (17.4 +/- 8.2 mm Hg), and decrease in the mean left ventricular mass index (124 +/- 37 cm(2)/m(2)). Prosthesis-patient mismatch (effective orifice area index < 0.85 cm(2)/m(2)) was present in 8 patients at discharge. In these patients as well as in those without prosthesis-patient mismatch, the left ventricular mass index decreased remarkably during follow-up. | Chronic ethanol (EtOH) has been shown to augment tumor necrosis factor (TNF)-alpha production, and this has been associated with EtOH-induced liver injury. We have recently described a chronic in vitro cell culture model where chronic ethanol exposure results in significantly augmented TNF production in Mono Mac 6 cells, a human monocytic cell line. This enhanced TNF production was redox regulated and associated with increased levels of TNF messenger RNA (mRNA) as well as increased processing of TNF by TNF converting enzyme (TACE), the enzymatic activity of which is regulated by the cellular redox state. We hypothesized that chronic ethanol through oxidative stress activates TACE-mediated ectodomain shedding of the preformed substrates p75 and p55 TNF receptors in Mono Mac 6 cells and L-selectin in Jurkat T cells. Mono Mac 6 or Jurkat T cells were treated with EtOH (0, 50, or 100 mM) for 4 to 6 days. Shedding of p75 and p55 TNF receptors (Mono Mac 6 cells) or L-selectin (Jurkat T cells) was induced by stimulation with lipopolysaccharide and phorbol myristate acetate for Mono Mac 6 cells and PMA alone for Jurkat T cells. Shedding was assessed by enzyme-linked immunosorbent assay for shed molecules in the cell supernatant as well as the cell-associated proteins recovered from cell pellets. Steady-state mRNA levels for p75 TNF receptor and L-selectin were determined by ribonuclease protection assay. Cell surface L-selectin and TACE were measured by flow cytometry, and cell associated p55 and p75 TNF receptors were measured by enzyme-linked immunosorbent assay. Chronic EtOH exposure for 6 days resulted in a significant dose-dependent increase in shedding of p75 and p55 TNF receptors from Mono Mac 6 cells and L-selectin from Jurkat T-cells. The enhanced shedding was correlated with an alcohol-induced increase in mRNA levels and cell surface protein levels for these TACE substrates. Although chronic EtOH exposure increased the total amount of p75 and p55 TNF receptor and L-selectin shed into the media, the efficiency of shedding was suppressed by EtOH. In the case of Mono Mac 6 cells, the EtOH exposure increased superoxide production. Inhibition of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase and hydrogen peroxide partially prevented the increased production of p75 TNF receptor in these cells. |
Does the mitogen-activated protein kinase Erk5 mediate human mesangial cell activation? | Mesangial activation occurs in many forms of renal disease that progress to renal failure. Mitogen-activated protein kinases (MAPKs) are important mediators involved in the intracellular network of interacting proteins that transduce extracellular stimuli to intracellular responses. The extracellular signal-regulated kinases 5 (Erk5) MAPK pathway has been involved in regulating several cellular responses. Thus, we examined the expression of Erk5 in human renal tissue and the function of Erk5 in cultured human mesangial cells. Erk5 was visualized in human renal tissue by immunohistochemistry and in mesangial cells by immunofluorescence microscopy using the anti-Erk5 C-terminus antibody. Erk5 expression and activation, and collagen I expression were determined by western blot. To generate a dominant-negative form of the Erk5 in human mesangial cells, an EcoRI fragment from wild-type pCEFL-HA-Erk5 was subcloned into the EcoRI site of pCDNA3. Cell proliferation was analysed by an MTT-based assay. Cell contraction was analysed by studying the changes in the planar cell surface area. Erk5 was expressed in the kidney, mainly localized at the glomerular mesangium. In cultured human mesangial cells, Erk5 was activated by foetal calf serum (FCS), high glucose, endothelin-1, platelet-activating factor (PAF), epidermal growth factor (EGF) and transforming growth factor beta-1 (TGF-beta1). The expression of a dominant-negative form of Erk5 in human mesangial cells resulted in a significant decrease in proliferation, EGF-induced cell contraction and TGF-beta1-induced collagen I expression. | We tested the hypothesis that harm avoidance, a trait associated with behavioral inhibition, is associated with the rate of change in parkinsonism in older adults. At baseline harm avoidance was assessed with a standard self-report instrument in 969 older people without dementia participating in the Rush Memory and Aging Project, a longitudinal community-based cohort study. Parkinsonism was assessed annually with a modified version of the motor section of the Unified Parkinson's Disease Rating Scale (mUPDRS). Average follow-up was 5 years. A linear mixed-effects model controlling for age, sex and education showed that for an average participant (female, 80 years old at baseline, with 14 years of education and a harm avoidance score of 10), the overall severity of parkinsonism increased by about 0.05 unit/ year (Estimate, 0.054, S.E., 0.007, p <0.001) and that the level of harm avoidance was associated with the progression of parkinsonism (Estimate, 0.004, S.E., 0.001, p <0.001). Thus, for an average participant, every 6 point (~1 SD) increase in harm avoidance score at baseline, the rate of progression of parkinsonism increased about 50% compared to an individual with an average harm avoidance score. This amount of change in parkinsonism over the course of the study was associated with about a 5% increased risk of death. The association between harm avoidance and progression of parkinsonism persisted when controlling for cognitive function, depressive symptoms, loneliness, neuroticism, late-life cognitive, social and physical activities and chronic health conditions. |
Do cell-surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia? | Although estrogen replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanism for this benefit remains unclear. Because nitric oxide (NO) is considered an important endothelium-derived relaxing factor and may function to protect blood vessels against atherosclerotic development, we investigated the acute effects of physiological levels of estrogen on NO release from human internal thoracic artery endothelia and human arterial endothelia in culture. We tested the hypothesis that estrogen acutely stimulates constitutive NO synthase activity in human endothelial cells by acting on a cell-surface receptor. NO release was measured in real time with an amperometric probe. 17beta-Estradiol exposure to internal thoracic artery endothelia and human arterial endothelia in culture stimulated NO release within seconds in a concentration-dependent manner. 17beta-Estradiol conjugated to bovine serum albumin also stimulated NO release, suggesting action through a cell-surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized this action. We further showed with the use of dual emission microfluorometry that 17beta-estradiol-stimulated release of endothelial NO was dependent on the initial stimulation of intracellular calcium transients. | To investigate the relationship between the damages of hand functions and the type of cerebral palsy (CP) in children with CP. A total of 280 children aged 4-12 years old with CP in the 20 districts of Chengdu were included. The damages of hand functions were assessed with the Chinese Version of Manual Ability Classification System (MACS) and its relationship with the type of CP were analyzed. Among the 280 investigated children, there were 195 chidren with spastic CP, which accounted for the largest proportion (69.64%), wherein the spastic diplegia was most common (56.41%). The classification of MACS was level I-II in 65.13% children with spastic CP, whereas the classification of MACS was level IU-V in 84. 44% and 80.95% children with mixed and dyskinetic CP, respectively. With the increase of the degree of cognitive dysfunction in children with CP, the level of MACS was also increased. There was a difference between the classification of MACS and the different type of CP (P<0.05). The children with spastic CP were mostly mild hand dysfunction, while the children with mixed and dyskinetic type of CP were mostly middle and severe hand dysfunction. A positive correlation was found between the MACS and the subtype of spastic CP (r=0.541, P<0.05). In most of the children with diplegia from spastic CP, the hand dysfunction was mild, whereas the children with quadriplegia from spastic CP were mostly middle and severe hand dysfunction. |
Does star-shaped tetraspermine enhance cellular uptake and cytotoxicity of T-oligo in prostate cancer cells? | An oligonucleotide termed 'T-oligo' having sequence homology with telomere overhang has shown cytotoxicity in multiple cancers. We have demonstrated that T-oligo can induce apoptosis in androgen independent prostate cancer cell line DU-145. In this report, we evaluate the use of star-shaped tetraspermine (SSTS) for delivery of T-oligo. SSTS was synthesized from spermine and its intrinsic cytotoxicity towards DU-145 cells was compared with spermine and branched polyethyleneimine (bPEI). Atomistic molecular dynamic (MD) simulations were conducted to understand binding and complexation of spermine and SSTS with T-oligo. Complexation was also determined using gel electrophoresis and SYBR gold assay. Complexes were characterized for size, cellular uptake and antiproliferative effect. SSTS exhibited significantly lower toxicity than spermine and bPEI. Its affinity towards T-oligo was significantly higher than spermine as determined by experimental studies and confirmed by MD simulations and it formed stable complexes (TONPs) with T-oligo. TONPs facilitated cellular uptake and nuclear accumulation of T-oligo and their cytotoxic potential was observed at concentration several folds lower than that required for T-oligo alone. | This study's purpose was to determine if individuals who have had a stroke primarily use sense of effort to gauge force production during static and dynamic lower limb contractions. If relying on sense of effort while attempting to generate equal limb forces, participants should produce equal percentages of their maximum voluntary strength rather than equal absolute forces in their limbs. Ten stroke participants performed isometric and isotonic lower limb extensions on an exercise machine. When participants attempted to produce equal bilateral isometric forces, there was a significant difference in absolute force between limbs (ANOVA, P < .0001) but no significant difference when force was normalized to each limb's maximum voluntary contraction (MVC) force (P = .5129). During bilateral isotonic contractions, participants produced less absolute force in their paretic limb (P = .0005) and less relative force in their paretic limb (normalized to MVC force) when participants were given no instructions on how to perform the extension (P = .0002). When participants were instructed to produce equal forces, there was no significant difference between relative forces in the 2 limbs (P = .2111). |
