instruction
stringlengths 22
321
| context
stringlengths 75
3.6k
| context_neg
stringlengths 75
3.6k
|
|---|---|---|
Do endothelial progenitor cells promote efficient ex vivo expansion of cord blood-derived hematopoietic stem/progenitor cells? | Cord blood (CB) hematopoietic stem cell transplantation has often been limited by the scarcity of stem cells. Therefore, the number of CB hematopoietic stem/progenitor cells (HSPCs) should be increased while maintaining the stem cell characteristics. We designed an ex vivo culture system using endothelial progenitor cells (EPCs) as stroma to determine the capacity of expanding CB-HSPCs in a defined medium, the effect on engraftment of the expanded cells in a mouse model and the underlying mechanism. After 7 days of culture, compared with those cultured with cytokines alone (3.25 ± 0.59), CD34+ cells under contact and non-contact co-culture with EPCs were expanded by 5.38 ± 0.61 (P = 0.003) and 4.06 ± 0.43 (P = 0.025)-fold, respectively. Direct cell-to-cell contact co-culture with EPCs resulted in more primitive CD34+ CD38- cells than stroma-free culture (156.17 ± 21.32 versus 79.12 ± 19.77-fold; P = 0.010). Comparable engraftment of day 7 co-cultured HSPCs with respect to HSPCs at day 0 in nonobese diabetic-severe combined immunodeficiency disease (NOD/SCID) mice was measured as a percentage of chimerism (13.3% ± 11.0% versus 16.0% ± 14.3%; P = 0.750). EPCs highly expressed interleukin 6 (IL6) and angiopoietin 1 (ANGPT1), the hematopoietic- related cytokines. A higher transcriptional level of WNT5A genes in EPCs and co-cultured HSPCs suggests that the activation of Wnt signaling pathway may play a role in HSPCs' expansion ex vivo. | The clinical value of oesophageal histology in non-complicated gastro-oesophageal reflux disease (GORD) is controversial. Our aim was to explore the role of histology in preoperative diagnosis and postoperative follow-up in GORD. From 40 patients 2 histopathologists graded and scored 191 oesophageal biopsies in a blinded manner to evaluate inter- and intraobserver variation pre- and postoperatively. Correlation between preoperative histology and objective clinical findings (endoscopy, esophageal 24-hour pH monitoring, and manometry) was calculated as well. Pathologist I interpreted 16 (50%) preoperative biopsies as normal, 5 (16%) with mild, 4 (12.5%) moderate, and 7 (21.9%) severe reflux changes. Pathologist II interpreted 11 (35.5%) preoperative biopsies as normal, 11 (35.5%) with mild, 6 (19.4%) moderate, and 3 (9.7%) severe reflux changes. In preoperative biopsies, interobserver variation was 33.8% and intraobserver variation 9.7%. A positive correlation was detectable between preoperative endoscopic and morphologic findings; no correlation existed between either acid reflux or LES pressure and oesophageal morphology. Normal pH monitoring and fundic wrap were noted postoperatively in all cases. In postoperative histology no significant differences according to pathologist I existed when compared with preoperative changes: 22 normal (69%), 7 mild (22%), 1 moderate (3.1%), and 2 severe (6.3%). Compared to preoperative analysis, pathologist II interpreted 24 (77%, p = 0.001) of the postoperative findings as normal, 1 (3%, p = 0.003) as mild, 4 (12.9%, n.s.) as moderate, and 2 (6.5% n.s.) as severe reflux changes. In postoperative biopsies interobserver variation was 21.1% and intraobserver variation 5.6%. |
Does hyperinflammation in patients with chronic granulomatous disease lead to impairment of hematopoietic stem cell functions? | Defects in phagocytic nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) function cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by dysfunctional microbicidal activity and chronic inflammation. We sought to study the effect of chronic inflammation on the hematopoietic compartment in patients and mice with X-linked chronic granulomatous disease (X-CGD). We used immunostaining and functional analyses to study the hematopoietic compartment in patients with CGD. An analysis of bone marrow cells from patients and mice with X-CGD revealed a dysregulated hematopoiesis characterized by increased numbers of hematopoietic progenitor cells (HPCs) at the expense of repopulating hematopoietic stem cells (HSCs). In patients with X-CGD, there was a clear reduction in the proportion of HSCs in bone marrow and peripheral blood, and they were also more rapidly exhausted after in vitro culture. In mice with X-CGD, increased cycling of HSCs, expansion of HPCs, and impaired long-term engraftment capacity were found to be associated with high concentrations of proinflammatory cytokines, including IL-1β. Treatment of wild-type mice with IL-1β induced enhanced cell-cycle entry of HSCs, expansion of HPCs, and defects in long-term engraftment, mimicking the effects observed in mice with X-CGD. Inhibition of cytokine signaling in mice with X-CGD reduced HPC numbers but had only minor effects on the repopulating ability of HSCs. | To determine whether during the initial phase of head and neck cooling, jugular bulb temperature (Tjb; which may reflect brain temperature) is lower than esophageal temperature (Tes). To compare Tes and Tjb, patients received head or head and neck cooling after cardiac arrest. The first series with head cooling (n = 5; mean age 54 with a range of 41-62 years; 1 female and 4 males; mean body weight 80 kg with a range of 70-85 kg) showed a mean difference of 0.22 degrees C (95% CI, -1.14 to 0.70; P = .55; limits of agreement, -3.17 to 2.73) between Tes and Tjb over 12 hours. For the second series, with head and neck cooling (n = 6, mean age 65 with a range of 56-76 years; 3 females and 3 males; mean body weight 75 kg with a range of 65-91 kg), Tjb was lower than Tes with a difference of 0.60 degrees C (95% CI, 0.22 to 0.99; P = .01; limits of agreement, -3.10 to 4.30). During the first 3 hours, Tjb decreased faster than Tes (1.1 degrees C/h [95% CI, 0.4 to 1.8; P < .01]). |
Do hemangioblasts from human embryonic stem cells generate multilayered blood vessels with functional smooth muscle cells? | The formation and regeneration of functional vasculatures require both endothelial cells (ECs) and vascular smooth muscle cells (SMCs). Identification and isolation of progenitors with potential for both EC and SMC lineage differentiation from an inexhaustible source, such as human embryonic stem (hES) or induced pluripotent stem cells, will be desirable for cell replacement therapy. Recently, we have developed a serum-free and animal feeder-free differentiation system to generate blast cells (BCs) from hESCs. These cells possess the characteristics of hemangioblasts in vitro and are capable of repairing damaged retinal vasculatures, restoring blood flow in hind-limb ischemia and reducing the mortality rate after myocardial infarction in vivo. We demonstrate here that BCs express markers of SMCs and differentiate into smooth muscle-like cells (SMLCs), in addition to ECs and hematopoietic cells. When BCs from individual blast colonies were cultured in SMC medium, they differentiated into both ECs and SMLCs, which formed capillary-vascular-like structures after replating on Matrigeltrade mark. The SMLCs expressed SMC-specific markers (alpha-SM actin and calponin) and contracted upon treatment with carbachol. When implanted in nude mice, these cells formed microvasculature with ECs in Matrigel plaques. The BCs differentiated into both ECs and SMLCs, and incorporated into blood vessels after injection into ischemic tissue. | The mechanism by which low dose methotrexate (MTX, the gold standard treatment for rheumatoid arthritis) exerts its anti-inflammatory effect in rheumatoid arthritis (RA) patients is still debated. Lately, the MTX immunosuppressive effect has been related to apoptosis, especially in active RA patients, with ROS involvement. In the present research we investigated MTX oxidative effect and its ability to modulate immune balance in active versus non-active RA patients. Our results show that MTX induces IL-10 secretion (a TH2 cytokine) and significantly reduces TH1 profile in Peripheral Mononuclear Cells (PMNC) derived from active RA patients (n=28). Additionally, we found that MTX modulates the immune status towards TH2 dominance by decreasing the IL-12R and the CXCR3 receptors typical for the TH1 population. Moreover, MTX was found to inhibit the production of nitric oxide (NO) in these patients, a phenomenon that might contribute to MTX action toward cytokine homeostasis. A significant correlation was found between MTX IL-10 induction and NO inhibition in active RA patients. |
Is the herpes simplex virus type 1 ( HSV-1 ) glycoprotein K ( gK ) essential for viral corneal spread and neuroinvasiveness? | To determine the role of herpes simplex virus-1 (HSV-1) glycoprotein K(gK) in corneal infection, neuroinvasion, and virus latency in trigeminal ganglia of mice. The recombinant virus HSV-1 (McKrae) Delta gK (MKDelta gK) carrying a deletion of the gK gene was constructed by insertional/deletion mutagenesis and replaced by a gene cassette constitutively expressing the enhanced green fluorescence protein. The gK deletion of the MKDelta gK virus was rescued to produce the wild-type-like virus MKgK. Balb/c mice were infected ocularly with either virus, and the infection pattern in the eye, clinical disease progression, and establishment of viral latency was monitored. Mice infected with the MKDelta gK strain produced in a gK complementing cell line did not exhibit clinical signs when compared with mice infected with the MKgK virus. Direct visualization of infected eyes revealed that the MKDelta gK virus was unable to spread in mouse corneas, while the MKgK rescued virus spread efficiently. Nineteen of 20 scarified and 5/12 unscarified mice infected with the MKgK virus produced infectious virus after coculture with permissive cells, while 0/20 scarified and 0/12 unscarified mice infected with the MKDelta gK virus produced infectious virus. HSV DNA was detected in trigeminal ganglia by PCR in 19/20 scarified and 9/12 unscarified mice inoculated with MKgK, while HSV DNA was detected in the trigeminal ganglia of 3/20 scarified and 0/12 unscarified mice inoculated with MKDelta gK. | Bioimpedance spectroscopy (BIS) is a valuable tool to assess nutrition and volume status in peritoneal dialysis (PD) patients. However, data about the influence of intraperitoneal fluid on body composition measures are conflicting, and there is no clear consensus about whether the abdomen should be drained before the procedure. We designed a comparison study to detect the influence of intra-abdominal fluid on BIS results. We performed 73 pairs of BIS measurements in 34 stable PD patients, first with the peritoneum filled with a 1.36% glucose dialysate solution and then after the solution was drained. Patients stayed in the supine position for 10 minutes before the BIS procedure, and the electrodes were not moved between measures. Clinical and demographic data were collected, as were analytic parameters of nutrition and volume status. Fluid overload is overestimated when BIS is performed with a full abdomen (1.82 ± 1.73 L vs 1.64 ± 1.68 L, p = 0.043). We also found a spurious overestimation in extracellular water (16.40 ± 3.21 L vs 16.24 ± 3.16 L, p < 0.001) and in relative overhydration (8.29% ± 6.96% vs 7.14% ± 6.79%, p = 0.017). No differences in intracellular water or parameters of nutrition were found. We observed negative correlations for the extracellular water overestimation with age (r = -0.245, p = 0.037), serum B-type natriuretic peptide (r = -0.366, p = 0.036), body mass index (r = -0.248, p = 0.035), and lean tissue index (r = -0.427, p = 0.001). The difference in extracellular water correlated only with body mass index (r = -0.259, p = 0.039). We also found that, assessed at 50 KHz, whole-body impedance (-4.52 ± 8.37, p = 0.001) and phase angle (-0.08 ± 0.23 degrees, p = 0.002) were both lower when BIS was performed in patients with a full abdomen. |
Does phospholipid transfer protein augment apoptosis in THP-1-derived macrophages induced by lipolyzed hypertriglyceridemic plasma? | Lipolysis of triglyceride-rich lipoproteins (TGRLPs) generates phospholipid-rich surface remnants and induces cytotoxic effects in adjacent vascular cells. We hypothesized that by integrating surface remnants into HDL, phospholipid transfer protein (PLTP) alleviates cytotoxicity. To test this hypothesis and gain insight into cytotoxicity during the postprandial phase in vivo, we injected normo-TG and hyper-TG human volunteers after a standardized fat meal (postprandial sample) with heparin, thereby stimulating lipolysis (postprandial heparinized sample). Incubation of (primary) human macrophages and primary human endothelial cells with postprandial heparinized hyper-TG plasma induced pronounced cytotoxic effects that were dose dependent on the TG content of the sample. No such effects were seen with normo-TG and postprandial hyper-TG plasma. In vitro lipolysis of VLDL and chylomicrons indicated that both lipoprotein fractions can cause cytotoxicity. Interestingly, in experiments with THP-1-derived macrophages stably transfected with PLTP, PLTP substantially augmented both net phospholipid uptake and apoptotic cell death due to postprandial heparinized hyper-TG plasma. We observed that activation of caspase-3/7, poly-ADP-ribose polymerase, and enhanced bioactivity of acid sphingomyelinase may all contribute to this augmented apoptosis. | To assess overactive bladder and its component symptoms among patients with type 2 diabetes mellitus and to explore whether higher glycosylated hemoglobin and other factors increase the risk of overactive bladder symptoms. A total of 279 diabetes mellitus patients from our outpatient clinic, and 578 age- and sex-matched subjects without diabetes mellitus from public health centers were enrolled from May to September of 2010. The collected data included overactive bladder and its component symptoms measured by using the Overactive Bladder Symptom Score, and collecting demographic and clinical data. Overactive bladder was defined as total Overactive Bladder Symptom Score ≥3 and urgency score ≥2 (once a week or more). Diabetes mellitus patients had a significantly higher proportion of overactive bladder symptoms/urgency compared with the controls (28.0% vs 16.3%, odds ratio 2.03, 95% confidence interval 1.44-2.86), as well as nocturia (48.0% vs 39.1%, odds ratio 1.44, 95% confidence interval 1.08-1.93). There were no significant effects of diabetes mellitus on urge urinary incontinence (14.0% vs 10.9%, odds ratio 1.32, 95% confidence interval 0.86-2.04) and daytime frequency (26.9% vs 32.4%, odds ratio 0.77, 95% confidence interval 0.56-1.05). After adjusting for all variables, high glycosylated hemoglobin levels were significantly associated with overactive bladder/urgency (odds ratio 1.24, 95% confidence interval 1.06-1.45), urge urinary incontinence (odds ratio 1.20, 95% confidence interval 1.00-1.45) and nocturia (odds ratio 1.17, 95% confidence interval 1.01-1.35). |
Does concern for Lost Income Following Donation deter Some Patients From Talking to Potential Living Donors? | Some living kidney donors report lost income during recovery from surgery. Little is known about whether concern for living donor's lost income affects the decision to undergo donation evaluation and the willingness of transplant candidates to discuss living kidney donation (LKD) with others. To examine whether transplant patients were told by potential donors about lost income concerns and whether patients chose not to discuss LKD with others due to lost income concerns. Kidney transplant patients (185 wait-listed candidates, 171 deceased donor recipients, and 100 live donor recipients) at 2 centers completed a questionnaire to assess whether concern about donor's lost income was a consideration in discussion about LKD with others. One-third (32%) were told by a family member/friend that they were willing to donate but were concerned about potential lost income. The majority of those who expressed financial concern (64%) did not initiate donation evaluation. Many patients (42%) chose not to discuss living donation with a family member/friend due to concern about the impact of lost income on the donor. In the multivariable model, lower annual household income was the only statistically significant predictor of both having a potential donor expressing lost income concern and choosing not to talk to someone because of lost income concern. | Neurofibrillary tangles (NFT) composed of Tau are hallmarks of neurodegeneration in Alzheimer disease. Transgenic mice expressing full-length pro-aggregant human Tau (2N4R Tau-ΔK280, termed Tau(ΔK)) or its repeat domain (TauRD-ΔK280, TauRD(ΔK)) develop a progressive Tau pathology with missorting, phosphorylation, aggregation of Tau, loss of synapses and functional deficits. Whereas TauRD(ΔK) assembles into NFT concomitant with neuronal death, Tau(ΔK) accumulates into Tau pretangles without overt neuronal loss. Both forms cause a comparable cognitive decline (with onset at 10mo and 12mo, respectively), which is rescued upon switch-off of transgene expression. Since methylene blue (MB) is able to inhibit Tau aggregation in vitro, we investigated whether MB can prevent or rescue Tau-induced cognitive impairments in our mouse models. Both types of mice received MB orally using different preventive and therapeutic treatment protocols, initiated either before or after disease onset. The cognitive status of the mice was assessed by behavior tasks (open field, Morris water maze) to determine the most successful conditions for therapeutic intervention. Preventive and therapeutic MB application failed to avert or recover learning and memory deficits of TauRD(ΔK) mice. Similarly, therapeutic MB treatment initiated after onset of cognitive impairments was ineffective in Tau(ΔK) mice. In contrast, preventive MB application starting before onset of functional deficits preserved cognition of Tau(ΔK) mice. Beside improved learning and memory, MB-treated Tau(ΔK) mice showed a strong decrease of insoluble Tau, a reduction of conformationally changed (MC1) and phosphorylated Tau species (AT180, PHF1) as well as an upregulation of protein degradation systems (autophagy and proteasome). This argues for additional pleiotropic effects of MB beyond its properties as Tau aggregation inhibitor. |
Is twin vaginal delivery associated with lower umbilical arterial blood pH of the second twin and less intrapartum blood loss? | To clarify actual differences in the neonatal as well as maternal outcome between completed twin vaginal delivery and cesarean delivery. We collected the data from women with a twin pregnancy who delivered two live fetuses between 1 January and 31 December 2014 at 20 teaching hospitals (1) (1) PARTICIPANTS: Adachi Hospital, Hyogo Prefectural Amagasaki General Medical Center, Japan Baptist Hospital, Kitano Hospital, Kobe City Medical Center General Hospital, Kosaka Women's Hospital, Kurashiki Central Hospital, Kyoto University Hospital, Mitsubishi Kyoto Hospital, Nagahama Red Cross Hospital, National Hospital Organization Kyoto Medical Center, National Hospital Organization Osaka National Hospital, Osaka Red Cross Hospital, Otsu Municipal Hospital, Otsu Red Cross Hospital, Red Cross Wakayama Medical Center, Saiseikai Noe Hospital, Shizuoka General Hospital, Takamatsu Red Cross Hospital and Tenri Hospital. in Japan. Only the cases that were retrospectively regarded as eligible for planned vaginal delivery were analyzed according to the actual mode of delivery. Umbilical arterial blood pH (UmA-pH) of the second twin was slightly but significantly lower in the vaginal delivery group (7.26 ± 0.009) than in a cesarean delivery group (7.30 ± 0.006). Vaginal delivery was the only independent risk factor for second twin's UmA-pH <7.20. Intrapartum blood loss was significantly larger in the cesarean delivery group (1444 ± 63 g) than in the vaginal delivery group (820 ± 109 g). Cesarean delivery was an independent risk factor for intrapartum blood loss ≥1500 g. | TAR DNA-binding protein of 43 kDa (TDP-43) is naturally located in the nucleus and has been identified as the major component of cytoplasmic ubiquitinated inclusions in patients with amyotrophic lateral sclerosis (ALS). We have reported that TDP-43 and phosphorylated Smad2 (pSmad2), an intracellular mediator protein of transforming growth factor-β (TGFβ) signaling, are co-localized within cytoplasmic inclusions in the anterior horn cells of sporadic ALS patients. To investigate the possible pathophysiological linkage between pathologic cytoplasmic inclusions containing TDP-43 and TGFβ/Smad signaling. We replicated cytoplasmic aggregates of TDP-43 in HEK293T cells by transfecting the cells with a nuclear localization signal deletion mutant of TDP-43 and inhibiting proteasome activity, and assessed the effect of TGFβ/Smad signaling on the cytoplasmic aggregate formation. The aggregates contained ubiquitinated, phosphorylated, and fragmented TDP-43, consistent with the essential features of the human pathology. Moreover, the aggregates were co-localized with pSmad2 under continuous TGFβ stimulation. Overexpression of Smad2 reduced the amount of cytoplasmic aggregates in HEK293T cells, and TGFβ stimulation augmented this reduction effect in a dose-dependent manner. |
Is sinR a mutational target for fine-tuning biofilm formation in laboratory-evolved strains of Bacillus subtilis? | Bacteria often form multicellular, organized communities known as biofilms, which protect cells from a variety of environmental stresses. During biofilm formation, bacteria secrete a species-specific matrix; in Bacillus subtilis biofilms, the matrix consists of protein polymers and exopolysaccharide. Many domesticated strains of B. subtilis have a reduced ability to form biofilms, and we conducted a two-month evolution experiment to test whether laboratory culturing provides selective pressure against biofilm formation in B. subtilis. Bacteria grown in two-month-long batch culture rapidly diversified their biofilm-forming characteristics, exhibiting highly diverse colony morphologies on LB plates in the initial ten days of culture. Generally, this diversity decreased over time; however, multiple types of colony morphology remained in our final two-month-old populations, both under shaking and static conditions. Notably, while our final populations featured cells that produce less biofilm matrix than did the ancestor, cells overproducing biofilm matrix were present as well. We took a candidate-gene approach to identify mutations in the strains that overproduced matrix and found point mutations in the biofilm-regulatory gene sinR. Introducing these mutations into the ancestral strain phenocopied or partially phenocopied the evolved biofilm phenotypes. | Temporo-parietal theta activity (TPTA), often detected in hemispheres with internal carotid (ICA) or middle cerebral artery (MCA) occlusive lesions, is more clearly separated from occipital alpha activity by magnetoencephalography (MEG) than electroencephalography. The present study investigated whether TPTA is correlated with misery perfusion, a surgically correctable type of hemodynamic impairment. Awake MEG was measured in 56 patients with ICA or MCA occlusive lesions. Regional cerebral blood flow (rCBF) and regional cerebrovascular reactivity (rCVR) to acetazolamide were measured in the MCA territory by xenon-133 single-photon emission computed tomography. MEG was repeated in 10 patients after vascular reconstruction surgery. Fourteen patients showed TPTA in the lesion hemisphere (n=13) or bilaterally (n=1). The presence of TPTA was significantly correlated with both reduced rCBF and reduced rCVR (P=0.0009). After surgery, TPTA disappeared in 7 of the 10 studied patients. |
Does interleukin-17A be Associated With Alveolar Inflammation and Poor Outcomes in Acute Respiratory Distress Syndrome? | Interleukin-17A is a proinflammatory cytokine known to play a role in host defense and pathologic inflammation in murine models of lung injury. The relationship between interleukin-17A and inflammation in human lung injury is unknown. Our primary objective was to determine whether interleukin-17A levels are associated with alveolar measures of inflammation and injury in patients with acute respiratory distress syndrome. Our secondary objective was to test whether interleukin-17A levels are associated with acute respiratory distress syndrome-related outcomes. Observational study. Six North American medical centers. We studied two groups of patients with acute respiratory distress syndrome: 1) patients previously enrolled in a placebo-controlled clinical trial of omega-3 fatty acids performed at five North American medical centers (n = 86, acute respiratory distress syndrome 1), and 2) patients with systemic inflammatory response syndrome admitted to an ICU who developed acute respiratory distress syndrome (n = 140, acute respiratory distress syndrome 2). In acute respiratory distress syndrome 1, we used paired serum and bronchoalveolar lavage fluid samples obtained within 48 hours of acute respiratory distress syndrome onset, whereas in acute respiratory distress syndrome 2, we used plasma obtained within the first 24 hours of ICU admission. None. We measured circulating interleukin-17A in acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2. We also measured interleukin-17A, neutrophil counts, and total protein in bronchoalveolar lavage fluid from acute respiratory distress syndrome 1. We found that bronchoalveolar lavage interleukin-17A was strongly associated with higher bronchoalveolar lavage percent neutrophils (p < 0.001) and bronchoalveolar lavage total protein (p < 0.01) in acute respiratory distress syndrome1. In both acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2, elevated interleukin-17A was associated with higher Sequential Organ Failure Assessment scores (p < 0.05). | To compare optic nerve head (ONH) morphology between eyes with normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG). Seventy-eight NTG patients and 78 POAG patients matched according to age and axial length were analyzed. Optic nerve head tilt and torsion were identified from cross-sectional images of optical coherence tomography. The degree of horizontal, vertical, and maximum ONH tilt and torsion was compared between NTG and POAG eyes, and additional comparisons were based on the presence of myopia and the location of the visual field defect. Logistic regression analysis was used to determine the factors related to the degree of ONH torsion. Vertical (P = 0.610) and horizontal tilt degree (P = 0.746) did not differ between NTG and POAG eyes. However, torsion degree (P = 0.022) differed significantly between NTG and POAG eyes. Direction of vertical tilt (P = 0.040) and torsion (P < 0.001) showed more prevalent superior tilt and torsion in NTG eyes (21.8% and 33.3%, respectively) compared to POAG eyes (10.3% and 10.3%, respectively). Myopic NTG eyes showed greater torsion degree (P = 0.014) than nonmyopic NTG eyes, which was not observed in the comparison between myopic and nonmyopic POAG eyes. Only NTG eyes showed a significant difference in the degree of maximum tilt (P < 0.001) and torsion (P < 0.001) and the direction of vertical tilt (P < 0.001) and torsion (P = 0.010) by the location of visual field defect. Longer axial length, maximum tilt degree, and diagnosis of NTG were the factors related to the degree of ONH torsion. |
Does site of positive surgical margins influence biochemical recurrence after radical prostatectomy? | To determine whether the number and location of positive surgical margins (PSMs) in radical prostatectomy (RP) surgical specimens affect biochemical recurrence (BCR) rates. The locations of PSMs were recorded for 1308 consecutive men who underwent RP between October 2000 and December 2006. BCR was defined as three consecutive prostate-specific antigen (PSA) level rises with the peak level >or=0.15 ng/mL. Multivariate regression analyses were used to identify preoperative predictors of PSMs and BCR. The estimated 5-year risk of BCR was calculated using the Kaplan-Meier method. In all, 128 (9.8%) men had one or more PSMs. The mean body mass index, mean preoperative serum PSA level, the distributions of clinical stage and biopsy Gleason scores, and the presence or absence of biopsy perineural invasion were significantly different between men with or with no PSMs. In multivariate analysis, baseline serum PSA level, Gleason score and perineural invasion were independent preoperative predictors of PSMs. The 5-year actuarial BCR rates were dependent on the site of the PSM (P = 0.035) and not the number of PSMs (P = 0.18). The rank order of estimated 5-year BCR rates according to the site of PSMs were base > anterior > posterolateral > apex approximately posterior. | Iron deficiency (ID) anemia leads to long-term neurodevelopmental deficits by altering iron-dependent brain metabolism. The objective of the study was to determine if ID induces metabolomic abnormalities in the cerebrospinal fluid (CSF) in the pre-anemic stage and to ascertain the aspects of abnormal brain metabolism affected. Standard hematological parameters [hemoglobin (Hgb), mean corpuscular volume (MCV), transferrin (Tf) saturation, and zinc protoporphyrin/heme (ZnPP/H)] were compared at 2, 4, 6, 8, and 12 months in iron-sufficient (IS; n = 7) and iron-deficient (ID; n = 7) infant rhesus monkeys. Five CSF metabolite ratios were determined at 4, 8, and 12 months using ID infants developed ID (Tf saturation < 25%) by 4 months of age and all became anemic (Hgb < 110 g/L and MCV < 60 fL) at 6 months. Their heme indices normalized by 12 months. Pyruvate/glutamine and phosphocreatine/creatine (PCr/Cr) ratios in CSF were lower in the ID infants by 4 months (P < 0.05). The PCr/Cr ratio remained lower at 8 months (P = 0.02). ZnPP/H, an established blood marker of pre-anemic ID, was positively correlated with the CSF citrate/glutamine ratio (marginal correlation, 0.34; P < 0.001; family wise error rate = 0.001). |
Is hIC2 a novel dosage-dependent regulator of cardiac development located within the distal 22q11 deletion syndrome region? | 22q11 deletion syndrome arises from recombination between low-copy repeats on chromosome 22. Typical deletions result in hemizygosity for TBX1 associated with congenital cardiovascular disease. Deletions distal to the typically deleted region result in a similar cardiac phenotype but lack in extracardiac features of the syndrome, suggesting that a second haploinsufficient gene maps to this interval. The transcription factor HIC2 is lost in most distal deletions, as well as in a minority of typical deletions. We used mouse models to test the hypothesis that HIC2 hemizygosity causes congenital heart disease. We created a genetrap mouse allele of Hic2. The genetrap reporter was expressed in the heart throughout the key stages of cardiac morphogenesis. Homozygosity for the genetrap allele was embryonic lethal before embryonic day E10.5, whereas the heterozygous condition exhibited a partially penetrant late lethality. One third of heterozygous embryos had a cardiac phenotype. MRI demonstrated a ventricular septal defect with over-riding aorta. Conditional targeting indicated a requirement for Hic2 within the Nkx2.5+ and Mesp1+ cardiovascular progenitor lineages. Microarray analysis revealed increased expression of Bmp10. | Dexamethasone is frequently used for the treatment of postoperative nausea and vomiting and as an adjunct in multimodal postoperative analgesia after total joint arthroplasty; however, the incidence of periprosthetic joint infection (PJI) after the use of perioperative dexamethasone in total joint arthroplasty has yet to be fully elucidated. A retrospective chart review was conducted of all patients who underwent total hip or knee arthroplasty (N = 6294) between January 1, 2002 and January 31, 2014. The primary outcome was PJI requiring surgical intervention. Patients were subdivided into 2 cohorts; patients who received perioperative dexamethasone, a single 4- to 10-mg intravenous dose, as prophylaxis against postoperative nausea and vomiting (Dex group; N = 557) and those that did not receive perioperative dexamethasone (No Dex group; N = 5737). Secondary measures included timing of infection, culture data, and the type and number of subsequent procedures. Statistical analysis was performed using a chi-square or Fisher's exact test where appropriate. Seventy-four joints of the 6294 joints included in this analysis ultimately developed a PJI for an overall incidence of infection of 1.2%. Seven of the 557 joints (1.3%) in the Dex group developed a PJI; 67 of the 5737 joints (1.2%) in the No Dex group developed an infection. This difference was not significant (P = .8022). No significant difference in the timing of infection or the number of subsequent procedures was seen. |
Does selective inhibition of histone deacetylase 6 alter the composition of circulating blood cells in a lethal septic model? | Phagocytes, especially monocytes, macrophages, and dendritic cells, play a pivotal role in the innate and adaptive immune responses during sepsis. We have shown that inhibition of histone deacetylase 6 improves survival and increases bacterial clearance in a mouse model of cecal ligation and puncture (CLP). The aim of this study was to determine whether this effect was associated with changes in the number and composition of different blood cell types in the circulation. C57BL/6J mice were subjected to CLP, and 1 h later given an intraperitoneal injection of either Tubastatin A dissolved in dimethyl sulfoxide, or dimethyl sulfoxide only. Sham-operated animals were treated in an identical fashion but not subjected to CLP. Forty-eight hours later, peripheral blood was obtained via cardiac puncture and analyzed using a HemaTrue veterinary hematology analyzer. Tubastatin A administration increased the number of circulating monocytes in the sham-operated and the CLP animals. In comparison with the sham, CLP animals displayed an increase in the granulocyte percentage in white blood cells and decrease in the lymphocyte number and percentage, with a resultant increase in the granulocyte-to-lymphocyte ratio. Treatment of CLP animals with Tubastatin A decreased the granulocyte percentage and restored the lymphocyte number and percentage, which decreased the granulocyte-to-lymphocyte ratio. In the sham animals, Tubastatin A increased red blood cell number, hematocrit, and hemoglobin. This effect was not seen in CLP animals. | Observational studies suggest that an association between vegetable consumption and coronary heart disease (CHD). However, the results are inconsistent. This study aimed to investigate the daily intake of vegetables on a national level and its effect on the risk of CHD risk, as determined by the Framingham Risk Score (FRS). This study was conducted a cross-sectional design of 2,510 male adults 40-64y of age who participated in the 2007-2009 Korean National Health and Nutrition Examination Survey. Daily intake of vegetable was assessed by 24-h recall, and the consumption frequency of vegetables was determined using a food frequency questionnaire. The odd ratio of CHD risk according to daily intake and frequency of vegetables was analyzed. Total vegetable intake was inversely and significantly associated with the risk of CHD (Model 1: 4th vs. 1st quartile, OR = 0.74, 95% CI = 0.58-0.96, P for trend = 0.0015), and the significant relationship with CHD risk remained even after adjusting for potential confounders (Model 3: 4th vs. 1st quartile, adjusted OR [aOR] = 0.69, 95% CI = 0.49-0.95, P for trend = 0.0492). Subjects in the higher quartiles of non-salted vegetable intake had 31% lower odds of the risk of CHD compared to those in the lowest quartile after adjusting for various potential confounders in model 3 (aOR = 0.69; 95% CI = 0.49-0.97, P for trend = 0.0478). No significant associations between the frequency of vegetable intake (total, green, white and red vegetable) and the risk of CHD were found. |
Is dNA aneuploidy associated with increased mortality for stage I endometrial cancer? | The current study was undertaken to determine if DNA ploidy is a useful prognostic variable for predicting recurrence in stage I endometrial cancer. For cancer of the endometrium, survival following recurrence may depend on a number of factors, including the pattern of recurrence and the response to second line treatment. Previous studies have demonstrated a worse survival for patients with DNA aneuploid tumors. It remains unclear, however, whether this is necessarily due to a higher risk of recurrence. This study was undertaken to assess DNA ploidy and risk of recurrence in patients with stage I endometrial cancer. This is a retrospective study of surgically treated patients with stages IB and IC endometrial cancer treated from 1992 to 2000. All patients underwent definitive surgery, including staging lymphadenectomy. None of the patients received postoperative treatment. DNA ploidy was determined using flow cytometry and image analysis. Grade, lymph-vascular space invasion, stage (stage IB versus IC), and DNA ploidy were analyzed with regard to recurrence and survival. There were 100 patients with stages IB and IC endometrial cancer in this analysis. There were 17 recurrences (17%) and 10 patients that died of cancer (10%). Grade 3 and the presence of lymph-vascular space invasion were associated with increased risk of recurrence; DNA aneuploidy and stage were not. Grade, lymph-vascular space invasion, and DNA ploidy were associated with survival. These findings indicate that DNA aneuploidy does not increase the risk of disease recurrence but is associated with overall survival. | The study investigated the effect of supplementation with maltodextrin (CHO) alone or associated to caffeine during exercise in T2DM subjects. Pilot study, using eight subjects with T2DM, aged 55±10 years, received CHO (1 g/kg) or caffeine (1.5 mg/kg) alone or associated before exercise protocol. The exercise was executed at 40% heart rate (HR) reserve for 40 min, with 10-min recovery. Blood pressure (BP) and perceived exertion scale (Borg) were checked every 2 min. Blood glucose (BG) was checked every 10 min. For statistical analysis, ANOVA test was used and the value was considered statistically significant at p <0.05. The results showed that BP and HR did not change significantly among all treatments. Caffeine promoted a significant reduction in BG of 75 mg/dL (65%, p <0.05) during 40 min of exercise protocol compared to all groups. |
Is health seeking behaviour of parents of burned children in Bangladesh related to family socioeconomics? | The study was design to explore the health seeking behaviour of Bangladeshi parents for their children during burn injuries. A population-based cross-sectional survey was conducted between January and December 2003 in Bangladesh. Nationally representative data were collected from 171,366 rural and urban households comprising of a total population of 819,429, including 351,651 children of 0-18 years. Mothers or heads of households were interviewed with a structured questionnaire in obtaining the information. About sixty percent parents seek health care from unqualified service providers for their children during a childhood burn injury. Educated and the higher income groups parents choose qualified service provider at significantly higher rate compared to illiterate and poor. Higher proportion of parents of urban residence chooses qualified service provider compared to rural. No significant difference of health seeking behaviour of parent in choosing care provider was found in relation to sex of the children. | The human immunodeficiency virus Vif protein overcomes the inhibitory activity of the APOBEC3G cytidine deaminase by prohibiting its packaging into virions. Inhibition of APOBEC3G encapsidation is paralleled by a reduction of its intracellular level presumably caused by the Vif-induced proteasome-dependent degradation of APOBEC3G. In this report we employed confocal microscopy to study the effects of Vif on the expression of APOBEC3G on a single cell level. HeLa cells dually transfected with Vif and APOBEC3G expression vectors revealed efficient co-expression of the two proteins. Under optimal staining conditions approximately 80% of the transfected cells scored double-positive for Vif and APOBEC3G. However, the proportion of double-positive cells observed in identical cultures varied dependent on the fixation protocol and on the choice of antibodies used ranging from as low as 40% to as high as 80% of transfected cells. Importantly, single-positive cells expressing either Vif or APOBEC3G were observed both with wild type Vif and a biologically inactive Vif variant. Thus, the lack of APOBEC3G in some Vif-expressing cells cannot be attributed to Vif-induced degradation of APOBEC3G. These findings are consistent with our results from immunoblot analyses that revealed only moderate effects of Vif on the APOBEC3G steady state levels. Of note, viruses produced under such conditions were fully infectious demonstrating that the Vif protein used in our analyses was both functional and expressed at saturating levels. |
Is bortezomib-associated peripheral neuropathy requiring medical treatment decreased by administering the medication by subcutaneous injection in Korean multiple myeloma patients? | Bortezomib-induced peripheral neuropathy (BIPN) is a significant neurotoxicity, requiring dose reduction or the delay of treatment. In a multicentre trial including 97 % Caucasians and 3 % Asians, BIPN was shown to occur less frequently in cases in which bortezomib was administered subcutaneously. Considering the different pharmacokinetics between Caucasians and Asians, we analysed BIPN according to the administration route, specifically in Korean myeloma patients. We surveyed the prescribed anticonvulsants for the treatment of BIPN and analysed the data after stratifying the results by the cumulative dose of bortezomib. Exclusion criteria were as follows: treated with <2 doses of bortezomib, change in the administration route during the treatment, or receiving anticonvulsants for other reasons prior to bortezomib administration. A total of 101 patients were enrolled; 60 were treated with bortezomib and dexamethasone, and 37 were treated with bortezomib, melphalan, and prednisolone. The median number of treatment courses was four for each regimens. The median exposure to bortezomib for all patients was 19 mg/m(2). Progression-free survival (PFS) and overall survival rates were not statistically different between the groups. There was no difference in the proportion of patients requiring medical treatment (p = 0.388). After stratifying the results, BIPN developed less frequently when bortezomib was administered subcutaneously rather than intravenously in patients receiving more than 23.4 mg/m(2) of bortezomib (p < 0.05). | Wheat (Triticum aestivum L.) is an economically important grain crop. Two-dimensional gel-based approaches are limited by the low identification rate of proteins and lack of accurate protein quantitation. The recently developed isobaric tag for relative and absolute quantitation (iTRAQ) method allows sensitive and accurate protein quantification. Here, we performed the first iTRAQ-based quantitative proteome and phosphorylated proteins analyses during wheat grain development. The proteome profiles and phosphoprotein characterization of the metabolic proteins during grain development of the elite Chinese bread wheat cultivar Yanyou 361 were studied using the iTRAQ-based quantitative proteome approach, TiO2 microcolumns, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Among 1,146 non-redundant proteins identified, 421 showed at least 2-fold differences in abundance, and they were identified as differentially expressed proteins (DEPs), including 256 upregulated and 165 downregulated proteins. Of the 421 DEPs, six protein expression patterns were identified, most of which were up, down, and up-down expression patterns. The 421 DEPs were classified into nine functional categories mainly involved in different metabolic processes and located in the membrane and cytoplasm. Hierarchical clustering analysis indicated that the DEPs involved in starch biosynthesis, storage proteins, and defense/stress-related proteins significantly accumulated at the late grain development stages, while those related to protein synthesis/assembly/degradation and photosynthesis showed an opposite expression model during grain development. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis of 12 representative genes encoding different metabolic proteins showed certain transcriptional and translational expression differences during grain development. Phosphorylated proteins analyses demonstrated that 23 DEPs such as AGPase, sucrose synthase, Hsp90, and serpins were phosphorylated in the developing grains and were mainly involved in starch biosynthesis and stress/defense. |
Does population-based mammography screening result in substantial savings in treatment costs for fatal breast cancer? | The aim was to assess the effect of population-based mammography screening on treatment costs for fatal breast cancer in Turku, Finland. The study included 556 women with invasive breast cancer, diagnosed at the age of 40-74 years in 1987-1993: 427 in the screened group (screen-detected or interval cancer) and 129 in the unscreened group (not yet invited or refused screening). Both groups were followed up for 8 years from diagnosis. In the unscreened group, 32 (25%) patients died of breast cancer versus 49 (12%) in the screened group (p < 0.001). The non-discounted mean treatment costs were 2.8-fold for those dying of breast cancer compared to survivors: 26,222 euros versus 9,434 euros; the difference between means was 16,788 euros (95% CI 14,915-18,660) (p<0.001). The mean costs for fatal cases were high, irrespective of the way cancer was detected: 23,800 euros in the unscreened group versus 27,803 euros in the screened group; the difference between means was -4,003 euros (-10,810 to 2802) (p=0.245). In the unscreened group, patients with fatal breast cancer accounted for 41% (0.76/1.87 million euros) of the total treatment costs versus 29% (1.36/4.76 million euros) in the screened group. It was estimated that about one third of costs for fatal breast cancer were avoided through mammography screening, accounting for 72-81% of the estimated total treatment cost savings achieved by screening. About 31-35% of the screening costs for 1987 to 1993 were offset by savings in treatment costs. | The study is to observe the effect of nitric oxide (NO) donor and scavenger to the hypoglossal motor nucleus (HMN) activity and explore the underlying mechanism. Male adult anesthetized Wistar rats were anesthetized. The activity of genioglossus (GG), diaphragma, blood pressure (BP) and respiratory rate (RR) were recorded when constant microdialysis perfusion of artificial cerebrospinal fluid (ACSF) to HMN as control, followed with diethylamine NONOate sodium salt hydrate (DEA), a NO donor, and 2-(4-carboxyphenyl)-4,4,5,5-tetra-methylimidazoline-1-oxyl-3-oxide potassium salt (carboxy-PTIO), a NO scavenger. Compared with ACSF, application of DEA and carboxy-PTIO at HMN increased and decreased the GG activity respectively and significantly (P<0.05), mainly respiratory-related activity. The tonic GG, diaphragma activity, BP and RR had not been affected statistically between 30-120 min when microdialysis perfusion of both DEA and carboxy-PTIO were delivered. |