Does vitamin E regulate changes in tissue antioxidants induced by fish oil and acute exercise? | Prooxidant effects of fish oil supplementation could unfavorably affect the cardiovascular benefits of fish oil. We tested the effects of 8 wk vitamin E cosupplementation with fish oil on antioxidant defenses at rest and in response to exhaustive exercise in rats. Rats (N = 80) were divided into fish oil, fish oil and vitamin E (FOVE), soy oil, and soy oil and vitamin E (SOVE) supplemented groups. For the vitamin E supplemented rats, corresponding groups (FOVE-Ex and SOVE-Ex) performed an acute bout of exhaustive exercise after the supplementation period. Fish oil supplementation increased the activity of catalase, glutathione peroxidase, and glutathione-S-transferase in the liver and red gastrocnemius (RG) muscle. Fish oil decreased liver total glutathione (TGSH) levels. Vitamin E supplementation decreased antioxidant enzyme activities to levels at or near those in SOVE in a tissue specific pattern. Vitamin E increased TGSH in liver, heart, and RG. Regression analysis showed TGSH to be a negative determinant of protein oxidative damage as measured by protein carbonyl levels in both liver and RG. Catalase activity was associated with liver lipid peroxidation as measured by thiobarbituric acid-reacting substances. The exercise-induced decrease in hepatic TGSH tended to be less in FOVE versus SOVE. Exhaustive exercise also modulated tissue antioxidant enzymes. | Known factors affecting the management of vesicoureteral reflux (VUR) include reflux grade, infection frequency, age and gender. We hypothesized that provider preference is highly associated with management. Utilizing the national billing database, Faculty Practice Solutions Center, a multivariable logistic regression model, was applied to analyze the association of pediatric urologist treatment patterns, patient age, gender, uni- or bilateral disease, insurance type, presence of nephropathy and race with the type of VUR treatment a patient would receive. We identified 59 pediatric urologists who managed 7,882 new reflux patients from 2009 to 2011. Over this 3-year period there was wide variation in surgical utilization between surgeons (mean 50 %) but minimal change for each surgeon (5 %). For every 100 new reflux patients, median utilization of reimplantation surgery and injection of dextranomer/hyaluronic acid copolymer (Deflux) was 26 and 20 %, respectively. Age ranked highest in predicting surgical versus non-surgical management, while a surgeon's historic Deflux utilization rate ranked highest in predicting surgery type. Older age, female gender and white race also increased the odds of Deflux utilization over reimplantation. |
Does zoledronic acid induce caspase-dependent apoptosis in renal cancer cell lines? | To study and characterize the potential antitumoral effects of zoledronic acid (ZA) on renal cancer cell lines in vitro. Three different and well-characterized renal cancer cell lines were studied, namely ACHN, A-498 and CAKI-2. The cytotoxic potential of ZA was evaluated using a fluorometric microculture cytotoxic assay. The degree of M30 induction following ZA treatment was measured using an M30 enzyme-linked immunosorbent assay (ELISA), and the blockage of this effect was studied using a pan-caspase inhibitor. Immunofluorescence of the M30 neoepitope was performed to visualize the M30-inducing properties of ZA. A significant reduction in viable cells was seen for all three cell lines following treatment with ZA, compared with untreated controls. This effect was most pronounced for the ACHN cells, as only 4% were viable following incubation with ZA for 72 h. A concomitant increase in the apoptosis significant caspase-dependent M30 antigen was demonstrated. This effect could be blocked by the pan-caspase inhibitor Z-VAD. | Obesity, a sirtuin-1 (SIRT-1) -deficient state, increases morbidity and resource utilization in critically ill patients. SIRT-1 deficiency increases microvascular inflammation and mortality in early sepsis. The objective of the study was to study the effect of resveratrol (RSV), a SIRT-1 activator, on microvascular inflammation in obese septic mice. ob/ob and C57Bl/6 (WT) mice were pretreated with RSV versus dimethyl sulfoxide (DMSO) (vehicle) prior to cecal ligation and puncture (sepsis). We studied (1) leukocyte/platelet adhesion, (2) E-selectin, ICAM-1, and SIRT-1 expression in small intestine, and (3) 7-day survival. A group of RSV-treated mice received SIRT-1 inhibitor (EX-527) with sepsis induction, and leukocyte/platelet adhesion and E-selectin/ICAM-1 expression were studied. We treated endothelial (HUVEC) cells with RSV to study E-selectin/ICAM-1 and p65-acetylation (AC-p65) in response to lipopolysaccharide (LPS). RSV treatment decreased leukocyte/platelet adhesion and E-selectin/ICAM-1 expression with increased SIRT-1 expression in septic ob/ob and WT mice, decreased E-selectin/ICAM-1 expression via increased SIRT-1 expression, and decreased AC-p65 expression in HUVEC. EX-527 abolished RSV-induced attenuation of microvascular inflammation in ob/ob septic mice. Finally, ob/ob mice in the sepsis+RSV group had significantly increased 7-day survival versus the sepsis+vehicle group. |
Are socioeconomic factors associated with frequency of repeat emergency department visits for pediatric closed fractures? | Previous research has demonstrated both greater difficulty in obtaining follow-up appointments and increased likelihood of return visits to the emergency department (ED) for patients with government-funded insurance plans. The purpose of the current study is to determine whether socioeconomic factors, such as race and insurance type, are associated with the frequency of repeat ED visits in pediatric patients with closed fractures. A review of ED visit data over a 2-year period from a statewide hospital discharge database in New York was conducted. Discharges for patients with a unique person identifier in the database age 17 years and younger were examined for an ICD-9 diagnosis of closed upper or lower extremity fracture. Age, sex, race, and insurance type for patients with a return ED visit within 8 weeks for the same fracture diagnosis were compared with those without a return visit using standard univariate statistical tests and logistic regression analyses. Of the 68,236 visits reviewed, the revisit rate was 0.85%. Patients of nonwhite or unidentified race were significantly more likely to have a revisit than white patients (OR, 1.27; P=0.006). Patients with government-funded insurance were significantly more likely to have a revisit than those without government-funded insurance (OR, 1.55; P<0.001). Patients with private insurance were significantly less likely to have a revisit than those without private insurance (OR, 0.72; P=0.001). | Increased rates of apoptosis have been reported to play a role in the pathophysiology of many disorders, including liver diseases. Conversely, genetic mutations that result in impairment of programmed cell death have been associated with cancer development. However, apoptosis resistance can also be the result of nongenetic stress adaptation, as seen in the cancer-prone metabolic liver disease hereditary tyrosinemia. To clarify whether stress-induced apoptosis resistance is a general feature of chronic liver diseases, an animal model of chronic cholestasis was examined. Studies were performed with mice before and 2 weeks following bile duct ligation and with Fah-/- and Fah/p21-/- mice before and after NTBC withdrawal. Here we show that bile duct ligation induced profound resistance against Fas monoclonal antibody-mediated hepatocyte death. The apoptosis signaling pathway was blocked downstream of caspase-8 activation and proximal to mitochondrial cytochrome c release. In controls, activation of the Fas receptor resulted in rapid dephosphorylation of Bid and its subsequent cleavage, whereas Bid remained phosphorylated and uncleaved in chronic cholestasis and other models of hepatic apoptosis resistance. |
Is chromosome 9p21 polymorphism associated with myocardial infarction but not with clinical outcome in Han Chinese? | rs1333049 polymorphism on chromosome 9p21 has been shown to affect susceptibility to coronary artery disease (CAD) in Caucasians. This study examined the association of rs1333049 with myocardial infarction (MI), angiographic severity of CAD and clinical outcome after a first acute MI in Han Chinese. rs1333049 polymorphism was genotyped in 520 patients with a first acute MI and in 560 controls. The number of angiographically documented diseased coronary arteries (luminal diameter stenosis > or = 50%), echocardiographic left ventricular ejection fraction (LVEF), and major adverse cardiac events (MACE) during follow-up (mean, 29+/-15 months) were recorded. Patients with MI had higher frequencies of the CC genotype (30.0% vs. 20.7%) or C allele (55.5% vs. 46.2%) compared with controls (all p<0.01). rs1333049 polymorphism was strongly associated with MI [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.22-1.79] after adjusting for traditional risk factors. Although longer hospitalization stay was observed in patients with the rs1333049-C allele, this polymorphism was not related to angiographic severity of CAD, LVEF, and occurrence of MACE after MI. | The aim of this study was to examine the efficacy and safety of a new digitized, controlled, scalp-cooling system to prevent chemotherapy-induced alopecia. Seventy-four female cancer patients who received 13 varying chemotherapy regimens were included in a nonrandomized pilot study. The Digni 2-3 with Dignicap system consists of a refrigerator unit and a control unit integrated into a mobile cabinet and connected to a tight-fitting cooling cap. This system maintains a constant scalp temperature of +5 degrees C for many hours. In this study, 60 patients were treated for ovarian cancer with either taxane or epirubicin combination chemotherapy. Eight patients with Hodgkin's lymphoma, three with breast cancer, two with endometrial cancer, and one with sarcoma were also included. Photo documentation and patient assessment of hair loss and discomfort were performed. In anthracycline-treated patients, total prevention of hair loss was observed, whereas hair loss in paclitaxel/docetaxel-treated patients was minimal to none. The combination of anthracycline and taxane resulted in more hair loss, but only three of six patients used a wig. Scalp cooling was generally very well tolerated; only two of 74 patients discontinued use of the cold cap due to discomfort. No scalp metastases occurred over a median follow-up period of 15 months. |