Does donor blood glucose 6-phosphate dehydrogenase deficiency reduce the efficacy of exchange transfusion in neonatal hyperbilirubinemia? | Acute intravascular hemolysis after exchange transfusion with glucose 6-phosphate dehydrogenase-deficient blood has been reported; however, it is not routine to screen donor blood for glucose 6-phosphate dehydrogenase deficiency while performing exchange transfusion. We hypothesized that exchange transfusion with glucose 6-phosphate dehydrogenase-deficient blood would lead to a less-than-expected decrease in total serum bilirubin. The objective of this study was to evaluate the effect of exchange transfusion with glucose 6-phosphate dehydrogenase-deficient blood in neonates with idiopathic hyperbilirubinemia on postexchange total serum bilirubin levels, duration of phototherapy, and need for repeat exchange transfusions. All neonates who were undergoing exchange transfusion for idiopathic hyperbilirubinemia were enrolled. A sample of donor blood was collected at the time of exchange transfusion for a glucose 6-phosphate dehydrogenase assay. The standard criteria for starting and stopping phototherapy and exchange transfusion were applied. During the 1-year study period, 21 infants underwent exchange with glucose 6-phosphate dehydrogenase-deficient blood, and 114 neonates with similar baseline characteristics underwent exchange transfusion with glucose 6-phosphate dehydrogenase-normal blood. From 6 to 60 hours after exchange transfusion, there was a significantly lesser drop in total serum bilirubin in the recipients of glucose 6-phosphate dehydrogenase-deficient donor blood compared with recipients of glucose 6-phosphate dehydrogenase-normal blood. The mean duration of phototherapy in the postexchange period and number of infants who underwent repeat exchange transfusions were significantly higher in recipients of glucose 6-phosphate dehydrogenase-deficient donor blood in comparison with control subjects. Concurrently, there was a significantly higher drop in hematocrit and rise in plasma hemoglobin in the glucose 6-phosphate dehydrogenase-deficient donor group. | Shaoyao decoction (SYD) is a traditional Chinese medicine prescription formulated by Liu Wan-Su, a master of traditional Chinese medicine in Jin-Yuan Dynasty. SYD is effective in treating ulcerative colitis. Paeonol, a component of SYD, inhibits colorectal cancer (CRC) cell proliferation and induces CRC cell apoptosis. In this study, azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated CRC (caCRC) model and CRC cell lines were used to examine the effects of SYD on CRC in vivo and in vitro. A translational medicine strategy based on phytomics quality control was adopted. Liquid chromatography was employed for the chemical characterization and chemical fingerprinting of SYD. Protein expression and macrophage existence were determined by immunohistochemistry and western blot. Serum cytokines were quantified by Luminex assay. AOM/DSS-induced caCRC phenotypically resembled human caCRC. SYD significantly increased the survival rate of the mice, ameliorated the general well-being of the mice, and reduced the incidence and multiplicity of colonic neoplasms. SYD inhibited epithelial-mesenchymal transition (EMT), as indicated by upregulated epithelia cadherin and downregulated neuronal cadherin, fibronectin, vimentin, and transcription factor Snail. SYD reduced the expression levels of serum interleukin 1β, interleukin-6, tumor necrosis factor α, tumor-associated macrophages, and p65. These results showed that SYD can attenuate proinflammatory cytokines and inhibit EMT. |
Is nedd4L expression decreased in ovarian epithelial cancer tissues compared to ovarian non-cancer tissue? | Recent studies have demonstrated that the neural precursor cell expressed, developmentally downregulated 4-like (Nedd4L) gene plays a role in the progression of various cancers. However, reports describing Nedd4L expression in ovarian cancer tissues are limited. A cohort (n = 117) of archival formalin-fixed, paraffin embedded resected normal ovarian epithelial tissues (n = 10), benign ovarian epithelial tumor tissues (n = 10), serous borderline ovarian epithelial tumor tissues (n = 14), mucous borderline ovarian epithelial tumor tissues (n = 11), and invasive ovarian epithelial cancer tissues (n = 72) were assessed for Nedd4L protein expression using immunohistochemistry. Nedd4L protein expression was significantly decreased in invasive ovarian epithelial cancer tissues compared to non-cancer tissues (P < 0.05). Decreased Nedd4L protein expression correlated with clinical stage, pathological grade, lymph node metastasis and survival (P < 0.05). | To investigate the efficacy of Ilizarov fixator on cicatricial foot drop after burn. Six patients with cicatricial foot drop after burn were treated with Ilizarov fixator during June 2004 approximately October 2007, the fixator was set on the leg and foot by fixed bone needles. Nuts on the threaded rod were turned from 3 post operation day, 2 approximately 4 rounds per time and 4 times per day in the first week, then 1 approximately 2 rounds per time and 4 times a day, which corrected the deformity of talipes equinus by shortening or lengthening the thread rod in the front and at the back. Ankle joint was maintained in neutral position for 2 approximately 3 months after effective correction. Weight carrying for patients was increased gradually after removal of fixator. Ankle joint was maintained in neutral position with fixator at least three months. Patients were followed up 5 approximately 10 months. Ankle joints from all patients were restored to neutral position after application with fixator for 4 approximately 6 weeks. All patients achieved 0 degrees dorsiflexion in weight carrying for whole planta pedis after use of fixator for 12 approximately 15 weeks with good locomotion function. |
Does overproduction of BCR-ABL induce apoptosis in imatinib mesylate-resistant cell lines? | Imatinib mesylate, a BCR-ABL tyrosine kinase inhibitor, induces apoptosis in chronic myeloid leukemia cells. Resistance to imatinib is currently the most important concern of this treatment. One of the main mechanisms of this resistance is overexpression of BCR-ABL. In the current study, the authors investigated the correlation between BCR-ABL overexpression and apoptosis in BaF/BCR-ABL and LAMA84 cell lines resistant to imatinib suddenly deprived of the inhibitor, and compared with their sensitive counterpart. Removal of imatinib from culture medium led to a decrease in Bcr-Abl protein expression by Day 5, which was sustained for > or = 3 weeks of imatinib deprivation. Apoptosis was observed after 3 days of imatinib deprivation in resistant lines accompanied by caspase activation, loss of membrane asymmetry (annexin V staining), and alteration of mitochondrial potential (dihexyloxacarbocyanine iodide [DiOC6]). Transient activation of the STAT5/Bcl-xL pathway and Akt kinase activity preceded these responses. | Sepsis from burn injuries can result from colonisation of burn wounds, especially in large surface area burns. Reducing bacterial infection will reduce morbidity and mortality, and mortality for severe burns can be as high as 15 %. There are various quantitative and semi-quantitative techniques to monitor bacterial load on wounds. In the UK, burn wounds are typically monitored for the presence or absence of bacteria through the collection and culture of swabs, but no absolute count is obtained. Quantitative burn wound culture provides a measure of bacterial count and is gaining increased popularity in some countries. It is however more resource intensive, and evidence for its utility appears to be inconsistent. This systematic review therefore aims to assess the evidence on the utility and reliability of different quantitative microbiology techniques in terms of diagnosing or predicting clinical outcomes. Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Bibliographic databases and ongoing trial registers will be searched and conference abstracts screened. Studies will be eligible if they are prospective studies or systematic reviews of burn patients (any age) for whom quantitative microbiology has been performed, whether it is compared to another method. Quality assessment will be based on quality assessment tools for diagnostic and prognostic studies and tailored to the review as necessary. Synthesis is likely to be primarily narrative, but meta-analysis may be considered where clinical and methodological homogeneity exists. |
Are blood cadmium levels associated with a decline in lung function in males? | Cadmium exposure was found to cause a decline in lung function among the general population, but these findings were limited to smokers and gender differences were not explored. To examine the relationship between cadmium and chronic obstructive pulmonary disease (COPD) according to gender and smoking status in Korea. Cross-sectional data from the Korean National Health and Nutrition Examination Survey from 2008 to 2011 were analyzed. COPD was defined by a pre-bronchodilator forced expiratory volume in 1s divided by forced vital capacity of <0.70. A logistic regression model was used to elucidate the association between blood cadmium levels and COPD according to gender and smoking status. Among 3861 eligible participants, 3622 were included in the analysis. The prevalence of COPD demonstrated an increasing trend in males (P for trend<0.001), but not in females (P for trend=0.67). After adjusting for covariates, a higher blood cadmium level, but within the normal range, was associated with COPD in males, including those who had never-smoked (P for trend <0.001 and P for trend=0.008). However, a higher blood cadmium level was not significantly associated with COPD in females, including those who had never smoked (P for trend=0.39 and P for trend=0.43). | Streptococcus mutans produces bacteriocins named mutacins. Studies of mutacins have always been hampered by the difficulties in obtaining active liquid preparations of these substances. Some of them were found to be lantibiotics, defined as bacterial ribosomally synthesised lanthionine-containing peptides with antimicrobial activity. The goal of this study was to produce and characterize a new mutacin from S. mutans strain 29B, as it shows a promising activity spectrum against current human pathogens. Mutacin H-29B, produced by S. mutans strain 29B, was purified by successive hydrophobic chromatography from a liquid preparation consisting of cheese whey permeate (6% w/v) supplemented with yeast extract (2%) and CaCO3 (1%). Edman degradation revealed 24 amino acids identical to those of mutacin II (also known as J-T8). The molecular mass of the purified peptide was evaluated at 3246.08 +/- 0.1 Da by MALDI-TOF MS. |
Does duration of treadmill exercise testing combined with QRS score predict adverse cardiac outcome at long-term follow-up? | Total exercise duration and abnormal QRS score values are treadmill exercise testing (TET) prognostic parameters that have been shown to be significantly and independently associated with cardiac mortality. We evaluated the prognostic value of a new index (M score, Michaelides score) incorporating TET duration and QRS score values in a simple index. In this study, we included 626 patients, who underwent TET and coronary arteriography. Cardiac catheterization showed the presence of coronary artery disease in 64.3% of these patients. The M score was calculated by adding the value of the Athens QRS score to the duration of TET (in minutes). The outcome measure was a composite of myocardial infarction or death. Patients were prospectively followed for 38+/-21 months (median 36 months). The composite endpoint was more frequent among the patients of the 1st quartile (M-score values <-5.8). In univariate analysis, mortality of the first-quartile patients was significantly higher (14 vs. 1.1%, P<0.001). In multivariate Cox's regression analysis for age, sex, diabetes, smoking status, hypertension, hypercholesterolemia, maximum ST depression at TET, angina during TET, coronary artery disease on angiography, and echocardiographic left ventricular ejection fraction, the first quartile of M-score values was found to be independently associated with the composite endpoint (relative risk = 3.26, 95% confidence interval = 2.01-5.29, P<0.001). | Suberoylanilide hydroxamic acid (SAHA) has been studied in adult solid and hematologic malignancies. However, little information has been reported on the effects of SAHA on central nervous system (CNS) tumors including medulloblastoma, the most common malignant brain tumor in children. We investigated SAHA in preclinical medulloblastoma models to determine its anti-cancer efficacy as well as its ability to affect intracranial lesions when administered systemically. Tissue culture studies were performed treating primary human fibroblasts, established medulloblastoma cell lines, and primary human medulloblastoma tumors with SAHA. At 10 microM concentration, SAHA had little effect on normal fibroblasts but caused >90% apoptosis in cultured medulloblastoma cells. Primary medulloblastomas from patients were sensitive to SAHA compared to vehicle alone in ex vivo studies. In athymic mice with medulloblastoma xenograft tumors, oral SAHA resulted in apoptosis of tumor tissue and significantly slowed tumor growth. In the ND2:Smo transgenic mouse medulloblastoma model, SAHA treatment caused significant apoptosis in these cerebellar tumors. |
Do consistent relationships between sensory properties of savory snack foods and calories influence food intake in rats? | Determine the influence of experience with consistent or inconsistent relationships between the sensory properties of snack foods and their caloric consequences on the control of food intake or body weight in rats. Rats received plain and BBQ flavored potato chips as a dietary supplement, along with ad lib rat chow. For some rats the potato chips were a consistent source of high fat and high calories (regular potato chips). For other rats, the chips provided high fat and high calories on some occasions (regular potato chips) and provided no digestible fat and fewer calories at other times (light potato chips manufactured with a fat substitute). Thus, animals in the first group were given experiences that the sensory properties of potato chips were strong predictors of high calories, while animals in the second group were given experiences that the sensory properties of potato chips were not predictors of high calories. Juvenile and adult male Sprague-Dawley rats. Following exposure to varying potato chip-calorie contingencies, intake of a novel, high-fat snack food and subsequent chow intake were assessed. Body weight gain and body composition as measured by DEXA were also measured. In juvenile animals, exposure to a consistent relationship between potato chips and calories resulted in reduced chow intake, both when no chips were provided and following consumption of a novel high-fat, high-calorie snack chip. Long-term experience with these contingencies did not affect body weight gain or body composition in juveniles. In adult rats, exposure to an inconsistent relationship between potato chips and calories resulted in increased consumption of a novel high-fat, high-calorie snack chip premeal along with impaired compensation for the calories contained in the premeal. | Several retinal ischemic diseases can cause neovascular glaucoma (NVG). Trabeculectomy with mitomycin C (MMC) is a relatively better treatment modality in the management of eyes with NVG than other glaucoma surgeries. The aim of this study was to investigate the factors that may influence the outcome of trabeculectomy with MMC for NVG. Forty-nine NVG eyes from 43 patients (26 males and 17 females) underwent primary trabeculectomy with MMC. The mean follow-up period was 16.8 ± 8.1 months (range, 6 to 34 months). Twenty-one eyes of 21 patients received intravitreal bevacizumab (IVB) 3.6 ± 1.8 days before trabeculectomy with MMC. A Kaplan-Meier survival-curve analysis was used to summarize the cumulative probability of success. We examined the relationship between the surgical outcome and the following surgical factors: gender, age, history of panretinal photocoagulation, history of cataract surgery, history of vitrectomy, preoperative IVB, NVG in the fellow eye, and postoperative complications (hyphema, choroidal detachment, and formation of fibrin) by multivariate analysis. The survival rate was 83.7% after 6 months, 70.9% after 12 months, and 60.8% after 24 months. The Kaplan-Meier survival curves showed no significant difference in the survival rate between the eyes with preoperative IVB (n = 21) and the eyes without preoperative IVB (n = 28) (p = 0.14). The multiple logistic regression analysis showed that postoperative hyphema (odds ratio, 6.54; 95% confidence interval, 1.41 to 35.97) was significantly associated with the surgical outcome (p = 0.02). |
Are health promotion lifestyle profile scores associatedwith obesity in high school students? | Obesity is a cause of preventable morbidity and mortality with an increasing prevalence. Health promoting lifestyle activities maintain or improve an individual's health and in adolescence many habits are configured. The aim of this study was to determine the prevalence of overweight and obesity among adolescents and the relation between obesity and health promoting behaviors. This is a cross-sectional study including 848 high school students aged 15-17. All students were administered a questionnaire including the Health Promotion Life-Style Profile Scale. Weight and height were measured and body mass index was calculated. Descriptive analysis, Pearson's chi-square test, Kruskal-Wallis and Mann-Whitney U tests, and multivariate logistic regression analysis were used. P < 0.05 was considered statistically significant. Of the included students, 80.8% (n = 685) had normal ranges of body mass index, 10.1% (n = 86) were overweight, and 9.1% (n = 77) were obese. The Health Promotion Life-Style Profile Scale average score was found to be 126.7 ± 20.4. There was no significant difference between Health Promotion Life-Style Profile Scale and obesity (P = 0.921). | Pharmacokinetic parameters derived from plasma sampling are used as a surrogate of tumor pharmacokinetics. However, pharmacokinetics-modulating strategies do not always result in increased therapeutic efficacy. Nonsurrogacy of plasma kinetics may be due to tissue-specific factors such as tumor perfusion. To assess the impact of tumor perfusion and plasma drug exposure on tumor pharmacokinetics, positron emission tomography studies were done with oxygen-15 radiolabeled water in 12 patients, with 6 patients undergoing positron emission tomography studies with carbon-11 radiolabeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and the other 6 with fluorine-18 radiolabeled 5-fluorouracil. We found that tumor blood flow (mL blood/mL tissue/minute) was significantly correlated to early tumor radiotracer uptake between 4 and 6 minutes [standard uptake value (SUV)4-6; rho = 0.79; P = 0.002], tumor radiotracer exposure over 10 minutes [area under the time-activity curve (AUC)0-10; predominantly parent drug; rho = 0.86; P < 0.001], and tumor radiotracer exposure over 60 minutes (AUC0-60; predominantly radiolabeled metabolites; rho = 0.80; P = 0.002). Similarly, fractional volume of distribution of radiolabeled water in tumor (Vd) was significantly correlated with SUV4-6 (rho = 0.80; P = 0.002), AUC0-10 (rho = 0.85; P < 0.001), and AUC0-60 (rho = 0.66; P = 0.02). In contrast, no correlation was observed between plasma drug or total radiotracer exposure over 60 minutes and tumor drug uptake or exposure. Tumor blood flow was significantly correlated to Vd (rho = 0.69; P = 0.014), underlying the interdependence of tumor perfusion and Vd. |
Does anti-LOX-1 rescue endothelial function in coronary arterioles in atherosclerotic ApoE knockout mice? | We hypothesized that atherosclerosis inhibits NO-mediated endothelium-dependent dilation of coronary arterioles through interaction of ox-LDL with its receptor, LOX-1, through the production of O2ÿ- in endothelial cells. We assessed the role of ox-LDL in endothelial dysfunction in a murine model of atherosclerosis (ApoE KO mice). Coronary arterioles from WT control and ApoE KO mice were isolated and pressurized without flow. Although dilation of vessels to endothelium-independent vasodilator SNP was not altered between ApoE KO and WT mice, dilation to the endothelium-dependent agonist, ACh was reduced in ApoE KO versus WT mice. Impaired vasodilation to ACh in ApoE KO mice is partially restored by NAD(P)H oxidase inhibitor, apocynin or DPI. Messenger RNA expression for NAD(P)H oxidases was higher in ApoE KO mice than that in WT and anti-LOX-1 treated ApoE KO mice. Anti-LOX-1, given in vivo, restored NO-mediated coronary arteriolar dilation in ApoE KO mice, but did not affect the endothelium-dependent vasodilation in controls. | Storage of cisatracurium at room temperature seems to have no effect on its degradation in vitro contrary to the recommendations of storage at +4°C. The purpose of this study was to evaluate the influence of cisatracurium' s storage temperature on its onset time. Prospective, randomized, double-blind trial study. Thirty patients were enrolled. The control group consisted of 15 patients receiving cisatracurium (0.15mg/kg) stored at room temperature and the intervention consisted of 15 patients receiving cisatracurium (0.15mg/kg) stored at +4°C. The primary endpoint was to compare cisatracurium onset time depending on the storage temperature. Cisatracurium onset time was 235 (180-292) seconds in the "room temperature" group vs. 240 (210-292) seconds in the "refrigerated" group. There was no difference between the onset of cisatracurium depending on the temperature of storage (p=0.51). Subgroups analysis in the "room temperature" group did not show any difference in cisatracurium onset depending on whether it was stored at room temperature for one, two or three weeks. Excellent intubation score was obtained for 100% of the patients. |
Does vEGFR-1 blockade disrupt peri-implantation decidual angiogenesis and macrophage recruitment? | Angiogenesis and macrophage recruitment to the uterus are key features of uterine decidualization; the progesterone-mediated uterine changes that allow for embryo implantation and initiation of pregnancy. In the current study, we characterized the expression of vascular endothelial growth factor receptor-1 (VEGFR-1) in macrophages and endothelial cells of the peri-implantation uterus and determined if VEGFR-1 function is required for decidual angiogenesis, macrophage recruitment, and/or the establishment of pregnancy. Expression of VEGFR-1 in uterine endothelial cells and macrophages was determined with immunohistochemistry. To assess the effect of continuous VEGFR-1 blockade, adult female mice were given VEGFR-1 blocking antibody, MF-1, every 3 days for 18 days. After 6 doses, females were mated and a final dose of MF-1 was given on embryonic day 3.5. Endothelial cells and macrophages were quantified on embryonic day 7.5. Pregnancy was analyzed on embryonic days 7.5 and 10.5. F4/80(+) macrophages are observed throughout the stroma and are abundant adjacent to the endometrial lumen and glands prior to embryo implantation and scatter throughout the decidua post implantation. VEGFR-1 expression is restricted to the uterine endothelial cells. F4/80(+) macrophages were often found adjacent to VEGFR-1(+) endothelial cells in the primary decidual zone. Continuous VEGFR-1 blockade correlates with a significant reduction in decidual vascular and macrophage density, but does not affect embryo implantation or maintenance of pregnancy up to embryonic day 10.5. | The main aim was to compare robotic gait training vs. balance training for reducing postural instability in patients with Parkinson's disease. The secondary aim was to compare their effects on the level of confidence during activities of daily living requiring balance, functional mobility and severity of disease. Randomized controlled trial. University hospital. A total of 66 patients with Parkinson's disease at Hoehn and Yahr Stage 3. After balanced randomization, all patients received 12, 45-minute treatment sessions, three days a week, for four consecutive weeks. A group underwent robot-assisted gait training with progressive gait speed increasing and body-weight support decreasing. The other group underwent balance training aimed at improving postural reactions (self and externally induced destabilization, coordination, locomotor dexterity exercises). Patients were evaluated before, after and one month posttreatment. Berg Balance Scale. Activities-Specific Balance Confidence Scale; Timed Up and Go Test; Unified Parkinson's Disease Rating Scale. No significant differences were found between the groups for the Berg Balance Scale either immediately after intervention (mean score in the robotic training group 51.58 ±3.94; mean score in the balance training group 51.15 ±3.46), or one-month follow-up (mean score in the robotic training group 51.03 ±4.63; mean score in the balance training group 50.97 ±4.28). Similar results were found for all the secondary outcome measures. |
Does psychological distress negatively affect self-assessment of shoulder function in patients with rotator cuff tears? | In many areas of orthopaedics, patients with greater levels of psychological distress report inferior self-assessments of pain and function. This effect can lead to lower-than-expected baseline scores on common patient-reported outcome scales, even those not traditionally considered to have a psychological component. This study attempts to answer the following questions: (1) Are higher levels of psychological distress associated with clinically important differences in baseline scores on the VAS for pain, the Simple Shoulder Test, and the American Shoulder and Elbow Surgeons score in patients undergoing arthroscopic rotator cuff repair? (2) Does psychological distress remain a negative predictor of baseline shoulder scores when other clinical variables are controlled? Eighty-five patients with full-thickness rotator cuff tears were prospectively enrolled. Psychological distress was quantified using the Distress Risk Assessment Method questionnaire. Patients completed baseline self-assessments including the VAS for pain, the Simple Shoulder Test, and the American Shoulder and Elbow Surgeons score. Age, sex, BMI, smoking status, American Society of Anesthesiologists classification, tear size, and tear retraction were recorded for each patient. Bivariate correlations and multivariate regression models were used to assess the effect of psychological distress on patient self-assessment of shoulder pain and function. Distressed patients reported higher baseline VAS scores (6.7 [95% CI, 4.4-9.0] versus 2.9 [95% CI, 2.3-3.6], p = 0.001) and lower baseline Simple Shoulder Test (3.7 [95% CI, 2.9-4.5] versus 5.7 [95% CI 5.0-6.4], p = 0.001) and American Shoulder and Elbow Surgeons scores (39 [95% CI, 34-45] versus 58 [95% CI, 53-63], p < 0.001). Distress remained associated with higher VAS scores (p = 0.001) and lower Simple Shoulder Test (p < 0.001) and American Shoulder and Elbow Surgeons scores (p < 0.001) when age, sex, BMI, American Society of Anesthesiologists classification, smoking status, tear size, and tear retraction were controlled. | Continuous efforts from scientists of diverse fields are necessary not only to better understand the mechanism by which multidrug-resistant (MDR) cancer cells occur, but also to boost the discovery of new cytotoxic compounds to fight MDR phenotypes. The present review reports on the contribution of African flora in the discovery of potential cytotoxic phytochemicals against MDR cancer cells. Methodology. Scientific databases such as PubMed, ScienceDirect, Scopus, Google Scholar, and Web of Knowledge were used to retrieve publications related to African plants, isolated compounds, and drug resistant cancer cells. The data were analyzed to highlight cytotoxicity and the modes of actions of extracts and compounds of the most prominent African plants. Also, thresholds and cutoff points for the cytotoxicity and modes of action of phytochemicals have been provided. Most published data related to the antiproliferative potential of African medicinal plants were from Cameroon, Egypt, Nigeria, or Madagascar. The cytotoxicity of phenolic compounds isolated in African plants was generally much better documented than that of terpenoids and alkaloids. |
Does negative arousal increase the effects of stimulus salience in older adults? | BACKGROUND/STUDY CONTEXT: Stimuli compete for mental representation, with salient stimuli attracting more attention than less salient stimuli. In a recent study, we found that presenting an emotionally negative arousing sound before briefly showing an array of letters with different levels of salience increased the reporting of the more salient letters but decreased reporting of the less salient letters (Sutherland & Mather, 2012, Emotion, 12, 1367-1372). In the current study we examined whether negative arousal produces similar effects on attention in older adults. Data from 55 older adults (61-80 years; M = 70.7, SD = 5.1) were compared with those from 110 younger adults (18-29 years; M = 20.3, SD = 2.3) from Sutherland and Mather (2012). Neutral or negative arousing sound clips were played before a brief presentation of eight letters, three of which were presented in a darker font than the others to create a group of high- and low-salience targets. Next, participants recalled as many of the letters as they could. At the end of the study, participants rated the emotional arousal and the valence of the sounds. Higher ratings of emotional arousal for the sounds predicted a greater advantage for high-salience letters in recall. This influence of arousal did not significantly differ by age. | Cdc42, a member of the Rho guanosine triphosphatase (GTPase) family, plays important roles in the regulation of the cytoskeleton, cell proliferation, cell polarity, and cellular transport, but little is known about its specific function in mammalian liver. We investigated the function of Cdc42 in regulating liver regeneration. Using a mouse model with liver-specific knockout of Cdc42 (Cdc42LK), we studied liver regeneration after partial hepatectomy. Histological analysis, immunostaining, and western blot analysis were performed to characterize Cdc42LK livers and to explore the role of Cdc42 in liver regeneration. In control mouse livers, Cdc42 became activated between 3 and 24 hours after partial hepatectomy. Loss of Cdc42 led to a significant delay of liver recovery after partial hepatectomy, which was associated with reduced and delayed DNA synthesis indicated by 5-bromo-2'-deoxyuridine staining. Consistent with this, expression of cyclins D1, A, and E was markedly delayed or reduced in Cdc42LK livers during regeneration. As a potential effector of Cdc42, Rac1 activation was dramatically attenuated in Cdc42LK livers after partial hepatectomy, suggesting it is regulated in a Cdc42-dependent manner. Activation of certain proliferative signaling pathways, such as extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p70S6 kinase pathways, was delayed in Cdc42LK livers. In addition, dilated bile canaliculi and excessive lipid accumulation were observed in mutant livers during liver regeneration, which may result from impaired cytoskeletal organization and intracellular trafficking in hepatocytes. |
Are pharmacokinetics of UH and LMWH similar with respect to antithrombin activity? | The ability to administer low molecular weight heparins (LMWH) subcutaneously without laboratory monitoring contributes to their popularity for the treatment of thrombotic disorders. Subcutaneous unfractionated heparin, although less expensive, is deemed to require routine laboratory monitoring on the basis of more variability in drug effect compared to LMWH. However, the more predictable pharmacokinetic profiles of low molecular weight heparins are largely based on anti-Xa activity, while antithrombin activity may be at least as important to their mechanisms of action. We performed a clinical pharmacokinetic trial to compare the variability in peak antithrombin effect between subcutaneous unfractionated heparin and various LMWHs, all given in recommended weight-adjusted treatment doses. Sixty-one patients enrolled in a warfarin clinic were randomized to receive one of four different weight-adjusted subcutaneous heparin doses: unfractionated heparin, 250 units/kg (n=15); tinzaparin, 175 units/kg (n=15); dalteparin, 200 units/kg (n=15); or enoxaparin, 1 mg/kg (n=16). The areas under the curves of antithrombin levels during the first 3 h after administration were determined for each patient, and the coefficients of variation (CV) and 95% confidence intervals of the AUCs were compared among the treatment groups. There was no statistically significant difference in the coefficients of variation of antithrombin effect between unfractionated heparin (52.8, 95% CI: 32.6-72.9) and enoxaparin (56.5, 95% CI: 35.7-77.4) or dalteparin (43.5, 95% CI 25.4-61.6). Tinzaparin had statistically significant decrease in coefficients of variation (21.6, 95% CI: 12.2-30.9) relative to unfractionated heparin, dalteparin and enoxaparin. | MicroRNAs (miRNAs) play key roles in mammalian gene expression and several cellular processes, including differentiation, development, apoptosis and cancer pathomechanisms. Recently the biological importance of primary cilia has been recognized in a number of human genetic diseases. Numerous disorders are related to cilia dysfunction, including polycystic kidney disease (PKD). Although involvement of certain genes and transcriptional networks in PKD development has been shown, not much is known how they are regulated molecularly. Given the emerging role of miRNAs in gene expression, we explored the possibilities of miRNA-based regulations in PKD. Here, we analyzed the simultaneous expression changes of miRNAs and mRNAs by microarrays. 935 genes, classified into 24 functional categories, were differentially regulated between PKD and control animals. In parallel, 30 miRNAs were differentially regulated in PKD rats: our results suggest that several miRNAs might be involved in regulating genetic switches in PKD. Furthermore, we describe some newly detected miRNAs, miR-31 and miR-217, in the kidney which have not been reported previously. We determine functionally related gene sets, or pathways to reveal the functional correlation between differentially expressed mRNAs and miRNAs. |
Is fOXF1 transcription factor required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells? | Inactivating mutations in the Forkhead Box transcription factor F1 (FOXF1) gene locus are frequently found in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a lethal congenital disorder, which is characterized by severe abnormalities in the respiratory, cardiovascular, and gastrointestinal systems. In mice, haploinsufficiency of the Foxf1 gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal, and gall bladder morphogenesis. Although FOXF1 is expressed in multiple mesenchyme-derived cell types, cellular origins and molecular mechanisms of developmental abnormalities in FOXF1-deficient mice and patients with alveolar capillary dysplasia with misalignment of pulmonary veins remain uncharacterized because of lack of mouse models with cell-restricted inactivation of the Foxf1 gene. In the present study, the role of FOXF1 in endothelial cells was examined using a conditional knockout approach. A novel mouse line harboring Foxf1-floxed alleles was generated by homologous recombination. Tie2-Cre and Pdgfb-CreER transgenes were used to delete Foxf1 from endothelial cells. FOXF1-deficient embryos exhibited embryonic lethality, growth retardation, polyhydramnios, cardiac ventricular hypoplasia, and vascular abnormalities in the lung, placenta, yolk sac, and retina. Deletion of FOXF1 from endothelial cells reduced endothelial proliferation, increased apoptosis, inhibited vascular endothelial growth factor signaling, and decreased expression of endothelial genes critical for vascular development, including vascular endothelial growth factor receptors Flt1 and Flk1, Pdgfb, Pecam1, CD34, integrin β3, ephrin B2, Tie2, and the noncoding RNA Fendrr. Chromatin immunoprecipitation assay demonstrated that Flt1, Flk1, Pdgfb, Pecam1, and Tie2 genes are direct transcriptional targets of FOXF1. | To investigate which single quantitative electro-encephalographic (QEEG) marker or which combination of markers correlates best with Alzheimer's disease (AD) severity as measured by the Mini-Mental State Examination (MMSE). We compared quantitative EEG markers for slowing (relative band powers), synchrony (coherence, canonical correlation, Granger causality) and complexity (auto-mutual information, Shannon/Tsallis entropy) in 118 AD patients from the multi-centric study PRODEM Austria. Signal spectra were determined using an indirect spectral estimator. Analyses were adjusted for age, sex, duration of dementia, and level of education. For the whole group (39 possible, 79 probable AD cases) MMSE scores explained 33% of the variations in relative theta power during face encoding, and 31% of auto-mutual information in resting state with eyes closed. MMSE scores explained also 25% of the overall QEEG factor. This factor was thus subordinate to individual markers. In probable AD, QEEG coefficients of determination were always higher than in the whole group, where MMSE scores explained 51% of the variations in relative theta power. |
Are objective cancer-related variables associated with depressive symptoms in women treated for early-stage breast cancer? | Women with breast cancer are thought to be vulnerable to depression for reasons associated with impact of diagnosis, treatment, and metabolic/endocrine changes. While the literature shows that most of these women do not become clinically depressed, 15% to 30% report elevated depressive symptoms that may be clinically important. The purpose was to identify and determine the relative importance of predictors of depressive symptoms in women treated for early-stage breast cancer. A total of 2,595 women (< or = 4 years following completion of initial treatment for early-stage breast cancer) provided data on cancer-related variables, personal characteristics, health behaviors, physical functioning/symptoms, and psychosocial variables. Participants were divided into high or low depressive groups using the Center for Epidemiologic Studies Depression Scale screening form. Results of the binary logistic regression analysis were significant (overall R2 = 32.4%). Before entry of psychosocial variables, younger age, being unmarried, poorer physical functioning, and more vasomotor and gastrointestinal symptoms were significant risk factors for elevated depressive symptoms (R2 = 16.1%), but objective cancer-related variables were not. After inclusion of psychosocial variables in the model (DeltaR2 = 16.3%), none of the preceding variables remained significant. Greater risk for depressive symptoms was associated with stressful life events, less optimism, ambivalence over expressing negative emotions, sleep disturbance, and poorer social functioning. | Elevated H2O2 levels are associated with inflammatory diseases and H2O2 exposure is known to disrupt epithelial barrier function, leading to increased permeability and decreased electrical resistance. In normal human bronchial epithelial (NHBE) cells, fully differentiated at the air liquid interface (ALI), H2O2 activates an autocrine prostaglandin pathway that stimulates transmembrane adenylyl cyclase (tmAC) as well as soluble adenylyl cyclase (sAC), but the role of this autocrine pathway in H2O2-mediated barrier disruption is not entirely clear. To further characterize the mechanism of H2O2-induced barrier disruption, NHBE cultures were treated with H2O2 and evaluated for changes in transepithelial resistance and mannitol permeability using agonist and inhibitors to dissect the pathway. A short (<10 min) H2O2 treatment was sufficient to induce resistance and permeability changes that occurred 40 min to 1 h later and the changes were partially sensitive to EP1 but not EP4 receptor antagonists. EP1 receptors were localized to the apical compartment of NHBE. Resistance and permeability changes were sensitive to inhibition of sAC but not tmAC and were partially blocked by PKA inhibition. Pretreatment with a PLC inhibitor or an IP3 receptor antagonist reduced changes in resistance and permeability suggesting activation of sAC occurred through increased intracellular calcium. |
Does glutamine alone or combined with short-chain fatty acids fail to enhance gut adaptation after massive enterectomy in rats? | To investigate the effect of oral glutamine alone or combined with short chain fatty acids (SCFA) in the intestinal adaptation of rats submitted to an massive enterectomy. After receiving 70% small bowel resection, 30 Wistar rats were randomized to received either standard rat chow (control group, n=10) or the same diet supplemented with 3,05% of glutamine alone (glutamine group, n=10) or combined with a solution containing SCFA (glutamine+SCFA group, n=10). Animals were killed on the 14th postoperative day. Mucosal weight, crypt depth, villus height, wall width, and the mucosal content of DNA, were assessed in basal conditions (resected gut specimen) and compared to the small bowel specimen collected on the postoperative day 14, at both jejunum and ileum sites. All groups presented similar pattern in weight evolution. In all groups, both the morphological findings and the DNA content were significantly higher at the end of the experiment than in basal conditions, at both the jejunum and ileum. Except for the jejunum wall width that was higher in control group (808+/-95 micro) than in the other two groups (glutamine = 649+/-88 micro and glutamine+SCFA = 656+/-92; p<0.01), there was no difference among them in all variables at both intestinal sites after 14 days. | To determine the prevalence of Raynaud's phenomenon (RP) in patients with primary Sjogren's syndrome (pSS) and to identify clinical and immunological characteristics associated with this manifestation. Since increased interferon-gamma (INF-gamma) has been associated with RP, we also compared the INF-gamma production in pSS patients with or without RP. RP was diagnosed if pSS patients presented with characteristic sequence of skin color changes of the digits. In uncertain cases noninvasive vascular tests were performed by ultrasound examination. The secretion of INF-gamma by peripheral blood mononuclear cells was assessed by enzyme-linked immunospot analysis. Further, we examined the expression of different lymphocyte activation markers (CD25, CD45RO, CD69) on CD4+ T-cells by flow cytometric analysis. Thirty-six of 108 patients with pSS had RP. In these patients we found a significantly increased number of INF-gamma-secreting peripheral blood mononuclear cells compared with patients without RP or to healthy controls. Further, in patients with RP a significantly increased percentage of CD25-positive T-helper cells was detectable. In addition we found an association of leukopenia, thyroiditis, and lower C3 levels with RP in pSS patients. |
Does magnesium supplementation help to improve carotid intima media thickness in patients on hemodialysis? | The atherosclerotic process progresses more dynamically in hemodialysis (HD) patients than in the general population. In HD patients, lower magnesium levels were reported to be associated with increased atherosclerosis of the common carotid artery. We tested the hypotheses that magnesium supplementation helps to improve carotid intima media thickness (IMT) in HD patients. A total of 47 patients on HD were included in the study. Patients were randomly divided into two groups: group A (Mg group), in which patients were given magnesium citrate orally at a dosage of 610 mg every other day for 2 months and group B (control group), in which patients received only calcium acetate therapy as a phosphate binder. At baseline and 2 months later, all patients underwent a carotid artery ultrasound scan to measure carotid IMT. At the end of 2 months, mean serum calcium, phosphorus, and calcium x phosphorus product were not changed in both groups. As expected, mean serum Mg level significantly increased in the Mg group at the end of 2 months. In addition, serum parathyroid hormone (PTH) level significantly decreased in the Mg group at the end of 2 months (P = 0.003). Baseline carotid IMT was similar between the groups. Bilateral carotid IMT was significantly improved in patients treated with magnesium citrate compared to initial values (P = 0.001 for left, P = 0.002 for right). | Single-incision laparoscopic colectomy (SILC) is one of several promising operation choices. Our previous study demonstrated that SILC with a self-made glove-port system both improves the feasibility of SILC and decreases the cost expense of surgery. Because the incision site for SILC could be made at either the umbilicus or McBurney's point, we are interested in whether the incision site affects the outcomes of patients, which is a less explored topic. The purpose of this study is not only to show the results of SILC with a self-made glove-port system for supporting its feasibility, but also to compare the short-term surgical outcomes between SILC with the incision made at the umbilicus and at McBurney's point. We collected and reviewed the medical records of patients who received SILC with a self-made glove-port system for tumors in the left side of the colon from August 2009 to March 2011. All operations were performed by a single surgeon. Comparisons of the demographic characteristics, perioperative data, and clinical outcomes between umbilical and McBurney's SILCs were performed. Postoperative pain was assessed by a visual analog scale and opiate demand. In total, 61 patients were enrolled in this retrospective study. Five of 48 (10.4%) tumors in the umbilical SILC group and 5 of 13 (38.5%) tumors in the McBurney's SILC group were located below the peritoneal reflection. The tumor location was significantly different between these two groups (P=.015). Patients in the umbilical SILC group had significantly higher frequency of opiate demand than those in the McBurney's SILC group (0.4±0.7 versus 1.4±1.8, respectively; P=.002). |