Is lymphovascular invasion associated with poor survival in gastric cancer : an application of gene-expression and tissue array techniques? | To examine a population-based cohort for the association between clinicopathologic predictors of survival and immunohistochemical markers (IHC), and to assess changes in gene expression that are associated with lymphovascular invasion (LVI). LVI has been associated with poor survival and aggressive tumor behavior. The molecular changes responsible for the behavior of gastric cancer have yet to be determined. Characterization of IHC markers and gene expression profiles may identify molecular alterations governing tumor behavior. : Clinicopathologic and survival data of 114 patients were reviewed. Archival specimens were used to construct a multitumor tissue array that was subjected to IHC of selected protein targets. Correlation of IHC with tumor thickness (T status), LVI and prognosis was studied. Microarray analysis of fresh gastric cancer tissue was conducted to examine the gene expression profile with respect to LVI. In a multivariate analysis, nodal status (N), metastasis (M), and LVI were independent predictors of survival. LVI was associated with a 5-year survival of 13.9% versus 55.9% in patients in whom it was absent. LVI correlated with advancing T status (P = 0.001) and N status (P < 0.001). IHC staining of cyclooxygenase-2 (COX-2) correlated with T status, tumor grade, lymph node positivity, and IHC staining of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Microarray analyses suggested differential expression of oligophrenin-1 (OPHN1) and ribophorin-II (RPNII) with respect to LVI. | To investigate whether intracytoplasmic sperm injection (ICSI) can improve the clinical outcomes of the male patients with 100% teratozoospermia. We retrospectively analyzed the clinical data of 152 couples undergoing in vitro fertilization-embryo transfer (IVF-ET), including 75 cycles of IVF and 77 cycles of ICSI. We compared the rates of normal fertilization, high-quality embryos, transferrable embryos, implantation, clinical pregnancy, and abortion between the two groups. In the 100% teratozoospermia patients the number of transferrable embryos was significantly lower in the IVF than in the ICSI group (78.91% vs 84.92%, P < 0.05), while the rates of normal fertilization and implantation were higher in the former than in the latter (60.26% vs 57.87% and 48.00% vs 39.55%, both P > 0.05). There were no statistically significant differences between the two groups in the female age, Gn days, Gn dose, BMI, infertility duration, endometrial thickness, and basal serum FSH and E2. |
Is epithelium-dependent bronchodilatory activity preserved in pig bronchioles after normothermic cardiopulmonary bypass? | Analogous to vascular endothelium, bronchial epithelium modulates bronchomotor activity by releasing epithelium-derived relaxing factors. Cardiopulmonary bypass (CPB) is associated with endothelial dysfunction. We examined whether CPB may be associated with bronchiolar epithelial dysfunction in pigs. Pigs were exposed to normothermic CPB for 1.5 h and then separated from CPB. Lung tissues were biopsied before and 30 min after CPB. For time control, lung tissues were biopsied at baseline and after 2 hr of anesthesia. Bronchioles measuring about 100 microm were dissected, and the epithelium was either left intact or denuded. Each bronchiolar segment was preconstricted with 10 microM 5-hydroxytryptamine and relaxation responses to nitroprusside 10(-9)-10(-4) M, isoproterenol 10(-9)-10(-4) M, or the inhaled anesthetics halothane or isoflurane 0-2.5 minimum alveolar anesthetic concentration were examined in vitro by videomicroscopy. Bronchiolar segments demonstrated concentration-dependent relaxation responses to each of the dilators examined. Epithelial denudation reduced bronchodilation to isoproterenol, isoflurane, and halothane, but not to nitroprusside. Bronchodilation was not significantly affected by CPB. We conclude that, unlike vascular endothelial function, porcine bronchiolar epithelium-modulated bronchomotor activity is not significantly affected by normothermic CPB. | Childhood onset arthritis is associated with low bone mass and strength. To determine whether childhood onset arthritis is associated with greater fracture risk. In a retrospective cohort study all subjects with onset of arthritis between 1 and 19 years of age in the United Kingdom General Practice Research Database were identified. As controls, all sex and age matched subjects from a practice that included a subject with arthritis were included. Incidence rate ratios (IRRs) for first fracture were generated using Mantel-Haenszel methods and Poisson regression. 1939 subjects with arthritis (51% female) and 207 072 controls (53% female) were identified. The median age at arthritis diagnosis was 10.9 years. A total of 129 (6.7%) first fractures were noted in subjects with arthritis compared with 6910 (3.3%) in controls over a median follow up of 3.90 and 3.95 years in the subjects with arthritis and controls, respectively. The IRR (95% confidence interval) for first fracture among subjects with arthritis, compared with controls, according to the age at the start of follow up were 1.49 (0.91 to 2.31) for age <10 years, 3.13 (2.21 to 4.33) at 10-15 years, 1.75 (1.18 to 2.51) at 15-20 years, 1.40 (0.91 to 2.08) at 20-45 years, and 3.97 (2.23 to 6.59) at >45 years. |
Are serum amyloid A , properdin , complement 3 , and toll-like receptors expressed locally in human sinonasal tissue? | There is a growing appreciation of the role that nasal mucosa plays in innate immunity. In this study, the expression of pattern recognition receptors known as toll-like receptors (TLRs) and the effector molecules complement factor 3 (C3), properdin, and serum amyloid A (SAA) were examined in human sinonasal mucosa obtained from control subjects and patients with chronic rhinosinusitis (CRS). Sinonasal mucosal specimens were obtained from 20 patients with CRS and 5 control subjects. Messenger RNA (mRNA) was isolated and tested using Taqman real-time polymerase chain reaction with primer and probe sets for C3, complement factor P, and SAA. Standard polymerase chain reaction was performed for the 10 known TLRs. Immunohistochemistry was performed on the microscopic sections using antibodies against C3. Analysis of the sinonasal sample mRNA revealed expression of all 10 TLRs in both CRS samples and in control specimens. Expression of the three effector proteins was detected also, with the levels of mRNA for C3 generally greater than SAA and properdin in CRS patients. No significant differences were found in TLR or innate immune protein expression in normal controls. Immunohistochemical analysis of sinonasal mucosal specimens established C3 staining ranging from 20 to 85% of the epithelium present. | The benefits from anthracycline chemotherapy are undermined by potentially life-threatening cardiotoxicity. Transthoracic echocardiography is the most commonly used method for monitoring cardiotoxicity, and centres on the measurement of left ventricular systolic function. The aim of this study was to utilize two-dimensional speckle tracking echocardiography (2DSTE) at baseline and immediately after anthracycline chemotherapy to investigate whether patients with significant changes in systolic function after anthracycline therapy would also develop alterations in diastolic parameters. Fifty-two women with histologically confirmed breast cancer were prospectively recruited. Echocardiograms were performed 1 week prior to and 1 week following chemotherapy (always before adjuvant trastuzumab or thoracic radiotherapy). Conventional Doppler, tissue velocity imaging (TVI), and 2DSTE were used to measure diastolic function. 2DSTE measurements included longitudinal diastolic strain, early (E-Sr), and late (A-Sr) myocardial strain rate. 2DSTE and left ventricular ejection fraction (LVEF) were used to measure longitudinal systolic function. Altered LV diastolic function (including E-Sr) was observed in the entire cohort after chemotherapy, with a differential reduction in participants with a post therapy LVEF <55%. Pre-chemotherapy systolic strain was found to predict reduced E-Sr post therapy (P = 0.04). Univariate predictors of E-Sr were LVEF post therapy (P = 0.049) and systolic strain post-therapy (P = 0.01). In a multivariate analysis, systolic strain after chemotherapy was the strongest independent predictor (P = 0.001). |
Does losartan counteract the hyper-reactivity to angiotensin II and ROCK1 over-activation in aortas isolated from streptozotocin-injected diabetic rats? | In streptozotocin-injected rats (STZ-rats), we previously demonstrated a role for angiotensin II (AT-II) in cardiac remodelling and insulin resistance partially counteracted by in vivo treatment with losartan, an AT-II receptor antagonist.We now aimed to investigate the effect of treating diabetic STZ-rats with losartan on diabetes vascular response to vasoconstrictors. Male Wistar rats were randomly divided in four groups, two of them were assigned to receive losartan in the drinking water (20 mg/kg/day) until the experiment ending (3 weeks afterward). After 1 week, two groups, one of which receiving losartan, were injected in the tail vein with citrate buffer (normoglycemic, N and normoglycemic, losartan-treated, NL). The remaining received a single injection of streptozotocin (50 mg/kg in citrate i.v.) thus becoming diabetic (D) and diabetic losartan-treated (DL). Plasma glycaemia and blood pressure were measured in all animals before the sacrifice (15 days after diabetes induction).In aortic strips isolated from N, NL, D and DL rats we evaluated i) the isometric concentration-dependent contractile response to phenylephrine (Phe) and to AT-II; ii) the RhoA-kinase (ROCK1) activity and expression by enzyme-immunoassay and Western blot respectively. The concentration-dependent contractile effect of Phe was similar in aortas from all groups, whereas at all concentrations tested, AT-II contraction efficacy was 2 and half and 1 and half times higher in D and DL respectively in comparison with N and NL. AT-II contracture was similarly reduced in all groups by AT-II receptor antagonists, irbesartan or irbesartan plus PD123319. HA-1077 (10 microM), an inhibitor of ROCK1 activity, reduced AT-II efficacy (Deltamg/mg tissue w.w.) by -3.5 +/- 1.0, -4.6 +/- 1.9, -22.1 +/- 2.2 and -11.4 +/- 1.3 in N, NL, D and DL respectively). ROCK1 activity and expression were higher in D than in N/NL and DL aortas. | Patients with MHI and a positive head computed tomography (CT) scan frequently have a routine repeat head CT (RRHCT) to identify possible evolution of the head injury requiring intervention. RRHCT is ordered based on the premise that significant injury progression may take place in the absence of clinical deterioration. In a Level I urban trauma center with a policy of RRHCT, we reviewed the records of 692 consecutive trauma patients with Glasgow Coma Scale scores of 13-15 and a head CT (October 2004 through October 2005). The need for medical or surgical neurologic intervention after RRHCT was recorded. Patients with a worse and unchanged RRHCT were compared, and independent predictors of a worse RRHCT were identified by stepwise logistic regression. There were 179 patients with MHI and RRHCT ordered. Of them, 37 (21%) showed signs of injury evolution on RRHCT and 7 (4%) required intervention. All 7 had clinical deterioration preceding RRHCT. In no patient without clinical deterioration did RRHCT prompt a change in management. A Glasgow Coma Scale score less than 15 (13 or 14), age higher than 65 years, multiple traumatic lesions found on first head CT, and interval shorter than 90 minutes from arrival to first head CT predicted independently a worse RRHCT. |