Does rapid warfarin reversal in anticoagulated patients with traumatic intracranial hemorrhage reduce hemorrhage progression and mortality? | A prospective cohort study at our institution demonstrated a 48% mortality rate in warfarin anticoagulated trauma patients sustaining intracranial hemorrhage (ICH) compared with a 10% mortality rate in nonanticoagulated patients. Forty percent of patients demonstrated progression of their ICH, despite anticoagulation reversal, with a resultant 65% mortality rate. Seventy-one percent of these patients initially presented with a Glasgow Coma Scale (GCS) score > or = 14 and a 'minor' ICH. We postulated that early diagnosis of ICH and rapid anticoagulation reversal would reduce ICH progression rates and mortality. All anticoagulated patients with known or suspected head trauma were entered into the Coumadin protocol. The protocol ensured immediate triage and physician evaluation, head computed tomography (CT) scan, and fresh frozen plasma administration in patients with documented ICH. Eighty-two patients were entered into the protocol with ICH documented in 19 (23%). Sixteen of 19 patients (84%) presented with GCS > or = 14. Median international normalized ratio (INR) for treated patients with ICH was 2.7 versus 2.5 for patients without ICH (p = 0.546). Mean time to initiate warfarin reversal was 1.9 hours for protocol patients versus 4.3 hours for preprotocol patients (p < 0.001). Two of 19 (10%) protocol patients with ICH died. However, both patients presented >10 hours after injury with a severe ICH. This 10% mortality rate is significantly less than the 48% mortality rate seen previously (p < 0.001) and is now consistent with that observed in similarly injured patients not on anticoagulation. | The mixed-lineage kinase (MLK) family member DLK has been proposed to serve as a regulator of differentiation in various cell types; however, its role in adipogenesis has not been investigated. In this study, we used the 3T3-L1 preadipocyte cell line as a model to examine the function of DLK in adipocyte differentiation. Immunoblot analyses and kinase assays performed on 3T3-L1 cells showed that the expression and activity of DLK substantially increase as differentiation occurs. Interestingly, DLK appears crucial for differentiation since its depletion by RNA interference impairs lipid accumulation as well as expression of the master regulators of adipogenesis C/EBPalpha and PPARgamma2 at both the mRNA and protein levels. In contrast, neither the expression nor the DNA binding activity of C/EBPbeta, an activator for C/EBPalpha and PPARgamma, is affected by DLK loss. |
Does physical exercise alleviate ER stress in obese humans through reduction in the expression and release of GRP78 chaperone? | Perturbation of the endoplasmic reticulum (ER) homeostasis has emerged as one of the prominent features of obesity and diabetes. This occurs when the adaptive unfolded protein response (UPR) fails to restore ER function in key metabolic tissues. We previously reported increased inflammation and impaired heat shock response (HSR) in obese human subjects that were restored by physical exercise. Here, we investigated the status of ER stress chaperone; glucose-regulated protein 78 (GRP78) and its downstream UPR pathways in human obese, and their modulation by a supervised 3-month physical exercise. Subcutaneous adipose tissue (SAT) and blood samples were collected from non-diabetic adult human lean (n=40) and obese (n=40, at baseline and after 3months of physical exercise). Transcriptomic profiling was used as a primary screen to identify differentially expressed genes and it was carried out on SAT samples using the UPR RT(2) Profiler PCR Array. Conventional RT-PCR, immunohistochemistry, immunofluorescence, Western blot and ELISA were used to validate the transcriptomic data. Correlation analyses with the physical, clinical and biochemical outcomes were performed using Pearson's rank correlation coefficient. Levels of GRP78 and its three downstream UPR arms; activating transcription factor-6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were increased in obese subjects. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects which correlated negatively with maximum oxygen uptake (VO2 Max) but positively with high-sensitivity C-reactive protein (hsCRP) and obesity indicators such as BMI, percentage body fat (PBF) and waist circumference. GRP78 increased secretion in obese was further confirmed in vitro using 3T3-L1 preadipocyte cells under ER stress. Finally, we showed that physical exercise significantly attenuated the expression and release of GRP78 with a concomitant reduction in the phosphorylation of IRE1α and eukaryotic initiation factor-2α (eIF2α). | To investigate the influences of bicortical anchorage on values of natural frequencies of dental implants utilizing the 3-dimensional finite element analysis. Using the commercial code of Solidworks, 3-D models of a screw-shaped dental implant and a mandibular bone segment were generated. After the 3-D implant-bone complex was meshed by ABAQUS software, effects of bicortical anchorage on the buccolingual and axial first-order natural frequencies of the implant were computed. Bicortical anchorage increased both the buccolingual and axial natural frequencies remarkably. As the bicortical anchorage got deeper, the frequencies correspondingly got higher. |
Does anthraquinonyl glycoside facilitate the standardization of graphene electrodes for the impedance detection of lectins? | Construction of electrochemical impedance sensors by the self-assembly technique has become a promising strategy for the 'label-free' detection of protein-ligand interactions. However, previous impedance sensors are devoid of an inherent electrochemical signal, which limits the standardization of the sensors for protein recognition in a reproducible manner. We designed and synthesized an anthraquinonyl glycoside (AG) where the anthraquinone (AQ) moiety can bind to the surface of a graphene-based working electrode while the glycoside serving as a ligand for lectin. By measuring the inherent voltammetric signal of AQ, the glycosides decorated on the working electrode could be simply quantified to obtain electrodes with a unified signal window. Subsequently, impedance analysis showed that the 'standardized' electrodes gave a reproducible electrochemical response to a selective lectin with no signal variation in the presence of unselective proteins. | Centrifuge training, while an integral component in pilot training, is not without risks. To date there has never been a reported case of isolated transverse process fractures associated with centrifuge training. A 32-yr-old Flight Surgeon underwent centrifuge training as part of an educational course. She had increasing back pain after exposure to the centrifuge. Follow-up studies showed left L2 and bilateral L3 transverse process fractures. No other contributory causes could be identified except for mild vitamin D deficiency. |
Does tularemia induce different biochemical responses in BALB/c mice and common voles? | Both BALB/c mice and common voles (Microtus arvalis) are considered highly susceptible to tularemia. However, the common vole is reported to harbour Francisella tularensis in European habitats as well as to survive longer with chronic shedding of the bacterium. The purpose of the present study was to compare the response of these two rodents to a wild Francisella tularensis subsp. holarctica strain infection. Rodents were evaluated for differences in the total antioxidant capacity derived from low-molecular-weight antioxidants, biochemistry including lipid metabolism, tissue bacterial burdens and histopathology following experimental intraperitoneal infection with 160 colony forming units (CFU) pro toto. Bacterial burdens in common voles started to develop later post-exposure and amounted to lower levels than in BALB/c mice. Elevation of liver function enzymes was more pronounced in mice than common voles and there were marked differences in lipid metabolism in the course of tularemia in these two species. Hypertriglyceridemia and hypercholesterolemia developed in mice, while physiologically higher levels of triglycerides and cholesterol showed a decreasing tendency in common voles. On the other hand, the total plasma antioxidant capacity gradually dropped to 81.5% in mice on day 5 post-infection, while it increased to 130% on day 6 post-infection in common voles. Significant correlations between tissue bacterial burdens and several biochemical parameters were found. | We hypothesized that P-wave amplitude in lead I is related to left atrial (LA) remodelling and inter-atrial conduction pattern, and has a predictive value for recurrence after radiofrequency catheter ablation (RFCA) among patients with paroxysmal atrial fibrillation (PAF). A total of 525 consecutive patients with PAF (76% male, 56 ± 12 years old) who underwent RFCA were included. We compared pre-procedural sinus rhythm electrocardiograms without antiarrhythmic drug effect with LA volume (CT), LA voltage (NavX), the earliest activation site (EAS) conduction pattern of LA, and clinical recurrence rate. P-wave amplitude in lead I was significantly lower in patients with recurrence than in those that remained in sinus rhythm (P < 0.001) during 21 ± 10-month follow-up. P-wave amplitude in lead I was linearly correlated with LA voltage (β = 2.52, 95% CI 0.606-4.425, P = 0.010), LA conduction velocity (β = 1.91, 95% CI 0.941-2.876, P < 0.001), and low septal displacement of EAS (β = -1.67, 95% CI -2.352 to -0.996, P < 0.001). P-wave amplitudes <0.1 mV in lead I were independently associated with clinical recurrence of AF on multivariate Cox regression analysis (adjusted HR 2.163, 95% CI 1.307-3.581, P = 0.003). The integrated area under the curves was 0.705 (95% CI 0.655-0.755). |
Does [ research on relationship between genetic differentiation and chemical variation of Cinnamomum migao ]? | To study the relationship between the genetic diversity and chemical variation of Cinnamomum migao. ISSR marker technique was used to research the genetic structure of 9 population, GC-MS was used to analyze the main ingredients of the volatile oil in C. migao. The analysis on the main ingredients of the volatile oil showed that there were significant or extremely significant differences in 9 populations. The minimum variation index of population was Yunnan Funing and the maximum variation index of population was Guangxi Yueye. ISSR marker analysis showed that the average of polymorphic loci percentage (P) was 42.41%, expected heterozygosity (H) was 0.181 0, Shannon's information index (I) was 0.293 8, the Nei's genetic diversity (H(s)) in the group was 0.188 9, genetic differentiation index (G(st)) was 2.269 1. The relationship between the genetic diversity and chemical variation showed that there was no significant correlation between the main ingredients of the volatile oil and 4 indexes of genetic structure of C. migao. | Heparin-induced thrombocytopenia (HIT) is an iatrogenic complication of heparin therapy caused by antibodies to a self-antigen, platelet factor (4) and heparin. The reasons why antibodies form to PF4/heparin, but not to PF4 bound to other cellular glycosaminoglycans are poorly understood. To investigate differences in cellular responses to cell-bound PF4 and PF4/heparin complexes, we studied the internalization of each by peripheral blood-derived monocytes, dendritic cells and neutrophils. Using unlabeled and fluorescently-labeled antigen and/or labeled monoclonal antibody to PF4/heparin complexes (KKO), we show that PF4/heparin complexes are taken up by monocytes in a heparin-dependent manner and are internalized by human monocytes and dendritic cells, but not by neutrophils. Complexes of PF4/low-molecular-weight heparin and complexes composed of heparin and murine PF4, protamine or lysozyme are internalized similarly, suggesting a common endocytic pathway. Uptake of complexes is mediated by macropinocytosis, as shown by inhibition using cytochalasin D and amiloride. Internalized complexes are transported intact to late endosomes, as indicated by co-staining of vesicles with KKO and lysosomal associated membrane protein-2 (LAMP-2). Lastly, we show that cellular uptake is accompanied by expression of MHCII and CD83 co-stimulatory molecules. |
Is human papillomavirus subtype 16 common in Pakistani women with cervical carcinoma? | Human papillomavirus (HPV) is recognized as a major causative agent for cervical carcinomas. Based on their oncogenic potential, HPV subtypes have been divided into high- and low-risk. In Pakistan, screening for HPV in female patients is not commonly practiced, and as a consequence, the degree of HPV prevalence and its correlation with cervical cancer is unknown. In this study, we have attempted to estimate the prevalence of HPV infection, and also the HPV subtype profile, among Pakistani women with cervical cancer from varied geographical, racial, and social backgrounds within Pakistan. Women visiting two tertiary care hospitals in Karachi, diagnosed with carcinoma of the cervix within the past 15 years, were analyzed for HPV subtypes in their cancer specimens. Retrospectively, 60 paraffin-embedded cervical cancer biopsies were examined for the presence of HPV DNA. After DNA extraction from these samples, polymerase chain reaction (PCR) was used to amplify the HPV L1 gene using the consensus (general) primers, and primers specific for subtypes 16 and 18. Of the 60 samples analyzed, only one sample was HPV negative; the rest of the samples were positive for the presence of HPV. Of the 59 HPV positive samples, 56 showed the presence of HPV16 and one sample was positive for HPV18; HPV subtype could not be determined in two samples. | Ischemic preconditioning (IPC) mitigates ischemia-reperfusion (I/R) injury in experimental models. However, the clinical significance of this protection has been unclear and a mortality reduction has not been previously reported in noncardiac models. This study examined the local and remote protection afforded by skeletal muscle IPC and sought to determine the significance of this protection on mortality. Mice subjected to 2 h hindlimb ischemia/24 h reperfusion (standard I/R injury) were compared with those undergoing a regimen of two 20-min cycles of IPC followed by standard I/R injury. Local injury was assessed via gastrocnemius histology, and remote injury was evaluated via intestinal histology and pulmonary neutrophil infiltration (n = 7). Mortality was compared in parallel groups for 1 week (n = 6). Groups were analyzed using an unpaired Student's t-test for gastrocnemius and pulmonary injury, and a Mann-Whitney rank sum test for intestinal injury. Mortality differences were interpreted through a hazard ratio. Significant protection was observed in preconditioned animals. There was a 35% local injury reduction in skeletal muscle (71.2% versus 46.0%, P < 0.01), a 50% reduction in remote intestinal injury (2.3 versus 1.1, P < 0.01), and a 43% reduction in remote pulmonary injury (14.9 versus 8.5, P < 0.01) compared with standard injury controls. Preconditioned animals were also significantly protected from mortality, demonstrating a 66.7% survival at 1 wk compared with 0% survival after standard injury alone (hazard ratio 0.20, 95% CI: 0.02-0.59). |
Do neonatal Pain and Infection Relate to Smaller Cerebellum in Very Preterm Children at School Age? | To examine whether specific neonatal factors differentially influence cerebellar subregional volumes and to investigate relationships between subregional volumes and outcomes in very preterm children at 7 years of age. Fifty-six children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-dimensional T(1)-weighted neuroimaging at median age 7.6 years. Children with severe brain injury were excluded. Cerebellar subregions were automatically segmented using the multiple automatically generated templates algorithm. The relation between cerebellum subregional volumes (adjusted for total brain volume and sex) and neonatal clinical factors were examined using constrained principal component analysis. Cognitive and visual-motor integration functions in relation to cerebellar volumes were also investigated. Higher neonatal procedural pain and infection, as well as other clinical factors, were differentially associated with reduced cerebellar volumes in specific subregions. After adjusting for clinical risk factors, neonatal procedural pain was distinctively associated with smaller volumes bilaterally in the posterior VIIIA and VIIIB lobules. Specific smaller cerebellar subregional volumes were related to poorer cognition and motor/visual integration. | LADA is thought to result from the chronic autoimmune destruction of the insulin-producing pancreatic beta cells. In addition to antidiabetic effects, the newly developed insulin sensitizer-thiazolidinediones have the potential to increase the insulin content of islet cells by downregulating local inflammation and autoimmune response. Therefore, we hypothesized that LADA patients might benefit from thiazolidinediones treatment. LADA patients, with a fasting C-peptide (FCP) of 0.3 nmol/L or more, were enrolled and randomly assigned to receive subcutaneous insulin alone (insulin group, n = 12) or rosiglitazone plus insulin (insulin + RSG group, n = 11) to compare the impacts on islet beta cell function. Plasma glucose, HbA 1c, fasting C-peptide (FCP) and C-peptide after 2 h 75-g glucose load (PCP) were determined every 6 months. GAD-Ab and C-peptide were measured with radioimmune assays. Islet beta cell function was evaluated by PCP and DeltaCP(DeltaCP = PCP-FCP). All of the 23 patients have been followed up for 6 months, 17 cases for 12 months and 14 for 18 months. (1) During 6 months' follow-up, there were no significant changes for DeltaCP and PCP levels in both groups. (2) PCP and DeltaCP levels in insulin + RSG group patients stayed steady during the 12 months' observation (P = 0.161 for both PCP and DeltaCP), while in the insulin alone group, both FCP (P = 0.021) and PCP (P = 0.028) levels decreased significantly. Furthermore, PCP (P = 0.004) and DeltaCP(P = 0.015) differences between 12th month and baseline were higher in insulin + RSG group than those in the insulin group. (3) When observed up to 18 months, PCP and DeltaCP levels in insulin + RSG group patients still stayed steady, while PCP and DeltaCP levels decreased more in the insulin alone group. |
Are all eotaxins CCL11 , CCL24 and CCL26 increased but to various extents in pulmonary tuberculosis patients? | Mycobacterium tuberculosis is a pulmonary pathogen responsible for tuberculosis. Tuberculosis (TB) is characterized histologically by granulomas at the site of disease activity. Primary pathologic feature of TB is formation of a granuloma, and chemokines are known to play an important role in the formation of granulomas during infection. Therefore, the aim of this study was to evaluate the serum levels of CCL11, CCL24, and CCL26 in the TB patients in comparison to healthy controls. The population of this cross-sectional study included 300 patients suffering from TB and 100 healthy controls. Concentrations of CCL11, CCL24, and CCL26 were measured by enzyme linked immunosorbent assay (ELISA) technique. The results were analyzed using SPSS software package version 18. Differences were considered significant where p was less than 0.05. The results showed significant elevated serum levels of CCL11, CCL24, and CCL26 in TB patients compared to controls. | We hypothesized that erythropoietin (EPO)-immersed gelatin hydrogel microspheres (GHM) injected into ischemic legs might continuously release a small amount of EPO to locally stimulate angiogenesis without unfavorable systemic effects. EPO is a potent angiogenic factor, but its use for relieving ischemic organs is limited because of the untoward systemic erythrogenic effect and its short half-life in plasma. The right femoral arteries of BALB/c mice were ligated. Recombinant human EPO (5,000 IU/kg)-immersed GHM was injected into the right hind limb muscles (n = 12); the control groups included a saline-injected group (n = 12), an EPO-injected group (n = 8), and an empty GHM-injected group (n = 8). Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the EPO-GHM group compared with any of the control groups. There was no increase in the hemoglobin level, nor was there any increase in endothelial progenitor cells. However, capillary and arteriolar densities were significantly increased in this group. Although the treatment did not affect the levels of vascular endothelial growth factor or interleukin-1 beta, it up-regulated the EPO receptor and matrix metalloproteinase-2 and activated the downstream signaling of Akt and also endothelial nitric oxide synthase in ischemic limbs, which might have been associated with the evident angiogenic and arteriogenic effects in the present system. |