Are high Atopobium vaginae and Gardnerella vaginalis vaginal loads associated with preterm birth? | Bacterial vaginosis is a risk factor for preterm birth. The various conventional methods for its diagnosis are laborious and not easily reproducible. Molecular quantification methods have been reported recently, but the specific risk factors they might identify remain unclear. A prospective multicenter national study included pregnant women at risk of preterm birth. A quantitative molecular tool using a specific real-time polymerase chain reaction assay and serial dilutions of a plasmid suspension quantified Atopobium vaginae, Gardnerella vaginalis, lactobacilli, Mycoplasma hominis, and the human albumin gene (for quality control). In 813 pregnancies, high vaginal loads of either or both of A. vaginae and G. vaginalis were associated with preterm birth (hazard ratio [HR], 3.9; 95% confidence interval {CI}, 1.1-14.1; P = .031). A high vaginal load of A. vaginae was significantly associated with shortened time to delivery and therefore pregnancy length. These times were, respectively, 152.2 and 188.2 days (HR, 5.6; 95% CI, 1.5-21.3; P < .001) before 22 weeks, 149.0 and 183.2 days (HR, 2.8; 95% CI, 1.1-8.2; P = .048) before 28 weeks, and 132.6 and 170.4 days (HR, 2.2; 95% CI, 1.1-4.6; P = .033) before 32 weeks. After multivariate analysis, A. vaginae levels ≥10(8) copies/mL remained significantly associated with delivery before 22 weeks of gestation (adjusted HR, 4.7; 95% CI, .2-17.6; P = .014). | We describe and report our results using endoscopic vein harvest (EVH) for lower extremity arterial bypass procedures, following the implementation of technical modifications specific to patients undergoing limb salvage procedures. We underwent training in EVH, followed by implementation of the technique in patients requiring limb salvage for lower extremity ischemia and aneurysms. After technical modifications in the technique were developed for limb salvage, we reviewed our experience in all patients who underwent minimally invasive distal bypass with EVH. Technical modifications include limited arterial dissection before vein harvest, the use of proximal and distal leg incisions for both exposure of arterial vessels and saphenous vein harvest, improved hemostasis techniques in the vein graft tunnel, avoidance of compression wraps to the ipsilateral harvest tunnel, complete removal of the vein with either reversed or nonreversed graft placement, and use of the endoscopic tunnel for conduit placement. Thirteen patients (14 limbs) have undergone minimally invasive distal bypass since technical modifications were implemented. Indications for EVH were rest pain (n = 12; 85.7%) and tissue loss (n = 8; 57.1%). Veins harvested were the ipsilateral great saphenous vein (n = 10; 71.4%), contralateral great saphenous vein (n = 2; 14.3%), and short saphenous vein (n = 2; 14.3%). No venous injuries occurred during endoscopic harvest, and all were used for bypass. Thirty-day primary and primary assisted patency rates were 85.7% and 92.9%, respectively. The limb salvage rate was 100%. Two patients developed postoperative hematomas, one early and one late, as a result of anticoagulation for cardiac comorbidities. Both patients required reoperation for successful re-establishment of patency. There were no perioperative deaths and no postoperative wound infections or complications. Two patients required a later prosthetic bypass, and two required a vein graft angioplasty. Complete wound healing was achieved in 75% of patients with preoperative tissue loss. |
Does feeding an elemental diet vs a milk-based formula decrease intestinal mucosal growth in infant pigs? | We previously showed that the level of enteral nutrient intake determines the rate of intestinal growth in piglets. Our objective was to determine whether providing enteral nutrition in the form of elemental nutrients (glucose, amino acids, lipid [ED]) rather than cow's milk formula (lactose, protein, lipid [FORM]) reduces small intestinal growth and lactase activity. Three-week-old piglets were fed either ED (n = 7) intragastrically or FORM (n = 6) orally for 6 days. Intestinal protein and DNA masses, villus height, and crypt depth were not different in ED and FORM pigs. Crypt cell proliferation, measured by in vivo bromodeoxyuridine labeling, was significantly (p < .05) higher (+37%) in ED than in FORM pigs. Rates of mucosal protein synthesis (%/d), measured by in vivo 2H-leucine incorporation, were higher (p < .05) in ED than FORM (147 vs 89) pigs. Circulating concentrations (pmol/L) of the intestinotrophic peptide, glucagon-like peptide-2 (GLP-2), were also higher (p < .05) in ED than in FORM (148 vs 87) pigs. The mean lactase-specific activity (micromol/min/g) in proximal and distal segments was higher (p < .05) in FORM than in ED (124 vs 58) pigs. | In patients with stroke, gradient-echo MRI commonly detects microbleeds, indicating small artery disease with increased risk of macroscopic intracranial bleeding. Antithrombotic treatments are frequently prescribed after TIA and stroke, but there have been no previous studies of microbleeds in TIA. Because microbleeds may predict the hemorrhagic risk of antithrombotic treatments, we studied the prevalence of microbleeds, risk factors, and pathophysiologic mechanisms in patients with ischemic stroke and TIA. One hundred twenty-nine consecutive patients with ischemic stroke or TIA were studied with MRI including T2, fluid-attenuated inversion recovery, and gradient-echo MRI sequences. Blinded observers counted microbleeds and graded white matter T2 hyperintensities throughout the brain. TIA patients with previous ischemic stroke were excluded. Sixty-seven percent of patients had ischemic stroke; 33% had TIA. Microbleeds were found in 23% of ischemic stroke patients but only 2% of TIA patients (p < 0.001). There were no significant differences in conventional risk factors or the severity of white matter disease on T2 MRI between stroke and TIA patients. Patients with microbleeds were more often hypertensive (81 vs 59%; p = 0.04) and had more severe MRI white matter disease on T2 MRI (p = 0.003). |
Does oxytocin modulate nitric oxide generation by human fetal membranes at term pregnancy? | Nitric oxide (NO), an important mediator of the inflammatory response, is involved in several reproductive processes including pregnancy and labor. Uterus, placenta and fetal membranes are significant sources of NO. Presently, there is no information on factors regulating NO production by fetal membranes. Human fetal membranes at term gestation were cultured for 24 hr in the presence of oxytocin. The concentrations of NO metabolites nitrites in culture medium were determined by the Griess reaction. The presence of inducible nitric oxide synthase (iNOS) was determined by reverse transcriptase-polymerase chain reaction and Western blot. Oxytocin increased nitrite release by fetal membranes. Messenger ribonucleic acid iNOS expression was also enhanced by oxytocin. These effects were more marked in tissues obtained after labor than before labor. | Hepatocholangiocarcinoma (HCC-CC) is a rare primary liver cancer. Its long-term prognosis is still not well-defined. Results from the Eastern and Western literature have been conflicting and no conclusions can be drawn. The aim of the present study was to review the long-term outcome of curative hepatectomy for HCC-CC. Prospectively collected data from December 1991 to 2006 recording patients with primary liver cancer receiving curative hepatectomy were reviewed. Twenty-five patients, 16 men and 9 women with a median age of 48 years, all ethnic Chinese, had HCC-CC. Their long-term outcome of resection was analyzed and compared to that of patients with cholangiocarcinoma (CC) or hepatocellular carcinoma (HCC). The HCC-CC patients had a median tumor size of 7.5 cm. Five of them developed postoperative complications. The median follow-up period was 25 months. All of the patients developed recurrence. The median overall survival was 25.2 months. The HCC-CC and CC groups had significantly worse overall survival than the HCC group (HCC versus HCC-CC, p = 0.012; HCC versus CC, p = 0.001) whereas between them there was no significant difference (p = 0.822). As for disease-free survival, there was no significant difference between the three groups; the median disease-free survival for HCC-CC patients was 13.5 months; that for CC patients, 16.1 months; and that for HCC patients, 19.0 months. All HCC-CC patients died within 120 months of primary surgery. |
Do male pheromone protein components activate female vomeronasal neurons in the salamander Plethodon shermani? | The mental gland pheromone of male Plethodon salamanders contains two main protein components: a 22 kDa protein named Plethodon Receptivity Factor (PRF) and a 7 kDa protein named Plethodon Modulating Factor (PMF), respectively. Each protein component individually has opposing effects on female courtship behavior, with PRF shortening and PMF lengthening courtship. In this study, we test the hypothesis that PRF or PMF individually activate vomeronasal neurons. The agmatine-uptake technique was used to visualize chemosensory neurons that were activated by each protein component individually. Vomeronasal neurons exposed to agmatine in saline did not demonstrate significant labeling. However, a population of vomeronasal neurons was labeled following exposure to either PRF or PMF. When expressed as a percent of control level labeled cells, PRF labeled more neurons than did PMF. These percentages for PRF and PMF, added together, parallel the percentage of labeled vomeronasal neurons when females are exposed to the whole pheromone. | Administration of infliximab to patients with acute severe ulcerative colitis (ASUC) (rescue therapy) can reduce the rate of early colectomy (within 12 months), but long-term rates of colectomy are the same as those of the pre-biologic era for these patients. The half-life of infliximab is shorter in patients with ASUC than in patients with non-severe UC, so more frequent dosing might be required to produce a therapeutic effect. We performed a retrospective analysis of 50 hospitalized patients who received infliximab for steroid-refractory ASUC at a single academic center from September 2005 through 2013. In 2011 an accelerated dosing strategy for infliximab was introduced; we compared outcomes of standard and accelerated dosing regimens. One group of patients (n = 35) were placed on a standard dosing regimen for infliximab and then given the drug at 0, 2, and 6 weeks and then every 8 weeks thereafter. A second group (n = 15) were placed on an accelerated regimen and received 3 induction doses of infliximab within a median period of 24 days. Rates of colectomy were compared between the groups during induction and follow-up periods. There were no differences between groups in median baseline levels of C-reactive protein, albumin, or hemoglobin. The rate of colectomy during induction therapy was significantly lower with the accelerated regimen (6.7%, 1 of 15) than with the standard regimen (40%, 14 of 35) (Fisher exact test, P = .039). The standard regimen was associated with shorter time to colectomy (log-rank test, P = .042). Among patients who completed induction therapy, subsequent need for colectomy was similar between the groups during the follow-up period. Multivariate analysis showed that factors independently associated with successful induction therapy were level of albumin (g/L) when the treatment began (P = .003) and the accelerated dosing regimen (P = .03). |