Are death receptor ( DR4 ) haplotypes associated with increased susceptibility of gallbladder carcinoma in north Indian population? | Defective apoptosis is a hallmark of cancer development and progression. Death receptors (DR4, FAS) and their ligands (TRAIL, FASL) are thought to mediate the major extrinsic apoptotic pathway in the cell. SNPs in these genes may lead to defective apoptosis. Hence, the present study aimed to investigate the association of functional SNPs of DR4 (rs20575, rs20576 and rs6557634), FAS (rs2234767) and FASL (rs763110) with gallbladder cancer (GBC) risk. This case-control study included 400 GBC and 246 healthy controls (HC). Genotyping was carried out by Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2.0, BIOSTAT, Englewood, NJ) to systematically summarize the possible association of SNP with cancer risk. Functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP). False discovery rate (FDR test) was used in multiple comparisons. The DR4 C rs20575 A rs20576 A rs6557634, G rs20575 A rs20576 G rs6557634 and G rs20575 C rs20576 G rs6557634 haplotypes conferred two-fold increased risk for GBC. Among these, the DR4 C rs20575 A rs20576 A rs6557634 haplotype emerged as main factor influencing GBC susceptibility as the risk was not modulated by gender or gallstone stratification. Our meta-analysis results showed significant association of DR4 rs6557634 with overall cancer risk, GI cancers as well as in Caucasians. We didn't find any association of FAS and FASL SNPs with GBC susceptibility. | The objective was to assess the safety and efficacy of L-NMMA in the treatment of cardiogenic shock. We enrolled 11 consecutive patients with cardiogenic shock that persisted after >24 hours from admission, despite coronary catheterization and primary percutaneous transluminal coronary revascularization, when feasible, and treatment with mechanical ventilation, intraaortic balloon pump (IABP), and high doses of catecholamines. L-NMMA was administered as an IV bolus of 1 mg/kg and continuous drip of 1 mg. kg(-1). h(-1) for 5 hours. Treatment with catecholamines, mechanical ventilation, and IABP was kept constant throughout the study. Within 10 minutes of L-NMMA administration, mean arterial blood pressure (MAP) increased from 76+/-9 to 109+/-22 mm Hg (+43%). Urine output increased within 5 hours from 63+/-25 to 156+/-63 cc/h (+148%). Cardiac index decreased during the steep increase in MAP from 2. 0+/-0.5 to 1.7+/-0.4 L/(min. m(2)) (-15%); however, it gradually increased to 1.85+/-0.4 L/(min. m(2)) after 5 hours. The heart rate and the wedge pressure remained stable. Twenty-four hours after L-NMMA discontinuation, MAP (+36%) and urine output (+189%) remained increased; however, cardiac index returned to pretreatment level. No adverse events were detected. Ten out of eleven patients could be weaned off mechanical ventilation and IABP. Eight patients were discharged from the coronary intensive care unit, and seven (64%) were alive at 1-month follow-up. |
Do vascular endothelial growth factor polymorphisms increase the risk of developing Graves ' disease? | Graves' disease (GD) is a consequence of genetic and environmental factors. Vascular endothelial growth factor (VEGF) is a strong angiogenic and mitogenic factor, which plays a key role in lymphocyte infiltration, and hypervascularization in the thyroid gland of patients with GD. The aim of this study is to investigate the relationship between GD and A-2578C, T-460C and G+405C single nucleotide polymorphisms (SNPs) of VEGF gene, as well as to evaluate whether there are any relationships between genotypes and some clinical/laboratory parameters of GD. We analyzed the genotype and allele distributions of the above mentioned SNPs in 167 patients with established GD diagnosis and 203 healthy controls by real-time PCR combined with melting curve analysis using fluorescence-labeled hybridization probes. The distribution of VEGF A-2578C and T-460C genotypes and allele frequencies in control and GD groups were not significantly different. With regard to the +405 polymorphism, the frequency of C allele was 1.8-fold increased in GD patients compared to controls, and the CC genotype was associated with a 4.6-fold increased disease risk. There was no relationship between some clinical/laboratory parameters with G+405C polymorphism. However, in -2578C allele carrying GD patients the anti-thyroid antibody levels were increased according to wild homozygous. Additionally, -2578C and -460T alleles were related with early (at age before 40) disease onset. | Aerosolized perfluorocarbon (PFC) has been proposed as an alternative method of PFC administration; however, the efficacy of aerosolized PFC in a preterm animal model has not yet been demonstrated. Twelve preterm lambs were randomized to two groups: a perfluorodecalin (PFD) aerosol group (n = 6) receiving 10 ml/kg/h of PFD delivered by an intratracheal inhalation catheter followed by 4 h of mechanical ventilation (MV) or the control group, in which animals (n = 6) were managed for 6 h with MV. Gas exchange, pulmonary mechanics, cardiovascular parameters, and cerebral blood flow (CBF) were measured. Both groups developed hypoxia, hypercarbia, and acidosis at baseline. Aerosolized PFD improved oxygenation (P < 0.0001) and pulmonary mechanics (P < 0.0001) and changed carbon dioxide values to normal physiological levels, unlike the treatment given to the controls (P < 0.0003). The time course of mean arterial blood pressure and CBF were significantly affected by PFD aerosolization, especially during the first hour of life. CBF gradually decreased during the first hour in the PFD aerosol group and remained stable until the end of the follow-up, whereas CBF remained higher in the control group (P < 0.0028). |
Does medroxyprogesterone acetate enhance monocyte-endothelial interaction under flow conditions by stimulating the expression of cell adhesion molecules? | Monocyte adhesion to endothelial cells is an important initial event in atherosclerosis and is partially mediated by adhesion molecule expression on the cell surface. Although estrogens inhibit atherosclerosis development, effects of coadministered progestogen remain controversial. We examined the effects of progestogen on cytokine-stimulated human umbilical venous endothelial cell (HUVEC) expression of adhesion molecules. In HUVECs, adhesion molecule mRNA levels were measured by real-time PCR. Protein expression was quantified by immunocytochemistry and ELISAs. To mimic the monocyte adherence to endothelial cells, we used a flow chamber system to assess progestogen effects on U937 monocytoid cell adherence to HUVEC monolayers. We also examined the suppression effects of adhesion molecules with small interference RNAs. mRNA levels of adhesion molecules in HUVECs treated with medroxyprogesterone acetate (MPA) or 17β-estradiol + MPA were 1.7- to 2.5-fold higher than those in the control. MPA increased the protein expression of E-selectin, P-selectin, and intercellular adhesion molecule-1 compared with that for the control (83.0 ± 0.7, 34.8 ± 1.2, and 5.4 ± 0.0 ng/mL, respectively), whereas other progestogens or 17β-estradiol additive to progestogens did not significantly change expression. MPA significantly increased U937 monocytoid cell adherence compared with the control (56.0 ± 1.5 vs 46.5 ± 3.5 adherent cells per 10 fields) but did not increase adherence to HUVECs with knocked down intercellular adhesion molecule-1. | Hypophosphatasia (HPP) is an inborn error of metabolism that, in its most severe perinatal and infantile forms, results in 50-100% mortality, typically from respiratory complications. Our objective was to better understand the effect of treatment with asfotase alfa, a first-in-class enzyme replacement therapy, on mortality in neonates and infants with severe HPP. Data from patients with the perinatal and infantile forms of HPP in two ongoing, multicenter, multinational, open-label, phase 2 interventional studies of asfotase alfa treatment were compared with data from similar patients from a retrospective natural history study. Thirty-seven treated patients (median treatment duration, 2.7 years) and 48 historical controls of similar chronological age and HPP characteristics. Treated patients received asfotase alfa as sc injections either 1 mg/kg six times per week or 2 mg/kg thrice weekly. Survival, skeletal health quantified radiographically on treatment, and ventilatory status were the main outcome measures for this study. Asfotase alfa was associated with improved survival in treated patients vs historical controls: 95% vs 42% at age 1 year and 84% vs 27% at age 5 years, respectively (P < .0001, Kaplan-Meier log-rank test). Whereas 5% (1/20) of the historical controls who required ventilatory assistance survived, 76% (16/21) of the ventilated and treated patients survived, among whom 75% (12/16) were weaned from ventilatory support. This better respiratory outcome accompanied radiographic improvements in skeletal mineralization and health. |
Does lentiviral vector-mediated siRNA knockdown of SR-PSOX inhibit foam cell formation in vitro? | To investigate the expression of scavenger receptor that binds phosphatidylserine and oxidized lipoprotein (SR-PSOX)/CXC chemokine ligand 16 (CXCL16) in the human monocyte-derived cell line THP-1, and the effect of lentiviral vectors for the stable delivery of SR-PSOX/CXCL16 short hairpin RNA on foam cell formation. A lentiviral expression vector containing enhanced green fluorescence protein (GFP) and SR-PSOX small interfering RNA (siRNA) (Lenti-SR-PSOXsi), or the control siRNA (Lenti-NC) gene was constructed. A human monocyte-derived cell line THP-1 was transfected with a different multiplicity of infection (MOI) of Lenti-SR-PSOXsi or Lenti-NC, and cultured to obtain stably-transfected THP- 1KD and THP-1NC cells. After incubation with oxidatively-modified, low-density lipoprotein (Ox-LDL), the expression of SR-PSOX/CXCL16 mRNA was determined by real-time PCR. The expression of the SR-PSOX/CXCL16 protein was detected by flow cytometry analysis. The effect of Lenti-SR-PSOXsi on foam cell formation was assessed by Oil red O-stain analysis. Ox-LDL increased the expression of SR-PSOX/CXCL16 mRNA in a time- and dose-dependent manner in THP-1 cells. Four days after transfection with Lenti-SR-PSOXsi (MOI: 100), the percentage of GFP expression cells was over 89.3%. The expression of the SR-PSOX/ CXCL16 mRNA and protein in THP-1KD cells significantly decreased compared with the parent cells, even the THP-1KD cells stimulated with 40 mg/L Ox-LDL. Ox-LDL uptake experiments in THP-1- and THP-1KD-derived macrophages indicated that SR-PSOX/CXCL16 deficiency decreased the development of macrophage- derived foam cell formation. | To describe the development and application of logic model templates for systematic reviews and health technology assessments (HTAs) of complex interventions. This study demonstrates the development of a method to conceptualize complexity and make underlying assumptions transparent. Examples from systematic reviews with specific relevance to Sub-Saharan Africa (SSA) and other low- and middle-income countries (LMICs) illustrate its usefulness. Two distinct templates are presented: the system-based logic model, describing the system in which the interaction between participants, intervention, and context takes place; and the process-orientated logic model, which displays the processes and causal pathways that lead from the intervention to multiple outcomes. |
Is whole-grain intake inversely associated with the metabolic syndrome and mortality in older adults? | Whole-grain intake has been inversely associated with the metabolic syndrome in middle-aged populations, but the association has not been investigated in older adults. The metabolic consequence of consuming high whole-grain diets may differ in elderly persons, who are prone to greater insulin resistance and impaired glucose tolerance. The aim of the present study was to examine the cross-sectional association between whole- and refined-grain intake, cardiovascular disease risk factors, prevalence of the metabolic syndrome, and the incidence of cardiovascular disease mortality in the same cohort of older adults. The nutritional status of 535 healthy persons aged 60-98 y was determined from 1981 to 1984. The subjects kept a 3-d food record and had their blood tested for metabolic risk factors. The metabolic syndrome was defined based on criteria set by the third report of the National Cholesterol Education Program. The vital status of the subjects was identified in October 1995. The results showed a significant inverse trend between whole-grain intake and the metabolic syndrome (P for trend = 0.005) and mortality from cardiovascular disease (P for trend = 0.04), independent of demographic, lifestyle, and dietary factors. Fasting glucose concentrations and body mass index decreased across increasing quartile categories of whole-grain intake (P for trend = 0.01 and 0.03, respectively), independent of confounders, whereas intake of refined grain was positively associated with higher fasting glucose concentrations (P for trend = 0.04) and a higher prevalence of the metabolic syndrome (P for trend = 0.01). | To evaluate the anti-HIV-1 activity of the cyclotriazadisulfonamide CADA against primary isolates in vitro and the combination of CADA with approved anti-HIV drugs for potential synergy. Peripheral blood mononuclear cells (PBMC) were treated with CADA and infected with 16 different clinical isolates. After 8 days of infection, the median inhibitory concentration (IC50) was calculated from the p24 viral antigen content in the supernatant. MT-4 cells were infected with HIV-1NL4.3 and then cultured with CADA or other antiretroviral drugs (i.e., several reverse transcriptase, protease and entry inhibitors), alone and in combination. After 4 days, IC50 was determined for the various drugs in replicate assays. Analysis of combined effects was performed using the median effect principle (CalcuSyn; Biosoft). The entry inhibitor CADA exerted a potent and consistent anti-HIV-1 activity against a wide range of R5, R5/X4 and X4 primary isolates in PBMC. From the two-drug studies, combination indices showed synergy between CADA and reverse transcriptase inhibitors (zidovudine, stavudine, lamivudine, zalcitabine, didanosine, abacavir, tenofovir, nevirapine, delavirdine and efavirenz), and protease inhibitors (lopinavir, saquinavir, indinavir, nelfinavir, amprenavir and ritonavir). In addition, the combination of CADA with the gp41 fusion inhibitor T-20 (enfuvirtide), the CXCR4 antagonist AMD3100 and the gp120-specific interacting plant lectins from Galanthus nivalis (GNA) and Hippeastrum hybrid (HHA) also resulted in a synergistic inhibition. |
Do pPARγ agonists regulate tobacco smoke-induced Toll like receptor 4 expression in alveolar macrophages? | Peroxisome proliferator-activated receptor-gamma (PPARγ) is a ligand-activated transcription factor that exerts multiple biological effects. Growing evidence suggests that PPARγ plays an important role in inflammation; however, the effects of this transcription factor on the inflammation caused by smoking are unclear. We measured the expression of inflammatory cytokines (leukotriene B4, LTB4 and interleukin 8, IL-8), PPARγ and toll-like receptors (TLR2 and TLR4) in alveolar macrophages (AMs) harvested from rats exposed to cigarette smoke (CS) for 3 months in vivo. Some of the rats were pre-treated with rosiglitazone (PPARγ agonist, 3 mg/kg/day, ip), rosiglitazone (3 mg/kg/day, ip) + BADGE (bisphenol A diglycidyl ether, a PPARγ antagonist, 30 mg/kg/day, ig), or BADGE alone (30 mg/kg/day, ig). We also measured the expression of PPARγ, TLR2, TLR4 and nuclear factor-kappaB (NF-κB) in AMs gained from normal rats, which exposed to 5% CSE (cigarette smoke extract) for 12 hrs, respectively pretreated with PBS, rosiglitazone (30 uM), rosiglitazone (30 uM) + BADGE (100 uM), 15 d-PGJ2 (PPARγ agonist, 5 uM), 15 d-PGJ2 (5 uM) + BADGE (100 uM), or BADGE (100 uM) alone for 30 min in vitro. In vivo, rosiglitazone counteracted CS-induced LTB4 and IL-8 release and PPARγ downregulation, markedly lowering the expression of TLR4 and TLR2. In vitro, both rosiglitazone and 15 d-PGJ2 inhibited CS-induced inflammation through the TLR4 signaling pathway. | Limited information exists about the impact of cytogenetic alterations on the protein expression profiles of individual meningioma cells and their association with the clinicohistopathological characteristics of the disease. The aim of this study is to investigate the potential association between the immunophenotypic profile of single meningioma cells and the most relevant features of the tumour. Multiparameter flow cytometry (MFC) was used to evaluate the immunophenotypic profile of tumour cells (n = 51 patients) and the Affymetrix U133A chip was applied for the analysis of the gene expression profile (n = 40) of meningioma samples, cytogenetically characterized by interphase fluorescence in situ hybridization. Overall, a close association between the pattern of protein expression and the cytogenetic profile of tumour cells was found. Thus, diploid tumours displayed higher levels of expression of the CD55 complement regulatory protein, tumours carrying isolated monosomy 22/del(22q) showed greater levels of bcl2 and PDGFRβ and meningiomas carrying complex karyotypes displayed a greater proliferation index and decreased expression of the CD13 ectoenzyme, the CD9 and CD81 tetraspanins, and the Her2/neu growth factor receptor. From the clinical point of view, higher expression of CD53 and CD44 was associated with a poorer outcome. |
Do anterior hypothalamic lesions inhibit antigen-induced airway eosinophilia in rats? | Although previous studies have found that electrolytic lesions of the anterior hypothalamic area (AHA) resulted in the suppression of anaphylaxis, their effect on late allergic responses has scarcely been investigated. To clarify the role of the AHA on possible late asthmatic responses, including their neuroendocrinological mechanisms, we examined the effect of electrolytic AHA lesions on antigen-induced eosinophilic infiltration into the airway tract and measured the plasma corticosterone and catecholamine levels in sensitized rats, i.e. a model of bronchial asthma. The rats were randomly divided into 3 groups, including: (1) an unoperated control group; (2) a sham AHA-lesioned group and (3) an AHA-lesioned group. Then, we investigated antigen-induced eosinophilic infiltration into right bronchoalveolar lavage fluid (BALF) and the lamina propria mucosae of the left main bronchus. The AHA-lesioned group showed the significantly lowest number of eosinophils in both the BALF (p < 0.01) and the main bronchus (p < 0.05). The plasma adrenaline levels in the AHA-lesioned group were significantly higher than those in the other groups (p < 0.05). No differences were found in the plasma corticosterone or noradrenaline levels among the 3 groups. | This study used extreme phenotype selection to define two trabecular bone phenotypes in a cohort of Chinese-American and Caucasian women. A trabecular plate-predominant phenotype is more common in Chinese-Americans while the rod-predominant phenotype is more typical of Caucasians. The robustness of these phenotypic associations with respect to lifestyle factors suggests that this trait may have a genetic basis and that these phenotypes can be utilized in future genetic studies. Compared to Caucasians, Chinese-Americans have more plate-like trabecular bone when measured by individual trabecula segmentation (ITS). These findings suggest a phenotypic difference between the races, which may be amenable to genetic analysis. We sought to identify a single ITS plate trait to pursue in genetic studies by conducting an extreme phenotype selection strategy to numerically define two distinct phenotypes-plate-like and rod-like-and determine whether the selected phenotypic associations were independent of lifestyle factors in order to conduct future genetic studies. A previously described cohort of 146 Chinese-American and Caucasian women with high-resolution peripheral quantitative computed tomography imaging and ITS analyses were studied with logistic regression and receiver operator characteristic analyses. The tibial plate-to-rod (TPR) ratio was the best ITS discriminator of race. Using extreme phenotypic selection, two TPR ratio phenotypes were defined numerically: plate-like as a TPR ratio value in the highest quartile (≥1.336) and rod-like as a TPR ratio value in the lowest quartile (≤0.621). Women with a plate-like phenotype were 25.7 times more likely (95 % CI 7.3-90.1) to be Chinese-American than women with rod-like morphology. After controlling for constitutional and lifestyle covariates, women in the highest vs. lowest TPR ratio quartile were 85.0 times more likely (95 % CI 12.7-568.0) to be Chinese-American. |
Does computer simulation of lumbar flexion show shear of the facet capsular ligament? | The lumbar facet capsular ligament (FCL) is a posterior spinal ligament with a complex structure and kinematic profile. The FCL has a curved geometry, multiple attachment sites, and preferentially aligned collagen fiber bundles on the posterior surface that are innervated with mechanoreceptive nerve endings. Spinal flexion induces three-dimensional (3D) deformations, requiring the FCL to maintain significant tensile and shear loads. Previous works aimed to study 3D facet joint kinematics during flexion, but to our knowledge none have reported localized FCL surface deformations likely created by this complex structure. The purpose of this study was to elucidate local deformations of both the posterior and anterior surfaces of the lumbar FCL to understand the distribution and magnitude of in-plane and through-plane deformations, including the prevalence of shear. The FCL anterior and posterior surface deformations were quantified through creation of a finite element model simulating facet joint flexion using a realistic geometry, physiological kinematics, and fitted constitutive material. Geometry was obtained from the micro-CT data of a healthy L3-L4 facet joint capsule (n=1); kinematics were extracted from sagittal plane fluoroscopic data of healthy volunteers (n=10) performing flexion; and average material properties were determined from planar biaxial extension tests of L4-L5 FCLs (n=6). All analyses were performed with the non-linear finite element solver, FEBio. A grid of equally spaced 3×3 nodes on the posterior surface identified regional differences within the strain fields and was used to create comparisons against previously published experimental data. This study was funded by the National Institutes of Health and the authors have no disclosures. Inhomogeneous in-plane and through-plane shear deformations were prominent through the middle body of the FCL on both surfaces. Anterior surface deformations were more pronounced because of the small width of the joint space, whereas posterior surface deformations were more diffuse because the larger area increased deformability. We speculate these areas of large deformation may provide this proprioceptive system with an excellent measure of spinal motion. | Acute intravascular hemolysis after exchange transfusion with glucose 6-phosphate dehydrogenase-deficient blood has been reported; however, it is not routine to screen donor blood for glucose 6-phosphate dehydrogenase deficiency while performing exchange transfusion. We hypothesized that exchange transfusion with glucose 6-phosphate dehydrogenase-deficient blood would lead to a less-than-expected decrease in total serum bilirubin. The objective of this study was to evaluate the effect of exchange transfusion with glucose 6-phosphate dehydrogenase-deficient blood in neonates with idiopathic hyperbilirubinemia on postexchange total serum bilirubin levels, duration of phototherapy, and need for repeat exchange transfusions. All neonates who were undergoing exchange transfusion for idiopathic hyperbilirubinemia were enrolled. A sample of donor blood was collected at the time of exchange transfusion for a glucose 6-phosphate dehydrogenase assay. The standard criteria for starting and stopping phototherapy and exchange transfusion were applied. During the 1-year study period, 21 infants underwent exchange with glucose 6-phosphate dehydrogenase-deficient blood, and 114 neonates with similar baseline characteristics underwent exchange transfusion with glucose 6-phosphate dehydrogenase-normal blood. From 6 to 60 hours after exchange transfusion, there was a significantly lesser drop in total serum bilirubin in the recipients of glucose 6-phosphate dehydrogenase-deficient donor blood compared with recipients of glucose 6-phosphate dehydrogenase-normal blood. The mean duration of phototherapy in the postexchange period and number of infants who underwent repeat exchange transfusions were significantly higher in recipients of glucose 6-phosphate dehydrogenase-deficient donor blood in comparison with control subjects. Concurrently, there was a significantly higher drop in hematocrit and rise in plasma hemoglobin in the glucose 6-phosphate dehydrogenase-deficient donor group. |
Are surgeons failing to recognize children with HIV infection? | Despite much clinical experience, there are few published accounts of the surgical manifestations of HIV/AIDS in children and still fewer guidelines for the best or most appropriate treatment. Our primary objective was to document the incidence of HIV infection in children who presented with a surgical emergency to a major pediatric surgical unit in South Africa. If possible, we aimed to provide a description of the impact of the disease in a surgical pediatric population and to raise awareness of the mode of presentation of HIV to the pediatric surgeon in a developing nation, now that specific antiretroviral therapies are available. This was a prospective observational study of consecutive surgical emergency admissions to the Division of Paediatric Surgery at the University of the Witwatersrand, Johannesburg, South Africa, between April 1 and May 31, 2005. Consent for inclusion in the study was sought in all cases. The clinical profile of children presenting during the study period was recorded. If relevant, permission was sought from the parent/guardian to undertake HIV status testing if this were not already known. Three hundred ninety-one children were admitted as emergency cases during the study period. Thirty-seven (9.5%) of 391 were excluded, because consent could not be obtained, leaving 354 children. Ages ranged between 1 day and 17 years, with a median age of 3 years. The diagnosis in most was trauma/burns (42%) and abdominal emergencies (27%). Infections occurred in 13% of these patients. Human immunodeficiency virus status was already known in 10 (3%) of 354 patients, and only 18 (5%) of 344 children were tested; of these, 10 (55%) were positive. As expected, the predominant surgical presentation of HIV positive children was sepsis. The prevalence of HIV/AIDS in those children not tested is unknown. | Resistance to chemotherapy is a major problem facing breast cancer patients, and identifying potential contributors to chemoresistance is a critical area of research. Bisphenol A (BPA) has long been suspected to promote carcinogenesis, but the high doses of BPA used in many studies generated conflicting results. In addition, the mechanism by which BPA exerts its biological actions is unclear. Although estrogen has been shown to antagonize anticancer drugs, the role of BPA in chemoresistance has not been examined. The objective of our study was to determine whether BPA at low nanomolar concentrations opposes the action of doxorubicin, cisplatin, and vinblastine in the estrogen receptor-alpha (ERalpha)-positive T47D and the ERalpha-negative MDA-MB-468 breast cancer cells. We determined the responsiveness of cells to anticancer drugs and BPA using the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) cytotoxicity assay. Specific ERalpha and ERbeta inhibitors and real-time polymerase chain reaction were used to identify potential receptor(s) that mediate the actions of BPA. Expression of antiapoptotic proteins was assessed by Western blotting. BPA antagonizes the cytotoxicity of multiple chemotherapeutic agents in both ERalpha-positive and -negative breast cancer cells independent of the classical ERs. Both cell types express alternative ERs, including G-protein-coupled receptor 30 (GPR30) and members of the estrogen-related receptor family. Increased expression of antiapoptotic proteins is a potential mechanism by which BPA exerts its anticytotoxic effects. |
Is prenatal farm exposure related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children? | There is increasing evidence that environmental exposures determining childhood illnesses operate early in life. Prenatal exposure to a farming environment through the mother might also play an important role. We sought to investigate the role of maternal exposures to environments rich in microbial compounds for the development of atopic sensitization, asthma, and corresponding alterations in the innate immune system in offspring. In the children of the cross-sectional Prevention of Allergy Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Life Style study, asthma and atopy were assessed by means of standardized questionnaires (n = 8263) and serum IgE measurements (n = 2086). In a subsample (n = 322) gene expression of Toll-like receptors (TLR2 and TLR4) and CD14 was assessed. Maternal exposures were defined through questionnaire information. Both atopic sensitization (adjusted odds ratio, 0.58; 95% CI, 0.39-0.86) and the gene expression of receptors of innate immunity were strongly determined by maternal exposure to stables during pregnancy, whereas current exposures had much weaker or no effects. A dose-response relation was found between the extent of upregulation of these genes and the number of different farm animal species the mother had encountered in her pregnancy. Each additional farm animal species increased the expression of TLR2, TLR4, and CD14 by a factor of 1.16 (95% CI, 1.07-1.26), 1.12 (95% CI, 1.04-1.2), and 1.10 (95% CI, 1.03-1.23), respectively. | Angiogenesis is a critical factor in the progression of solid tumors and metastasis. The aim of this study was to characterise the roles of angiogenic and anti-angiogenic factors on ovarian cancer. The expression levels of vascular endothelial growth factor (VEGF, angiogenic factor) and pigment epithelial growth factor (PEDF, anti-angiogenic factor) were measured by real-time polymerase chain reaction and Western blotting in ovarian tumors. Microvessel density (MVD) was evaluated by the total microvessel length in high-power field of tumor tissue preparations. MVD correlated with tumor malignancy. The tissues with the highest expression levels of VEGF (VEGF-H) were malignant tumors. The VEGF expression levels in some malignant tumors (VEGF-L) were as low as that in benign tumors. Therefore, the expression of PEDF was examined. The PEDF expression levels in VEGF-L malignant tumors were significantly lower than those in benign tumors. On the other hand, the PEDF expression levels in VEGF-H malignant tumor tissues were not significantly different from those in benign tumors. |
Is early-cleavage a reliable predictor for embryo implantation in the GnRH agonist protocols but not in the GnRH antagonist protocols? | To test if early-cleavage was a strong predictor of pregnancy in patients receiving either a GnRH agonist long protocol or a GnRH antagonist protocol for in-vitro fertilization treatment (IVF) and intracytoplasmic sperm injection (ICSI). This retrospective study included 534 patients undergoing a fresh cycle of oocyte retrieval and the day-3 embryo transfer (from 22 to 46 years old). Of the 534 patients treated, 331 received a GnRH agonist long stimulation protocol (GnRH agonist group) for ovarian stimulation and 203 patients received a GnRH antagonist protocol (GnRH antagonist group). In each group, patients who had at least one early-cleavage embryo transferred were designated as the 'early-cleavage' subgroup. Patients who had no early-cleavage embryos transferred were designated as the 'late-cleavage' subgroup. The early cleavage rate was significantly lower in the GnRH antagonist group compared with that in the GnRH agonist group (IVF cycles: 34% versus 20%; ICSI cycles: 50% versus 37.8%, respectively, P < 0.0001). In the GnRH agonist group, the pregnancy rates were significantly higher in the early-cleavage subgroup than those in the late-cleavage subgroup (53.7% vs 33.9%, P < 0.0001). In the GnRH antagonist group, the pregnancy rates were not significantly different between the early-cleavage and late-cleavage subgroups (45.9% vs 43.8%, P > 0.05). | Esophageal squamous cell carcinoma (ESCC) has a poor prognosis due to its high frequency of metastasis and invasion. Recent studies have suggested glucose-regulated protein 78KD (GRP78) may play important roles in progression and development of malignant tumors. However, the mechanisms of invasion and metastasis of ESCC in relation to GRP78 still remain obscure. The aim of this study was to investigate the effect of GRP78 on invasion and metastasis of ESCC and to explore its potential mechanism. GRP78 expression levels in ESCC tissues were examined by immunohistochemistry. RT-PCR and western blot were used to test the relative expression of GRP78 in non-metastatic and high-metastatic ESCC cells. In vitro and in vivo studies were both performed to investigate the role of GRP78 in invasion and metastasis of ESCC cells. The expression of metastasis-related proteins was examined by western blot in GRP78-depleted cells. The expression of GRP78 is correlated with invasion, metastasis and poor prognosis in ESCC patients. GRP78 expression was significantly higher in highly metastatic cells compared with ESCC non-metastatic cells. In addition, down-regulation of GRP78 significantly inhibited the metastatic potential of ESCC cells in both in vitro and in vivo studies. The expression of MMP-2 and MMP-9 were down-regulated in GRP78-depleted ESCC cells. |
Does treatment with the aromatase inhibitor letrozole during adolescence increase near-final height in boys with constitutional delay of puberty? | We investigated whether inhibition of oestrogen biosynthesis with the aromatase inhibitor, letrozole, during adolescence improves near-final height in boys with constitutional delay of puberty. Seventeen boys with constitutional delay of puberty were randomized to receive testosterone (T) enanthate (1 mg/kg i.m.) every 4 weeks for 6 months in combination with placebo (Pl, n = 8), or the aromatase inhibitor letrozole (Lz, 2.5 mg/day orally) (n = 9), for 12 months. After treatment, patients were followed up until near-final height. Height discrepancy was calculated as near-final height minus mid-parental target height. The primary end point was the difference in near-final height between the groups treated either with T + Pl or T + Lz. Secondarily, height discrepancy and gain in height standard deviation score (SDS) were analysed in both groups. Boys treated with T + Lz reached a higher mean near-final height than did boys on T + Pl (175.8 vs. 169.1 cm, respectively, P = 0.04). In T + Lz-treated boys, mean near-final height did not differ from their mid-parental target height (175.8 vs. 177.1 cm, P = 0.38), whereas in T + Pl-treated boys, mean near-final height was lower than mid-parental target height (169.1 vs. 173.9 cm, P = 0.007). T + Lz-treated boys had a greater increment in height SDS over the pretreatment height SDS than T + Pl-treated boys (+1.4 SDS vs.+0.8 SDS, P = 0.03). | Upregulated CD64 expression on neutrophils is the most useful marker for acute bacterial infections and systemic inflammation. However, it is unknown whether CD64 is involved in the pathogenesis of acute pancreatitis (AP). This study was designed to determine whether CD64 is implicated in severe acute pancreatitis (SAP), and thus, is a suitable marker for SAP. SAP was induced in rats with an intraperitoneal injection of L-arginine. CD64 expression in the rat pancreas was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. Additionally, the CD64 mRNA expression in peripheral blood leukocytes from 21 patients with mild acute pancreatitis (MAP) and 10 patients with SAP was investigated at the time of admission and during remission by qRT-PCR. CD64 mRNA and protein expression in the pancreas was significantly higher in rats with SAP, compared to the controls. The CD64 expression was higher in the patients with SAP than in the patients with MAP. During remission, CD64 mRNA decreased in both the MAP and SAP patients. The area under the curve of CD64 expression for the detection of SAP was superior to both the Ranson and the Acute Physiology and Chronic Health Evaluation II scores. |
Do histone deacetylase and GATA-binding factor 6 regulate arterial remodeling in angiotensin II-induced hypertension? | Histone deacetylase (HDAC) inhibitors have been reported to improve essential and secondary hypertension. However, the specific HDAC that might serve as a therapeutic target and the associated upstream and downstream molecules involved in regulating hypertension remain unknown. Our study was aimed at investigating whether a selective inhibitor of class II HDAC (MC1568) modulates hypertension, elucidating the underlying mechanism. Hypertension was established by administering angiotensin II (Ang II) to mice before treatment with MC1568. SBP was measured. Treatment with MC1568 reduced elevated SBP; attenuated arterial remodeling in the kidney's small arteries and thoracic aorta; and inhibited cell cycle regulatory gene expression, vascular smooth muscle cell (VSMC) proliferation, DNA synthesis, and VSMC hypertrophy in vivo and in vitro. Ang II enhanced the expression of phosphorylated HDAC4 and GATA-binding factor 6 (GATA6) proteins, which were specifically localized in the cytoplasm of cells in the arteries of kidneys and in aortas. Forced expression and knockdown of HDAC4 increased and decreased, respectively, the proliferation and expression of cell cycle genes in VSMCs. GATA6, a newly described binding partner of HDAC4, markedly enhanced the size and number of VSMCs. Calcium/calmodulin-dependent kinase IIα (CaMKIIα), but not HDAC4, translocated from the nucleus to the cytoplasm in response to Ang II. CaMKIIα and protein kinase D1 were associated with VSMC hypertrophy and hyperplasia via direct interaction with HDAC4. MC1568 treatment weakened the association between HDAC4 and CaMKIIα. | To evaluate the Gram stain with carbol-fuchsin counterstain for the rapid detection of Campylobacter species in faecal samples. In total, 842 consecutive diarrhoeic faecal samples were prospectively examined for Campylobacter species by Gram stain and culture. Campylobacter species were isolated from 84 faecal samples (all Campylobacter jejuni). Compared with culture, Gram stain microscopy had a sensitivity of 89%, specificity of 99.7%, positive predictive value of 97%, and negative predictive value of 99% for detecting Campylobacter species. |
Does lack of p53 function promote radiation-induced mitotic catastrophe in mouse embryonic fibroblast cells? | We have demonstrated that in some human cancer cells both chronic mild heat and ionizing radiation exposures induce a transient block in S and G2 phases of the cell cycle. During this delay, cyclin B1 protein accumulates to supranormal levels, cyclin B1-dependent kinase is activated, and abrogation of the G2/M checkpoint control occurs resulting in mitotic catastrophe (MC). Using syngenic mouse embryonic fibroblasts (MEF) with wild-type or mutant p53, we now show that, while both cell lines exhibit delays in S/G2 phase post-irradiation, the mutant p53 cells show elevated levels of cyclin B1 followed by MC, while the wild-type p53 cells present both a lower accumulation of cyclin B1 and a lower frequency of MC. | The plasma activity of phospholipid transfer protein (PLTP), which has putative pro- and anti-atherogenic roles in lipoprotein metabolism, is increased in type 2 diabetes mellitus. We analysed the relationship between carotid artery intima-media thickness (IMT), an established marker of atherosclerosis, and PLTP activity in diabetic patients and control subjects. The IMT (mean of three segments in both carotid arteries by ultrasonography), clinical variables, plasma PLTP activity (phospholipid vesicle-HDL system), lipoproteins, C-reactive protein and insulin were measured in 87 non-smoking men and women, who had type 2 diabetes mellitus, no cardiovascular disease, and were not on insulin or lipid-lowering medication, and in 83 age-matched control subjects. In diabetic patients, carotid IMT (p=0.02), pulse pressure (p=0.003), plasma PLTP activity (p<0.001), triglycerides (p=0.01), C-reactive protein (p<0.01) and insulin (p<0.001) were higher, whereas HDL cholesterol was lower (p<0.001) than in control subjects. Multiple stepwise linear regression analysis demonstrated that in type 2 diabetic patients IMT was independently associated with age (p<0.001), sex (p=0.001), pulse pressure (p=0.003), plasma PLTP activity (p=0.03) and HDL cholesterol (p=0.03), but not with very low density lipoprotein+LDL cholesterol, triglycerides, C-reactive protein and insulin (all p>0.20). The relationship between plasma PLTP activity and IMT was not significant in control subjects. |
Does short-term glucocorticoid treatment cause spinal osteoporosis in ovariectomized rats? | In humans, glucocorticoid-induced osteoporosis is the most common cause of medication-induced osteoporosis. Recent clinical data suggest that glucocorticoid therapy increases the risk of vertebral fractures within a short treatment period. Therefore, this study aimed at investigating vertebral bone in a rat model of glucocorticoid-induced postmenopausal osteoporosis. Fifty Sprague-Dawley rats were randomly assigned into three groups: 1) untreated controls, 2) Sham-operated group, and 3) ovariectomized rats treated with glucocorticoid (dexamethasone) for 3 months (3M) after recovery from bilateral ovariectomy. Osteoporotic bone status was determined by means of the gold standard dual energy X-ray absorptiometry (DEXA) scan. Vertebral bodies were examined using µCT, histological analysis, mRNA expression analysis, and biomechanical compression testing. Further systemic effects were studied biochemically using serum marker analysis. Dexamethasone treatment showed at 3M a significantly lower bone mineral density in ovariectomized rats compared to Sham-operated control (p < 0.0001) as analyzed in vivo by DEXA. Furthermore, Z scores reached levels of -5.7 in the spine indicating sever osteoporotic bone status. Biomechanical testing of compression stability indicated a lower functional competence (p < 0.0001) in the spine of treated rats. µCT analysis showed significant reduction of bone volume density (BV/TV%; p < 0.0001), significantly enhanced trabecular spacing (Tb.Sp; p < 0.0001) with less trabecular number (Tb.N; p < 0.001) and complete loss of trabecular structures in glucocorticoid-treated ovariectomized rats. Histological analysis by osteoblast and osteoclast activities reflected a higher bone catabolism reflected by osteoclast counts by TRAP (p < 0.019) and lower bone catabolism indicated by ALP-stained area (p < 0.035).Serum analysis showed a significant increase in osteocalcin (p < 0.0001), osteopontin (p < 0.01) and insulin (p < 0.001) at 3M. Expression analysis of molecular markers in the vertebral body revealed lower expression in tenascin C in the OVX-steroid animals at 3M. | The foremost important aetiological factor for malignant melanoma is considered to be sunlight exposure. However, primary lesions are also seen in non-sun-exposed areas. Vulvar melanoma is rare and associated with impaired outcome. Herein, we attempt to increase physicians' awareness for early diagnosis in order to improve prognosis. A 64-year-old female presented with pruritus and irritation at her external genitalia. At examination a pigmented lesion of the vulva 3 cm in diameter was seen. Incisional biopsy revealed melanoma. Clinical examination and imaging studies did not show evidence for metastatic disease. She underwent wide excision of the melanoma with primary wound closure and biopsy of sentinel lymph nodes, which were free of disease. After a follow-up period of 43 months, she remains free of disease. |
Is wound healing impaired in rats undergoing perioperative treatment with the antineoplastic agent taurolidine? | The aim of this study was to determine whether an intravenous or an intraperitoneal application of the antineoplastic agent taurolidine (TRD) impairs wound healing in the absence of tumor load in rats. Eighty rats were randomized into eight groups (n = 10). Median laparotomy was performed in all animals. Three groups were treated by intravenous injection and three groups by local administration using a central port catheter system. For each group, 1 ml was applied: isotone sodium chloride solution (control groups), 1% TRD, 2% TRD, and 3% TRD. Fascia and skin were closed using a standardized running suture technique with 4-0 Vicryl. Wounds were evaluated once a day. Animals were treated every 8 h for 7 days (ports were then removed) and wounds were evaluated at day 28. Macroscopic and histopathologic examinations of scar tissue biopsies (hemalaun-eosin stain) were performed at the end of the experiment. No animal died. No relevant impairment of wound healing was observed independent of the different treatment strategies. | 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. |
Does decoy receptor 3 ( DcR3 ) overexpression predict the prognosis and pN2 in pancreatic head carcinoma? | This study was carried out to examine decoy receptor 3 (DcR3) expression and investigate its clinical and prognostic significance in patients with pancreatic head carcinoma. Tissue samples were obtained from 50 patients with pancreatic head carcinoma. DcR3 protein expression in tissues and sera was assessed by immunohistochemistry and ELISA. Correlations between DcR3 and clinicopathologic features and prognoses were analyzed statistically. Serum DcR3 levels were significantly elevated in patients with pancreatic head carcinoma compared with patients with cystadenoma and healthy individuals (P < 0.01 and P < 0.01, respectively). DcR3 overexpression correlated with lymph node metastases and TNM stages (P < 0.05 and P < 0.05, respectively). Median overall survival for the high DcR3 group was 16.3 months, compared to 21.6 months for the low DcR3 group (P < 0.05). In the low DcR3 group, no significant difference was found in the overall survival between patients who underwent standard pancreatoduodenectomy (SPD) and those who had radical pancreatoduodenectomy (RPD) (P > 0.05). In the high DcR3 group, the median overall survival rates were 16.8 months in the RPD group and 13.5 months in the SPD group (P < 0.05). | Three-year treatment with eldecalcitol has been shown to improve lumbar and total hip bone mineral density (BMD), decrease bone turnover markers, and lower the incidences of vertebral and wrist fractures in patients with osteoporosis more than with treatment with alfacalcidol under vitamin D repletion. The purpose of this study was to determine whether there was a risk of eldecalcitol causing severely suppressed bone turnover in osteoporosis patients with low pre-treatment levels of bone turnover markers. Post-hoc analysis was conducted on the data from a 3-year, randomized, double-blind, active-comparator, clinical trial of eldecalcitol versus alfacalcidol under vitamin D repletion conducted in Japan. Enrolled patients with baseline measurements of bone turnover markers were stratified into tertiles according to their pre-treatment levels of serum bone-specific alkaline phosphatase, serum procollagen type I N-terminal propeptide, or urinary collagen-N-telopeptide. Eldecalcitol treatment rapidly reduced bone turnover markers, and kept them within the normal range. However, in the patients whose baseline values for bone turnover were low, eldecalcitol treatment did not further reduce bone turnover markers during the 3-year treatment period. Further long-term observation may be required to reach the conclusion. CLINICALTRIALS.GOV NUMBER: NCT00144456. |