Does miR-219-5p modulate cell growth of papillary thyroid carcinoma by targeting estrogen receptor α? | Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. It has been demonstrated that micro-RNAs (miRNAs) are involved in the development of PTC. The miRNA-chromatin immunoprecipitation microarray assay revealed down-regulation of miR-219-5p; however, the effect of miR-219-5p on PTC cell growth remains unknown. This result implied the critical role of miR-219-5p in the development of PTC. We investigated the association between miR-219-5p and PTC development. Expression of miR-219-5p was monitored in 30 PTC tissue specimens and compared with that in 30 normal thyroid tissue specimens. The effect of miR-219-5p on PTC development was studied by cell proliferation, migration, and apoptosis assays. The underlying mechanism was clarified by a reporter assay and rescue experiment. The current study confirmed that miR-219-5p expression was inhibited in PTC tissue samples. There were statistically significant differences in the expression of miR-219-5p with regard to sex, tumor size, and lymph node metastasis in patients with PTC. Forced expression of miR-219-5p suppressed PTC cell proliferation and migration and promoted apoptosis. Further study showed that estrogen receptor (ER) α was the direct target of miR-219-5p and mediated the effect of miR-219-5p on PTC occurrence. Expression of miR-219-5p was inversely correlated with that of ERα. Importantly, ERα overexpression in PTC cells rescued the inhibitory effect of miR-219-5p on PTC cell proliferation and migration. Thus, our results indicated that miR-219-5p played a critical role in PTC growth by inhibiting ERα. | The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children. A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12-47 months in general good health.Children were randomised in a 1ratio1 fashion to receive either FMP1/AS02 (50 microg) or Rabipur(R) rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature >/=37.5 degrees C with asexual parasitaemia of >/=50,000 parasites/microL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations. 374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-1(42) antibody concentrations increased from1.3 microg/mL to 27.3 microg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: -26% to +28%; p-value = 0.7). |
Is failure to recover somatotropic axis function associated with mortality from pediatric sepsis-induced multiple organ dysfunction syndrome? | To describe the associations between mediators of the somatotropic axis and mortality from sepsis-induced multiple organ dysfunction syndrome in children; and to examine the relationship between immune function and the somatotropic axis in this setting. Retrospective study using banked plasma. Single mixed surgical/medical intensive care unit at a quaternary level children's hospital. A total of 24 children (n = 17 survivors, 7 nonsurvivors) with severe sepsis or septic shock and dysfunction of >or=2 organ systems. None. Plasma samples were available from days 3, 7, and 14 of multiple organ dysfunction syndrome. Insulin-like growth factor 1 and insulin-like growth factor binding protein 3 levels were measured by chemiluminescence. Immune function was quantified using previously determined ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha production levels and absolute lymphocyte counts. Insulin-like growth factor 1 levels were lower in nonsurvivors compared with survivors (p = .004) with the greatest difference seen on day 14 (25 [25-69] ng/mL vs. 314 [123-582] ng/mL; p = .038). insulin-like growth factor binding protein 3 levels were reduced similarly over time (p = .019). A drop in plasma insulin-like growth factor binding protein 3 level at any time after day 3 of illness resulted in a 35-fold increased odds of death (odds ratio, 35 [1.6-750]; p = .004). Both ex vivo tumor necrosis factor-alpha and absolute lymphocyte count were reduced in nonsurvivors compared with survivors, but these differences occurred earlier (days 3 and 7). | The risk of breast cancer in carriers of BRCA1 and BRCA2 mutations is influenced by factors other than the genetic mutation itself. Modifying factors include a woman's reproductive history and family history of cancer. Risk factors are more likely to be present in women with breast cancer than in women without breast cancer, and therefore the risk of cancer in the two breasts should not be independent. It is not clear to what extent modifying factors influence the risk of a first primary or a contralateral breast cancer in BRCA carriers. We conducted a matched case-control study of breast cancer among 3920 BRCA1 or BRCA2 mutation carriers. We asked whether a past history of breast cancer in the contralateral breast was a risk factor for breast cancer. After adjustment for age, country of residence, and cancer treatment, a previous cancer of the right breast was found to be a significant risk factor for cancer of the left breast among BRCA1 or BRCA2 carriers (relative risk: 2.1; 95% confidence interval: 1.4 to 3.0; p < 0.0001). |
Is sinonasal epithelial cell expression of toll-like receptor 9 decreased in chronic rhinosinusitis with polyps? | Innate immune recognition of pathogens by sinonasal epithelial cells may play an important role in the pathogenesis of chronic rhinosinusitis (CRS). Previous studies have indicated that toll-like receptor (TLR) mRNA is present in sinonasal mucosa, and levels of TLR9 expression are decreased in recalcitrant CRS with nasal polyps (CRSwNP). However, the cellular source and function of TLR9 in the sinonasal epithelium is not known. In this study, primary epithelial cell cultures were analyzed from control subjects and CRSwNP patients to determine the presence and function of TLR9 protein. Primary epithelial cell cultures were established from 5 controls and 10 CRSwNP patients undergoing sinus surgery. Flow cytometry was used to confirm purity of epithelial cells and to assess expression of TLR9 protein. Epithelial cells were stimulated with TLR9 agonist, and mRNA was analyzed by real-time PCR for expression of human beta-defensin (HBD) 2 and interleukin (IL)-8. Flow cytometry showed TLR9 protein in 100% of epithelial cells from controls and CRSwNP patients. The level of expression was 50% lower in CRS patients than in controls. Stimulation of epithelial cells with TLR9 agonist produced a 1.5- to 9-fold increase in HBD-2 and IL-8 mRNA expression. | GH replacement for 1-5 yr improves, but does not fully normalize, muscle strength. OBJECTIVE, DESIGN, AND PATIENTS: In this single-center, open-labeled, prospective study, the effects of 10 yr of GH replacement on muscle strength and neuromuscular function were followed in 109 consecutive adults (61 men; mean age 50.0 yr; range 22-74 yr) with adult-onset GH deficiency. The mean initial GH dose of 0.88 mg/d was gradually lowered to 0.47 mg/d. The mean IGF-I sd score increased from -1.54 at baseline to 1.12 at study end. GH replacement induced a sustained increase in lean mass and isometric knee flexor strength (60 degrees). In most other measures of upper leg and handgrip strength, there were transient increases during the first half of the study (0-5 yr), whereas during the second half (5-10 yr), the absolute values of muscle strength decreased and returned to or even below the baseline values. However, after correction for age and gender using observed/predicted value ratios, there were sustained and, until 7 yr, even progressive increases in the measures of muscle strength. At study end, knee flexor strength had increased to 104-110% of predicted, knee extensor strength to 93-108%, and handgrip strength to 88-93%. Measurements of neuromuscular function showed reduced voluntary motor unit activation after 10 yr. |
Do polymeric nanoparticles containing taxanes enhance chemoradiotherapeutic efficacy in non-small cell lung cancer? | To reduce the side effects and improve the efficacy of chemoradiation therapy, taxanes were incorporated into polymeric nanoparticles (PNP), and their synergic effect on radiation therapy in non-small cell lung cancer was evaluated. The properties of PNP-taxanes were characterized by transmission electron microscopy and dynamic light scattering. The chemoradiotherapeutic efficacy of PNP-taxanes was determined by clonogenic assay, cellular morphology, and flow cytometry in A549 cells. In mice bearing A549-derived tumors, the tumor growth delay was examined after the treatment of PNP-taxanes and/or ionizing radiation (IR). The PNP-taxanes were found to be approximately 45 nm in average diameter and to have high solubility in water. They showed the properties of active internalization into cells and preserved the anticancer effect of free taxanes. The survival fraction of A549 cells by clonogenic assay was significantly reduced in the group receiving combined treatment of PNP-taxanes and IR. In addition, in vivo radiotherapeutic efficacy was markedly enhanced by the intravenous injection of PNP-taxanes into the xenograft mice. | Hyperinsulinemia has been considered to be a potent cardiovascular risk factor. The present investigation examines persistently elevated fasting insulin levels from childhood to young adulthood and its influence on cardiovascular risk factors. A longitudinal cohort was constructed from two cross-sectional surveys in a community-based population over an 8-year period: 1606 individuals (39% were black) aged 5 to 23 years participated in the first survey. Stability in rankings (persistence) of insulin levels was shown by the presence of significant correlations between year 1 and year 8 values (r=.23 to .36, P<.0001), with a greater magnitude in older subjects. Compared with subjects with levels of insulin consistently in the lowest quartile, those with levels always in the highest quartile showed higher (P<.001) levels of body mass index (+9 kg/m2), triglycerides (+58 mg/dL), LDL cholesterol (+11 mg/dL), VLDL cholesterol (+8 mg/dL), glucose (+9 mg/dL), systolic blood pressure (+7 mm Hg), and diastolic blood pressure (+3 mm Hg); lower (P<.001) levels of HDL cholesterol (-4 mg/dL): and higher (P<.05) prevalence of parental history of diabetes (3.3-fold) and hypertension (1.2-fold). There were 739 young adults aged 20 to 31 years at follow-up. As adults, individuals with consistently elevated insulin versus those with consistently decreased insulin had increased (P<.05) prevalence of obesity (36-fold), hypertension (2.5-fold), and dyslipidemia (3-fold), which was attributed to both baseline insulin and change of insulin from baseline to follow-up. In addition, clustering of these risk factors was stronger (P<.05) in adults with persistent insulin elevation. |
Is pharmacogenetic effect of the UGT polymorphisms on mycophenolate modified by calcineurin inhibitors? | Mycophenolic acid (MPA) is glucuronidated primarily by uridine diphosphate glucuronosyltransferase enzymes (UGT) 1A9 and 1A8. These enzymes are highly polymorphic resulting in low activity and high expression phenotypes. We hypothesized that polymorphisms of UGT1A9 and 1A8 may alter MPA pharmacokinetics in kidney transplantation. One hundred seventeen kidney (n = 93), pancreas (n = 11), or simultaneous kidney and pancreas (SPK) (n = 13) transplant recipients were studied for the effect of UGT1A9 and UGT1A8 polymorphisms on MPA dose-corrected trough concentrations. Individuals were genotyped for UGT1A8 and UGT1A9 polymorphisms (1A8*2, 1A8*3, 1A9*3, 1A9-275 and 1A9-2152). Linear regression was used to estimate the effect of UGT polymorphisms on the individual's mean MPA dose-corrected trough concentration with and without stratification by calcineurin inhibitor. A multiple linear regression analysis was performed to assess the dependence between the average MPA dose-corrected trough concentration and age, gender, UGT genotype (1A8*2, 1A8*3, 1A9*3, 1A9-275, 1A9-2152), serum albumin, hemoglobin (Hgb), hematocrit (HCT), liver transaminases (AST, ALT), serum creatinine, and bilirubin. Mycophenolic acid dose-corrected trough concentrations were 60% higher in subjects heterozygous or homozygous for UGT1A8*2 than in those with the wild type (p = 0.02); however, this effect was dependent on concomitant calcineurin inhibitor. When subjects were stratified by calcineurin inhibitor status, the UGT1A8*2 effect was only apparent in the tacrolimus group (p < 0.01). Mycophenolic acid dose-corrected trough concentrations were 70% lower in carriers of the UGT1A9 -275T>A/-2152 C>T polymorphism who received cyclosporine (p < 0.01). There was no effect of the UGT1A9 -275T>A/-2152C>T polymorphism in the tacrolimus group. | Clinical trials of adjuvant radiotherapy after mastectomy have largely excluded women aged 70 years or over, even though they comprise 30% of the breast cancer population. This study examined outcomes in elderly women with high-risk breast cancer treated with or without postmastectomy radiotherapy (PMRT). Data were analysed for 233 women aged 70 years or over with high-risk breast cancer (tumours > 5 cm or > or = 4 positive axillary nodes) treated with mastectomy and referred to the British Columbia Cancer Agency from 1989 to 1997. Tumour and treatment characteristics were compared between two cohorts: women treated with PMRT (n = 147) vs women treated without PMRT (n = 86). Univariate and multivariate analyses of 10-year Kaplan-Meier locoregional recurrence (LRR), distant recurrence, breast cancer-specific survival and overall survival were carried out. Median follow-up time was 5.5 years. The distribution of tumour sizes was similar in the two groups. Compared with women treated without PMRT, higher proportions of women who underwent PMRT had four or more positive nodes (83% vs 67%, P = 0.01) and positive surgical margins (14% vs 4%, P = 0.02). Systemic therapy, used in 94% of women, was comparable in the two cohorts (P = 0.63). Elderly women treated with PMRT had significantly lower LRR compared with women treated without PMRT (16% vs 28%, P = 0.03). No differences in distant recurrence, breast cancer-specific survival or overall survival were observed in the two treatment groups (all P > 0.05). On multivariate analysis, the omission of PMRT and the presence of high-grade histology were significant predictors of LRR, whereas an increasing number of positive nodes was significantly associated with distant recurrence and overall survival. |
Does supplementary oxygen in healthy subjects and those with COPD increase oxidative stress and airway inflammation? | Hyperoxia increases oxidative stress through the generation of reactive oxygen species and may therefore enhance inflammation in the lungs. The aim of this study was to investigate whether short term supplementary oxygen (28%) increases oxidative stress and inflammation in the airways by measuring 8-isoprostane and interleukin 6 (IL-6) concentrations in exhaled breath condensate. Twenty three healthy subjects (12 men, mean (SD) age 48 (7) years) and 23 patients with chronic obstructive pulmonary disease (COPD; 15 men, mean (SD) age 56 (5) years) were studied. 8-isoprostane and IL-6 concentrations were measured by immunoassay. Increased concentrations of 8-isoprostane and IL-6 were found in all subjects after breathing 28% oxygen for 1 hour. In healthy subjects the concentrations of 8-isoprostane and IL-6 were 10.9 (2.9) pg/ml and 4.9 (0.8) pg/ml, respectively, compared with baseline concentrations of 6.1 (1.3) pg/ml and 2.9 (0.6) pg/ml, and in patients with COPD the concentrations were 27.9 (3.1) pg/ml and 8.3 (1.2) pg/ml), respectively, compared with baseline concentrations of 18.9 (3.6) pg/ml and 6.3 (0.6) pg/ml. By contrast, breathing air through the same face mask for 1 hour had no significant effects on 8-isoprostane or IL-6 concentrations in normal subjects or those with COPD. | Extranodal tumor deposits are involved in TNM classification. However, it is uncertain whether a tumor deposit is a regular lymph node metastasis, and its prognostic significance in patients with stage II or III colorectal cancer remains to be established. This study aimed to determine the prognostic significance of tumor deposits for stage II and III colorectal cancer. This study is a retrospective review of clinicopathological data. This study was conducted at a tertiary care hospital/referral center in Japan. We reviewed the clinical course of 171 stage II and 173 stage III consecutive patients between January 1999 and December 2006. We examined the clinicopathological features of colorectal cancers with tumor deposits and calculated overall survival and recurrence-free survival of the patients according to the status of tumor deposits. The primary outcome was the impact of tumor deposits on patient survival. Thirty-five (10.2%) patients with colorectal cancers had tumor deposits in the pericolic and/or mesocolic region. Survival rates among the patients with tumor deposits were significantly lower than those without (5-year overall survival: 58.4% vs 81.0%, p < 0.0001; 5-year recurrence-free survival: 47.1% vs 73.4%, p < 0.0001). Tumor deposit was an independent prognostic factor for patients with colorectal cancer in multivariate analysis (overall survival: HR, 2.30; 95% CI, 1.26-4.04; p = 0.04; recurrence-free survival: HR, 2.42; 95% CI, 1.04-4.90; p = 0.04). Tumor deposit was an independent prognostic factor in N0 and N1 colorectal cancer, whereas N2 cancer had poor survival outcome regardless of tumor deposit. |
Does cyclic AMP activate B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys? | The proliferation of mural epithelial cells is a major cause of progressive cyst enlargement in autosomal-dominant polycystic kidney disease (ADPKD). Adenosine 3', 5' cyclic monophosphate (cAMP) stimulates the proliferation of cells from ADPKD cysts, but not cells from normal human kidney cortex (HKC), through the activation of protein kinase A (PKA), mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK/MAPK). In the current study, we examined the signaling pathway between PKA and MEK in ADPKD and HKC cells. Primary cultures of human ADPKD and HKC cells were prepared from nephrectomy specimens. We determined the effects of cAMP and epidermal growth factor (EGF) on the activation of ERK, B-Raf and Raf-1 in ADPKD and HKC cells by immune kinase assay and Western blot. 8-Br-cAMP increased phosphorylated ERK (2.7- +/- 0.6-fold, N = 7), and B-Raf kinase activity (3.6- +/- 1.1-fold, N = 5) in cells from ADPKD kidneys; levels of phosphorylated Raf-1 were not changed. Inhibition of PKA by H89 strikingly decreased cAMP-stimulated phosphorylation of ERK and B-Raf, and MAPK inhibition by PD98059 blocked the effect of the nucleotide to activate ERK. By contrast, in HKC cells 8-Br-cAMP did not activate B-Raf and ERK. EGF stimulated the phosphorylation of ERK and Raf-1 in both ADPKD and HKC cells, but had no effect on B-Raf. 8-Br-cAMP and EGF conjointly increased ERK activation above that of either agonist alone in ADPKD cells, and this combined effect was abolished by PD98059, indicating that ERK was activated by EGF- and cAMP-responsive cascades that converge at MAPK. | Primary percutaneous coronary intervention (PCI) is more effective than fibrinolytic therapy for ST-segment elevation myocardial infarction (STEMI), but initial treatment delay to intervention is the main limitation of this strategy. Upstream use of high-dose tirofiban could reduce myocardial infarct size, using analysis of contrast-enhanced magnetic resonance imaging (CE-MRI). Patients with STEMI within 12 hours after symptom onset were randomized to a facilitated PCI group (n = 19) or to a primary PCI group (n = 20). The primary endpoint was myocardial infarct size evaluated by the volume of delayed hyperenhancement on CE-MRI at 1 month after index procedure. The baseline clinical characteristics were not significantly different between the 2 groups. Although the incidence of pre-PCI thrombolysis in myocardial infarction (TIMI) flow grade 2 to 3 was significantly higher in the facilitated PCI group than in the primary PCI group (47.4% vs 15.0%, P = 0.03), the achievement of myocardial blush grade 2 to 3 or ST-segment resolution at 30 minutes after procedure was not significantly different between the facilitated PCI and the primary PCI group (36.8% vs 40%, P = 0.84 and 31.6% vs 20%, P = 0.41, respectively). Infarct size on CE-MRI was similar in the facilitated PCI group and the conventional primary PCI group (22.1% +/- 11.7% vs 25.2% +/- 13.2%, P = 0.44). At 6 months, the left ventricular ejection fraction (LVEF) on echocardiography was 52.6% +/- 10.4% in the facilitated PCI group and 50.9% +/- 9.8% in the primary PCI group (P = 0.68). |
Does induced-hyperglycemia attenuate erythromycin-induced acceleration of hypertonic liquid-phase gastric emptying in type-I diabetic patients? | Erythromycin has been found to be a gastrointestinal prokinetic agent of hypertonic liquids, while acute hyperglycemia has been associated with delayed gastric emptying in diabetic patients. To investigate whether hyperglycemia, per se, reduces gastric motility during erythromycin-induced acceleration on gastric emptying of hypertonic liquids in diabetic patients. In 12 type-I diabetic patients following a hypertonic radiolabeled liquid meal, gastric emptying was measured scintigraphically during normoglycemia (5-8.9 mmol/l glucose) or hyperglycemia induced by intravenous (16-19 mmol/l) glucose infusion. The tests were performed on 4 separate days in random order after administering either placebo or 200 mg i.v. erythromycin. In the hyperglycemic state compared to normoglycemia, the gastric emptying of the hypertonic liquid was reduced after placebo or erythromycin administration. The lag-phase duration (17.8+/-5.5 and 7.8+/-4.5 vs. 10.8+/-3.4 and 3.7+/-2.5 min, respectively, p<0.001), the overall gastric emptying time of the half meal (52.8+/-13 and 24.9+/-5.5 vs. 42.5+/-10.5 min and 16.6+/-6 min, respectively, p<0.001) and the retained percentage of liquid meal in the stomach at 60 and 100 min postprandially (p<0.001) were significantly increased. | Anthropogenic activities cause metal pollution worldwide. Plants can absorb and accumulate these metals through their root system, inducing stress as a result of excess metal concentrations inside the plant. Ethylene is a regulator of multiple plant processes, and is affected by many biotic and abiotic stresses. Increased ethylene levels have been observed after exposure to excess metals but it remains unclear how the increased ethylene levels are achieved at the molecular level. In this study, the effects of cadmium (Cd) exposure on the production of ethylene and its precursor 1-aminocyclopropane-1-carboxylic acid (ACC), and on the expression of the ACC Synthase (ACS) and ACC Oxidase (ACO) multigene families were investigated in Arabidopsis thaliana. Increased ethylene release after Cd exposure was directly measurable in a system using rockwool-cultivated plants; enhanced levels of the ethylene precursor ACC together with higher mRNA levels of ethylene responsive genes: ACO2, ETR2 and ERF1 also indicated increased ethylene production in hydroponic culture. Regarding underlying mechanisms, it was found that the transcript levels of ACO2 and ACO4, the most abundantly expressed members of the ACO multigene family, were increased upon Cd exposure. ACC synthesis is the rate-limiting step in ethylene biosynthesis, and transcript levels of both ACS2 and ACS6 showed the highest increase and became the most abundant isoforms after Cd exposure, suggesting their importance in the Cd-induced increase of ethylene production. |
Do dexamethasone and GLP-2 given to lactating rat dams influence glucose uptake in suckling and postweanling offspring? | Glucagon-like peptide-2 (GLP-2) enhances intestinal absorption in adult animals. Glucocorticosteroids accelerate the ontogeny of the intestine and increase sugar uptake in adult animals. Modifying the maternal diet during lactation alters nutrient uptake in the offspring. The authors hypothesized that GLP-2 and dexamethasone, when administrated to lactating rat dams, enhance sugar uptake in the suckling and postweanling offspring. Rat dams were treated during lactation with GLP-2 (0.1 microg/g/day subcutaneously [SC], twice daily), dexamethasone (0.128 microg/g/day SC, once daily), GLP-2 + dexamethasone (same doses), or placebo. The suckling offspring were sacrificed at 19-21 days of age, and the postweanlings were sacrificed 4 weeks later. Intestinal glucose and fructose uptake was assessed using an in vitro ring technique. GLP-2 and dexamethasone resulted in lower body weights, and dexamethasone caused intestinal atrophy in sucklings. The jejunal atrophy in sucklings given dexamethasone was prevented by GLP-2 + dexamethasone. In sucklings, the maximal transport rate and the Michaelis affinity constant for ileal glucose uptake were both increased by GLP-2 and GLP-2 + dexamethasone. In contrast, in postweanlings, the maximal transport rate for jejunal glucose uptake was reduced by dexamethasone and GLP-2, as was ileal fructose uptake. | Endothelial progenitor cells (EPCs) that may repair vascular injury are reduced in patients with coronary artery disease (CAD). We reasoned that EPC number and function may be increased by granulocyte colony-stimulating factor (G-CSF) used to mobilize hematopoietic progenitor cells in healthy donors. Sixteen CAD patients had reduced CD34(+)/CD133(+) (0.0224+/-0.0063% versus 0.121+/-0.038% mononuclear cells [MNCs], P<0.01) and CD133(+)/VEGFR-2(+) cells, consistent with EPC phenotype (0.00033+/-0.00015% versus 0.0017+/-0.0006% MNCs, P<0.01), compared with 7 healthy controls. Patients also had fewer clusters of cells in culture, with out-growth consistent with mature endothelial phenotype (2+/-1/well) compared with 16 healthy subjects at high risk (13+/-4/well, P<0.05) or 14 at low risk (22+/-3/well, P<0.001) for CAD. G-CSF 10 microg/kg per day for 5 days increased CD34(+)/CD133(+) cells from 0.5+/-0.2/microL to 59.5+/-10.6/microL and CD133(+)/ VEGFR-2(+) cells from 0.007+/-0.004/microL to 1.9+/-0.6/microL (both P<0.001). Also increased were CD133(+) cells that coexpressed the homing receptor CXCR4 (30.4+/-8.3/microL, P<0.05). Endothelial cell-forming clusters in 10 patients increased to 27+/-9/well after treatment (P<0.05), with a decline to 9+/-4/well at 2 weeks (P=0.06). |
Does clostridium difficile Infection be Associated With Lower Inpatient Mortality When Managed by GI Surgeons? | Patients admitted with Clostridium difficile infection are managed in a variety of settings. If their care is inadequate, these patients can rapidly deteriorate. The purpose of this study was to evaluate whether mortality for patients admitted with C difficile differed between medical and general/colorectal surgery services. This was a retrospective cohort study with multivariable logistic regression used to evaluate the effect of admitting service on in-hospital mortality rates, with propensity score matching used to validate this relationship. The study was conducted at a single, tertiary care center. Inpatients with a positive C difficile stool test within 24 hours of admission to medical or surgical services were identified (2005-2015) using institutional electronic data sources. We measured inpatient mortality rate. Of 1175 patients, 985 (83%) were admitted to medical services, whereas 190 (17%) were admitted by surgeons. Medical patients were older (63.9 vs 58.9 years; p = 0.001) and had a mean of 0.6 additional comorbidities (p < 0.001); cohorts were similar regarding vasopressors, peak white blood cell counts, and rate of intensive care unit admissions. Mortality was lower among surgery patients (2.6% vs 6.8%; p = 0.028), and logistic regression demonstrated lower odds of mortality for this group OR = 0.18 (95% CI, 0.05-0.58)). After propensity score matching for age, comorbidities, and severity of disease, this difference was confirmed (2.6% vs. 9.5%). A higher incidence of total colectomy for surgery patients (14.2% vs 0.4%) was a causal factor in their longer lengths of stay and higher total hospital costs. The time between orders for stool testing and metronidazole therapy was shorter in the surgery group (1.8 vs 3.8 hours; p = 0.002), although this trend was not observed with vancomycin therapy. | DNA replication and transcription are dynamic processes regulating plant development that are dependent on the chromatin accessibility. Proteins belonging to the Agenet/Tudor domain family are known as histone modification "readers" and classified as chromatin remodeling proteins. Histone modifications and chromatin remodeling have profound effects on gene expression as well as on DNA replication, but how these processes are integrated has not been completely elucidated. It is clear that members of the Agenet/Tudor family are important regulators of development playing roles not well known in plants. Bioinformatics and phylogenetic analyses of the Agenet/Tudor Family domain in the plant kingdom were carried out with sequences from available complete genomes databases. 3D structure predictions of Agenet/Tudor domains were calculated by I-TASSER server. Protein interactions were tested in two-hybrid, GST pulldown, semi-in vivo pulldown and Tandem Affinity Purification assays. Gene function was studied in a T-DNA insertion GABI-line. In the present work we analyzed the family of Agenet/Tudor domain proteins in the plant kingdom and we mapped the organization of this family throughout plant evolution. Furthermore, we characterized a member from Arabidopsis thaliana named AIP1 that harbors Agenet/Tudor and DUF724 domains. AIP1 interacts with ABAP1, a plant regulator of DNA replication licensing and gene transcription, with a plant histone modification "reader" (LHP1) and with non modified histones. AIP1 is expressed in reproductive tissues and its down-regulation delays flower development timing. Also, expression of ABAP1 and LHP1 target genes were repressed in flower buds of plants with reduced levels of AIP1. |
Does the parathyroid/pituitary variant of multiple endocrine neoplasia type 1 usually have causes other than p27Kip1 mutations? | One variant of multiple endocrine neoplasia type 1 (MEN1) is defined by sporadic tumors of both the parathyroids and pituitary. The prevalence of identified MEN1 mutations in this variant is lower than in familial MEN1 (7% vs. 90%), suggesting different causes. Recently, one case of this variant had a germline mutation of p27(Kip1)/CDKN1B. The objective was to test p27 in germline DNA from cases with tumors of both the parathyroids and pituitary. Medical record review and sequence analysis in DNA were performed. This study involved an inpatient and outpatient referral program for cases of endocrine tumors. Sixteen index cases had sporadic tumors of two organs, both the parathyroids and the pituitary. There were 18 additional index cases with related features of familial tumors. Five subjects were normal controls. No case had an identified MEN1 mutation. Clinical status of endocrine tumors was tabulated. Sequencing of germline DNA from index cases and control cases for the p27 gene was performed by PCR. Endocrine tumor types and their expressions were measured, as were sequence changes in the p27 gene. Tumor features were documented in index cases and families. One p27 germline single nucleotide change was identified. This predicted a silent substitution of Thr142Thr. Furthermore, there was a normal prevalence of heterozygosity for a common p27 polymorphism, making a large p27 deletion unlikely in all or most of these cases. | To assess the beneficial effects of silver foam dressing on the healing of wounds with ulcers and infection control of burn patients. Eighty-four second-degree burn patients were selected and divided into a study group and a control group (n=42). After disinfection and cleaning, wound beds of the study group were covered with silver-containing soft-silicone foam dressing, and wound surfaces of the control group were wiped with 1% silver sulfadiazine cream (60 g/100 cm(2)). The two groups were checked weekly to observe wound healing progress and adverse reactions of the skin around wounds. Wound secretions were collected and subjected to bacterial culture. Related indices were recorded and quantified. Thirty seven cases of the study group (88.1%) and 36 cases of the control group (85.7%) recovered to normal, and 3 (7.1%) and 2 cases (4.8%) in the two groups failed to recover. The recovery rates of the two groups were similar (P>0.05), but unrecovered patients in the study group had significantly higher proportions of repaired wounds (P<0.05). Wounds of the study group were healed significantly more rapidly than those of the control group (22.3±3.1 vs. 25.1±4.4, P<0.05). The study group had significantly higher proportions of repaired wounds from Day 7 to Day 21 (P<0.05), but the difference became less obvious with extended time to Day 28. The bacterial culture-positive (exceeding 10(5) organisms per gram of tissue) rates of both groups significantly reduced after treatment (Day 7 for the study group and Day 14 for the control group), and the rate of the study group was significantly lower at last (P<0.05). The study and control groups were observed 134 and 149 person-times respectively, with the normal wound-surrounding skin rates of 96.3% (129/134) and 88.6% (132/149) (P>0.05 except for on Day 14). Except for on Day 28, the study group had significantly lower pain scores than those of the control group (P<0.05), especially on Day 7 and Day 14 (P<0.01). From Day 7 to Day 28, the study group was significantly less prone to burning sensation than the control group (P<0.05), but both groups felt anxious during dressing change (P>0.05). Dressing of the study group was changed significantly more easily (P<0.05), but the fixing outcomes were similar (P>0.05). |
Does vitamin D increase serum levels of the soluble receptor for advanced glycation end products in women with PCOS? | Elevation of serum proinflammatory advanced glycation end products (AGEs) is involved in the pathogenesis of polycystic ovary syndrome (PCOS). The soluble receptor for AGEs (sRAGE) acts as a decoy by binding circulating AGEs. Vitamin D supplementation attenuates the deposition of AGEs in the vascular system of diabetic animals and improves some metabolic aspects of vitamin D-deficient women with PCOS. Additionally, serum anti-Mullerian hormone (AMH) is elevated in women with PCOS, reflecting abnormal ovarian folliculogenesis. The objective of the study was to evaluate the effect of 1,25 dihydroxyvitamin D3 (vit D3) supplementation on serum sRAGE and AMH in vitamin D-deficient women with PCOS. DESIGN, SETTINGS, PARTICIPANTS, AND INTERVENTION: Sixty-seven women with (n = 22) or without (control; n = 45) PCOS who were diagnosed with vitamin D deficiency were enrolled. Fifty-one women were replaced with oral vit D3 for 8 weeks (16 with PCOS and 35 controls) and 16 women were not treated (six with PCOS and 10 controls). Serum 25-hydroxyvitamin D (25 OH-D), sRAGE, and AMH concentrations were measured at baseline and after vit D3 supplementation in the treated group and 8 weeks apart in the nontreated group. Changes in serum sRAGE and AMH concentrations after vit D3 replacement were measured. In all participants, there was a negative correlation between body mass index and serum sRAGE levels (r = -0.3, P = .01). In women with PCOS, but not in controls, vit D3 increased serum sRAGE (P = .03) and decreased serum AMH levels (P < .001). The increase in serum sRAGE positively correlated with the increase in serum 25 OH-D after supplementation in women with PCOS (r = 0.6, P = .01). | To evaluate if the preexistant filling state, assessed by right atrial pressure (RAP), pulmonary artery occlusion pressure (PAOP), and right ventricular end-diastolic volume index (EDVI), would define the subsequent hemodynamic effects of increases in airway pressure (Paw). Prospective open clinical study. Postoperative intensive care unit, university hospital. Twenty-two consecutive ventilator-dependent patients with mild to severe acute lung injury with Murray scores (scoring infiltrates on chest radiograph, oxygenation index, lung compliance, and the level of positive end-expiratory pressure) ranging from 0.5 to 3.0 without history of preexisting cardiopulmonary disease. Paw varied during apnea from 0 to 10, 20, and 30 cm H2O using inspiratory hold maneuvers of 15 secs. Cardiac index and right ventricular ejection fraction were measured by the thermodilution technique. We made measurements in triplicate using manual injection of iced saline. Right ventricular volumes were calculated. Increasing Paw induced variable changes in cardiac index among subjects (+6% to -43% change from baseline 0 cm H2O Paw values), which correlated with percentage changes in both stroke index (r2 = .89) and right ventricular EDVI (r2 = .75), whereas heart rate and right ventricular ejection fraction did not change. The change in cardiac index from 0 to 30 cm H2O Paw correlated with baseline values for RAP, PAOP, and right ventricular EDVI (r2 = .68, .43, and .34, respectively, p < 0.01). Increases in RAP correlated with lung compliance if baseline RAP was >10 mm Hg but did not if it was < or =10 mm Hg. Similarly, patients with baseline RAP < or =10 mm Hg had a greater decrease in cardiac index than patients with a RAP >10 mm Hg (for 30 cm H2O Paw: -30% +/- 9% vs. -8% +/- 7%, p < .01). |
Are pectic polysaccharides attacked by hydroxyl radicals in ripening fruit : evidence from a fluorescent fingerprinting method? | Many fruits soften during ripening, which is important commercially and in rendering the fruit attractive to seed-dispersing animals. Cell-wall polysaccharide hydrolases may contribute to softening, but sometimes appear to be absent. An alternative hypothesis is that hydroxyl radicals ((•)OH) non-enzymically cleave wall polysaccharides. We evaluated this hypothesis by using a new fluorescent labelling procedure to 'fingerprint' (•)OH-attacked polysaccharides. We tagged fruit polysaccharides with 2-(isopropylamino)-acridone (pAMAC) groups to detect (a) any mid-chain glycosulose residues formed in vivo during (•)OH action and (b) the conventional reducing termini. The pAMAC-labelled pectins were digested with Driselase, and the products resolved by high-voltage electrophoresis and high-pressure liquid chromatography. Strawberry, pear, mango, banana, apple, avocado, Arbutus unedo, plum and nectarine pectins all yielded several pAMAC-labelled products. GalA-pAMAC (monomeric galacturonate, labelled with pAMAC at carbon-1) was produced in all species, usually increasing during fruit softening. The six true fruits also gave pAMAC·UA-GalA disaccharides (where pAMAC·UA is an unspecified uronate, labelled at a position other than carbon-1), with yields increasing during softening. Among false fruits, apple and strawberry gave little pAMAC·UA-GalA; pear produced it transiently. | The International Atomic Energy Agency sponsored a large, multinational, prospective study to further define PET for risk stratification of diffuse large B-cell lymphoma and to test the hypothesis that international biological diversity or diversity of healthcare systems may influence the kinetics of treatment response as assessed by interim PET (I-PET). Cancer centers in Brazil, Chile, Hungary, India, Italy, the Philippines, South Korea, and Thailand followed a common protocol based on treatment with R-CHOP (cyclophosphamide, hydroxyadriamycin, vincristine, prednisolone with rituximab), with I-PET after 2-3 cycles of chemotherapy and at the end of chemotherapy scored visually. Two-year survivals for all 327 patients (median follow-up, 35 mo) were 79% (95% confidence interval [CI], 74%-83%) for event-free survival (EFS) and 86% (95% CI, 81%-89%) for overall survival (OS). Two hundred ten patients (64%) were I-PET-negative, and 117 (36%) were I-PET-positive. Two-year EFS was 90% (95% CI, 85%-93%) for I-PET-negative and 58% (95% CI, 48%-66%) for I-PET-positive, with a hazard ratio of 5.31 (95% CI, 3.29-8.56). Two-year OS was 93% (95% CI, 88%-96%) for I-PET-negative and 72% (95% CI, 63%-80%) for I-PET-positive, with a hazard ratio of 3.86 (95% CI, 2.12-7.03). On sequential monitoring, 192 of 312 (62%) patients had complete response at both I-PET and end-of-chemotherapy PET, with an EFS of 97% (95% CI, 92%-98%); 110 of these with favorable clinical indicators had an EFS of 98% (95% CI, 92%-100%). In contrast, the 107 I-PET-positive cases segregated into 2 groups: 58 (54%) achieved PET-negative complete remission at the end of chemotherapy (EFS, 86%; 95% CI, 73%-93%); 46% remained PET-positive (EFS, 35%; 95% CI, 22%-48%). Heterogeneity analysis found no significant difference between countries for outcomes stratified by I-PET. |
Is serum surfactant protein-A a strong predictor of early mortality in idiopathic pulmonary fibrosis? | Serum surfactant protein (SP) A and SP-D had prognostic value for mortality in patients with idiopathic pulmonary fibrosis (IPF) in prior studies before the reclassification of the idiopathic interstitial pneumonias. We hypothesized that baseline serum SP-A and SP-D concentrations would be independently associated with mortality among patients with biopsy-proven IPF and would improve a prediction model for mortality. We evaluated the association between serum SP-A and SP-D concentrations and mortality in 82 patients with surgical lung biopsy-proven IPF. Regression models with clinical predictors alone and clinical and biomarker predictors were used to predict mortality at 1 year. After controlling for known clinical predictors of mortality, we found that each increase of 49 ng/mL (1 SD) in baseline SP-A level was associated with a 3.3-fold increased risk of mortality (adjusted hazard ratio, 3.27; 95% confidence interval, 1.49 to 7.17; adjusted p = 0.003) in the first year after presentation. We did not observe a statistically significant association between serum SP-D and mortality (adjusted hazard ratio, 2.04; p = 0.053). Regression models demonstrated a significant improvement in the 1-year mortality prediction model when serum SP-A and SP-D (area under the receiving operator curve [AROC], 0.89) were added to the clinical predictors alone (AROC, 0.79; p = 0.03). | The present study explored the effect of dietary oils on lipid composition, antioxidant status, and the activity of the main steroidogenic enzymes in the testis. Forty Wistar rats were randomly assigned to one of four groups (n = 10) fed for 60 d on the same basal diet plus different lipid sources as commercial oils: soybean, olive, coconut, or grapeseed. After sacrifice, testicular lipids and fatty acid composition, free radical biomarkers, antioxidant levels, hormones, and steroidogenic enzymes were determined. The lipid composition of diets produced significant changes in neutral/phospholipids, free/esterified cholesterol, and plasmalogen proportion. Fatty acid patterns of these lipids were also strongly modified, influencing the double bond index. We also found a close correlation between the type of diet and the generation of free radicals. The oxidative stress in testes was higher with the grapeseed oil-supplemented diet and decreased with the other diets in this order: soybean oil > olive oil > coconut oil. Animals fed with the olive oil and coconut oil diets showed the highest testicular levels of antioxidants in addition to significantly high levels of testosterone and 3beta- or 17beta-hydroxysteroid dehydrogenase enzymes. |
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