Does cephalometric Angular Measurements of the Mandible Using Three-Dimensional Computed Tomography scan in Koreans? | We conducted this study to analyze the values of the key cephalometric angular measurements of the mandible using 3-dimensional (3D) computed tomography scans. In the 106 enrolled patients, a 3D cephalometric analysis was performed to measure the angular variables of the mandible. These values were compared between the two sides and between the two sexes. The frontal measurements revealed that the mandibular body curve angle was larger on the left (Lt) side (right [Rt], 141.24±7.54; Lt, 142.68±6.94; P=0.002) and the gonial angle was larger on the right side (Rt, 134.37±8.44; Lt, 131.54±7.14; P<0.001). The sagittal measurements showed that the gonial angle was larger on the right side (Rt, 134.37±8.44; Lt, 131.54±7.14; P>0.05). Further, the transverse measurements revealed that the mandibular body curve angle was larger on the right side (Rt, 140.28±7.05; Lt, 137.56±6.23; P<0.001). | Damaged, necrotic, or apoptotic hepatocytes release damage-associated molecular patterns that initiate sterile inflammation, and liver inflammation drives liver injury and fibrosis. Here we identified hepatic nuclear factor kappa B (NF-κB)-inducing kinase (NIK), a Ser/Thr kinase, as a novel trigger of fatal liver inflammation. NIK is activated by a broad spectrum of stimuli. It was up-regulated in injured livers in both mice and humans. In primary mouse hepatocytes, NIK overexpression stimulated, independently of cell injury and death, release of numerous chemokines and cytokines that activated bone marrow-derived macrophages (BMDMs). BMDMs in turn secreted proapoptotic molecules that stimulated hepatocyte apoptosis. Hepatocyte-specific expression of the NIK transgene triggered massive liver inflammation, oxidative stress, hepatocyte apoptosis, and liver fibrosis, leading to weight loss, hypoglycemia, and death. Depletion of Kupffer cells/macrophages reversed NIK-induced liver destruction and death. |
Does sacral Nerve Stimulation fail to Offer Long-term Benefit in Patients With Slow-Transit Constipation? | Sacral nerve stimulation is proposed as a treatment for slow-transit constipation. However, in our randomized controlled trial we found no therapeutic benefit over sham stimulation. These patients have now been followed-up over a long-term period. The purpose of this study was to assess the long-term efficacy of sacral nerve stimulation in patients with scintigraphically confirmed slow-transit constipation. This study was designed for long-term follow-up of patients after completion of a randomized controlled trial. It was conducted at an academic tertiary public hospital in Sydney. Adults with slow-transit constipation were included. At the 1- and 2-year postrandomized controlled trial, the primary treatment outcome measure was the proportion of patients who reported a feeling of complete evacuation on >2 days per week for ≥2 of 3 weeks during stool diary assessment. Secondary outcome was demonstration of improved colonic transit at 1 year. Fifty-three patients entered long-term follow-up, and 1 patient died. Patient dissatisfaction or serious adverse events resulted in 44 patients withdrawing from the study because of treatment failure by the end of the second year. At 1 and 2 years, 10 (OR = 18.8% (95% CI, 8.3% to 29.3%)) and 3 patients (OR = 5.7% (95% CI, -0.5% to 11.9%)) met the primary outcome measure. Colonic isotope retention at 72 hours did not differ between baseline (OR = 75.6% (95% CI, 65.7%-85.6%)) and 1-year follow-up (OR = 61.7% (95% CI, 47.8%-75.6%)). | Dengue is a mosquito-borne viral disease caused by the four dengue viruses (DENV-1 to 4) that can also be transmitted by blood transfusion and organ transplantation. The distribution of DENV in the components of blood from infected donors is poorly understood. We used an in-house TaqMan qRT-PCR assay to test residual samples of plasma, cellular components of whole blood (CCWB), serum and clot specimens from the same collection from blood donors who were DENV-RNA-reactive in a parallel blood safety study. To assess whether DENV RNA detected by TaqMan was associated with infectious virus, DENV infectivity in available samples was determined by culture in mosquito cells. DENV RNA was detected by TaqMan in all tested blood components, albeit more consistently in the cellular components; 78.8% of CCWB, 73.3% of clots, 86.7% of sera and 41.8% of plasma samples. DENV-1 was detected in 48 plasma and 97 CCWB samples while DENV-4 was detected in 21 plasma and 31 CCWB samples. In mosquito cell cultures, 29/111 (26.1%) plasma and 32/97 (32.7%) CCWB samples were infectious. A subset of samples from 29 donors was separately analyzed to compare DENV viral loads in the available blood components. DENV viral loads did not differ significantly between components and ranged from 3-8 log10 PCR-detectable units/ml. |
Do patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities? | The 34-gene classifier, ClearCode34, identifies prognostically distinct molecular subtypes of clear cell renal cell carcinoma (ccRCC) termed clear cell A (ccA) and clear cell B (ccB). The primary objective of this study was to describe clinical characteristics and comorbidities of relevance in patients stratified by ClearCode34. In this retrospective analysis, 282 patients from Moffitt Cancer Center with ccRCC with gene expression analyses of the primary tumor were identified and ClearCode34 was applied to identify tumors as ccA or ccB. The medical record and institutional databases were queried to define patient characteristics, comorbidities, and outcomes. We validated in this external cohort the superior overall survival, cancer-specific survival, and recurrence-free survival of ccA patients relative to ccB patients (P<0.001). Addressing other clinical characteristics, the ccA patients were more likely to be obese (48% vs. 34%, P = 0.021) and diabetic (26% vs. 13%, P = 0.035). The ccA patients also trended toward having been more frequent users of angiotensin system inhibitors (71% vs. 52%, P = 0.055). In multivariate analyses, ccB status is independently associated with inferior cancer-specific survival (hazard ratio = 3.26, 95% confidence interval: 1.84-5.79) and overall survival (hazard ratio = 2.50, 95% confidence interval: 1.53-4.08). | An increased incidence of necrotizing enterocolitis (NEC) has been noted in infants who are born to mothers with chorioamnionitis. Our objective was to test the hypothesis that newborn rat pups born to mothers exposed to prenatal lipopolysaccharide during pregnancy would be more susceptible to intestinal injury in a rat model of NEC and that the increased intestinal injury is mediated by dysregulation of inducible nitric oxide synthase. Time-dated pregnant Sprague-Dawley dams were given an intraperitoneal injection of either 2 mg/kg of lipopolysaccharide or vehicle. Rat pups from each group of dams were delivered at term and placed in a rat NEC model. A subset of pups was given either vehicle or aminoguanidine. Intestines were harvested and graded for degree of intestinal injury. Maternal prenatal lipopolysaccharide exposure increased the frequency and severity of intestinal injury in the neonatal rat NEC model. Treatment with aminoguanidine significantly decreased plasma nitric oxide levels. Additionally, aminoguanidine significantly decreased intestinal injury. |
Does dietary supplementation of carbonate promote spontaneous tumorigenesis in a rat gastric stump model? | Food supplements are known to affect the development of gastric adenocarcinoma. In this study, an animal model of gastric resection was used to investigate the effects of calcium carbonate on spontaneous development of gastric adenocarcinoma. Ninety-two Wistar rats with gastric resections (performed to induce spontaneous gastric cancer) and 60 without resections (controls) were used to analyse the carcinogenic potential of different ion supplements in food. Among the resected rats, cancer developed in 3 out of 18 (17%, NS) given NaCl but in 11 out of 18 (61%, p<0.01) exposed to calcium carbonate. No tumours were found in the unresected (unoperated) animals. These findings were further analysed by separately investigating the effects of calcium and carbonate ions on tumorigenesis in the gastric stump model. Cancer developed in one of 26 (4%) resected animals given a diet supplemented with CaHPO(4), which was lower than the rate observed in the resected control group fed a normal diet, although this difference was not statistically significant. However, tumour development increased significantly in the resected animals given a diet supplemented with NaHCO(3) (tumours in 13 out of 24 rats, 54%; p<0.01). | The clinical trial design for primary progressive multiple sclerosis (PPMS) requires understanding of disability progression in modern patient cohorts. The objective of this paper is to characterize demographic and clinical characteristics of PPMS and assess rate of disability progression. We studied PPMS (n = 73) and relapsing-onset MS (ROMS) patients (n = 1541) enrolled in CLIMB, a longitudinal study of MS patients at the Brigham and Women's Hospital (Boston, MA). Disability progression for each group was compared using interval-censored survival analysis and time to six-month sustained progression. The PP group had a 1.09:1 male:female ratio compared to 1:2.89 for the RO group and greater mean age of onset (PP: 44.4±9.6; RO: 32.7±9.9; p < 0.0001). Motor symptoms at onset and first symptoms localized to spinal cord were each strongly associated with PPMS (p < 0.001). Median time from onset to EDSS 6.0 was faster in PPMS (p < 0.001). PPMS patients progressed faster to EDSS 3 (p < 0.001) and from EDSS 3 to 6 (p < 0.001). Median time to sustained progression in the PP group was 4.85 years (95% CI 2.83-8.35), significantly faster than the RO group (p < 0.001). |
Is atherosclerosis in mice affected by a reduction in tissue factor expression? | To determine whether tissue factor (TF) contributes to the progression of atherosclerotic lesions in mice. We determined the effect of a 50% reduction of TF levels in all cells on atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. No differences were observed in the extent of atherosclerosis in apoE(-/-)/TF(+/+) and apoE(-/-)/TF(+/-) mice fed regular chow for 34 weeks. Atherosclerosis could not be analyzed in apoE(-/-) mice expressing low levels of TF because of premature death of these mice. Macrophages are a major source of TF in atherosclerotic plaques. Therefore, in a second series of experiments, we investigated the effect on atherosclerosis of selectively reducing hematopoietic cell-derived TF by transplanting bone marrow from mice expressing low levels of TF into low-density lipoprotein receptor deficient (LDLR(-/-)) mice. Atherosclerosis within the arterial tree and aortic root were similar in LDLR(-/-) mice with low-TF bone marrow compared with control bone marrow (TF(+/+) or TF(+/-)) after 4 and 16 weeks on an atherogenic diet. Furthermore, the cellular composition of the aortic root lesions was similar between the 2 groups. | Delirium has recently been shown as a predictor of death, increased cost, and longer duration of stay in ventilated patients. Sedative and analgesic medications relieve anxiety and pain but may contribute to patients' transitioning into delirium. In this cohort study, the authors designed a priori an investigation to determine whether sedative and analgesic medications independently increased the probability of daily transition to delirium. Markov regression modeling (adjusting for 11 covariates) was used in the evaluation of 198 mechanically ventilated patients to determine the probability of daily transition to delirium as a function of sedative and analgesic dose administration during the previous 24 h. Lorazepam was an independent risk factor for daily transition to delirium (odds ratio, 1.2 [95% confidence interval, 1.1-1.4]; P = 0.003), whereas fentanyl, morphine, and propofol were associated with higher but not statistically significant odds ratios. Increasing age and Acute Physiology and Chronic Health Evaluation II scores were also independent predictors of transitioning to delirium (multivariable P values < 0.05). |
Does loss of Bace1 in mice alter the severity of caerulein induced pancreatitis? | Beta-site alpha-amyloid protein cleaving enzyme1 (BACE1) plays a key role in the pathogenesis of Alzheimer's disease. Additional to its moderate expression in the brain, high levels of BACE1 mRNA were found in the pancreas. Murine Bace1 has been immunohistochemicaly detected at the apical pole of acinar cells within the exocrine pancreas of mice and Bace1 activity was observed in pancreatic juice. In vitro experiments revealed enteropeptidase as a putative substrate for Bace1 suggesting a role in acute pancreatitis. The aim of this study was to address a protective mechanism of Bace1 in acute experimental pancreatitis in mice. Acute experimental pancreatitis was induced by intraperitoneal injection of caerulein in homozygote Bace1-/- mice and wild type mice. Serum and tissue analyses were carried out after 4 h, 8 h and 24 h. Measurement of plasma amylase and lipase was performed to confirm pancreatitis induction. In order to assess the severity of pancreatitis H&E stained pancreatic sections were examined regarding edema, inflammation and apoptosis. Immunohistochemical detection of myeloperoxidase (MPO) positive cells was carried out to further quantify the extent of inflammation. Expression of Bace2 within the pancreas was analyzed by immunohistochemistry and RT-qPCR. We demonstrate that total loss of Bace1 in mice leads to no alterations in the course of acute experimental caerulein-pancreatitis. Bace1-/- mice develop a moderate pancreatitis that is comparable in histomorphological and serological features with those seen in wild type mice. | To investigate the relationship between follicular blood flow and the follicular fluid vascular endothelial growth factor (VEGF) and nitric oxide (NO) concentrations and to determine which factor might be a better predictor of the outcome of IVF-ET. Prospective study. Academic research laboratory. Forty-seven cycles of IVF (tubal factor, 25 cycles; male factor, 22 cycles) at the infertility clinic of Pusan National University Hospital from February 2002 to June 2002. Follicular blood flow was estimated on the day of hCG administration. Each follicular fluid sample was collected at oocyte retrieval, and follicular fluid VEGF and NO concentrations were assessed. Follicular blood flow and follicular fluid VEGF and NO concentrations according to the age of patients, the cause of infertility, and pregnancy rate. Of 47 cycles, 18 (38.3%) cycles resulted in a pregnancy. Follicular blood flow was significantly higher in the pregnant group compared with the nonpregnant group, but there was no statistically significant difference in age and infertility cause. Follicular fluid concentrations of VEGF and NO did not show statistically significant differences in age, infertility cause, or pregnancy outcome. As the follicle size increases, the follicular blood flow and follicular fluid VEGF concentrations increased significantly but the follicular fluid NO concentrations decreased. There was no correlation between VEGF and NO concentrations in the follicular fluid by linear regression analysis. |
Is low-molecular-weight heparinoid orgaran more effective than aspirin in the prevention of venous thromboembolism after surgery for hip fracture? | The study objective was to determine the relative efficacy and safety of a low-molecular-weight heparinoid (Orgaran) compared with aspirin for the prevention of postoperative venous thromboembolism in patients undergoing surgery for fractured hips. A double-blind, randomized, controlled trial was used to study 251 consecutive eligible and consenting patients undergoing surgery for hip fracture in seven participating hospitals. Patients received either fixed-dose Orgaran by subcutaneous injection every 12 hours in a dose of 750 anti-Factor Xa units or aspirin 100 mg orally twice daily; both regimens were started 12 to 24 hours after surgery and continued for 14 days or until discharge, if sooner. All patients had postoperative 125I-fibrinogen leg scanning and impedance plethysmography. If the results of one or both tests were positive, then venography was performed. Otherwise, venography was done at day 14, or sooner if the patient was ready for discharge. Pulmonary embolism in symptomatic patients was diagnosed on the basis of a high probability perfusion/ventilation lung scan, a positive angiogram, or a clinically significant embolism detected at autopsy. Evaluable venograms were obtained in 90 of the 125 patients randomly assigned to receive Orgaran and in 87 of the 126 patients assigned to receive aspirin. Venous thromboembolism was detected in 25 (27.8%) patients in the Orgaran group and in 39 (44.3%) patients in the aspirin group. Thus, there was a relative risk reduction of 37% with Orgaran (P=.028; 95% confidence interval, 3.7% to 59.7%). Six (6.8%) of 88 patients in the Orgaran group and 12 (14.3%) of 84 patients in the aspirin group developed proximal deep vein thrombosis or pulmonary embolism, a relative risk reduction of 52% with Orgaran (P=.137; 95% confidence interval, -30.7% to 84.6%). Hemorrhagic complications occurred in 2 (1.6%) patients given Orgaran and 8 (6.4%) patients given aspirin (P=.10). There was one major bleed in the Orgaran group compared with four in the aspirin group. | Urinary concentrating defects and polyuria are the most important renal manifestations of hypercalcemia and the resulting hypercalciuria. In this study, we tested the hypothesis that hypercalciuria-associated polyuria in kidney collecting duct occurs through an impairment of the vasopressin-dependent aquaporin 2 (AQP2) water channel targeting to the apical membrane possibly involving calcium-sensing receptor (CaR) signaling. AQP2-transfected collecting duct CD8 cells were used as experimental model. Quantitation of cell surface AQP2 immunoreactivity was performed using an antibody recognizing the extracellular AQP2 C loop. Intracellular cyclic adenosine monophosphate (cAMP) accumulation was measured in CD8 cells using a cAMP enzyme immunoassay kit. To study the translocation of protein kinase C (PKC), membranes or cytosol fractions from CD8 cells were subjected to Western blotting using anti-PKC isozymes antibodies. The amount of F-actin was determined by spectrofluorometric techniques. Intracellular calcium measurements were performed by spectrofluorometric analysis with Fura-2/AM. We demonstrated that extracellular calcium (Ca2+ o) (5 mmol/L) strongly inhibited forskolin-stimulated increase in AQP2 expression in the apical plasma membrane. At least three intracellular pathways activated by extracellular calcium were found to contribute to this effect. Firstly, the increase in cAMP levels in response to forskolin stimulation was drastically reduced in cells pretreated with Ca2+ o compared to untreated cells. Second, Ca2+ o activated PKC, known to counteract vasopressin response. Third, quantification of F-actin demonstrated that Ca2+ o caused a nearly twofold increase in F-actin content compared with basal conditions. All these effects were mimicked by a nonmembrane permeable agonist of the extracellular CaR, Gd3+. |
Does the expression of vascular endothelial growth factor in mast cells promote the neovascularisation of human pterygia? | To analyse the relationship between mast cells and vascularisation in pterygia and to determine whether mast cells play an important role in the vascularisation of pterygia through the secretion of vascular endothelial growth factor (VEGF). Fifty-two pterygia and forty-four normal conjunctiva samples were obtained. Formalin-fixed, paraffin wax-embedded tissues were analysed by immunohistochemistry with CD31 and VEGF antibodies. Dual-immunofluorescence was used to see the location of mast cells and microvessels. To prove that mast cells have the function of secreting VEGF, we used dual-immunofluorescence, toluidine blue stain and immunohistochemisty study. Mast cells are located near the microvessels. The numbers of mast cells in pterygia (10.8 ± 2.7) were significantly higher compared with those in conjunctiva (4.7 ± 2.4, p<0.01). The numbers of microvessels in pterygia (20.7 ± 5.4) were also significantly higher than those in conjunctiva (9.3 ± 2.9, p<0.01). There was an association between mast cell count and microvessel density in pterygia (r=0.77, p<0.001). The cells were positive for toluidine blue staining and could express VEGF through a serial section stain. Dual-immunofluorescence showed that VEGF and mast cell tryptase (MCT) were expressed in the same cell. | The GNB3 C825T polymorphism has been shown to affect lipid parameters, atherosclerosis progression, and incidence of myocardial infarction (MI). Therefore, we assessed whether the effectiveness of statins in reducing the risk of MI was modified by the GNB3 C825T polymorphism. In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they used antihypertensive drugs and had a diagnosis of hypercholesterolemia before their first MI. Controls met the same eligibility criteria, but were not hospitalized for MI. Logistic regression analysis was used to calculate odds ratios (OR) and synergy index with corresponding 95% confidence intervals (CI), and to adjust for potential confounding factors. We included 459 cases and 1805 controls. The risk of MI was significantly lower among participants exposed to statins compared with participants not exposed to statins (adjusted OR: 0.37, 95% CI: 0.29-0.47). The GNB3T allele was associated with a reduced risk of MI (adjusted OR: 0.74, 95% CI: 0.60-0.92). Among homozygous wild-type (CC) individuals (n=1119), exposure to statins was associated with a lower risk of MI (OR: 0.48, 95% CI: 0.34-0.67). However, T allele carriers (CT and TT) who used statins had an even stronger reduced risk of MI (OR: 0.27, 95% CI: 0.19-0.39). Overall, the interaction between exposure to statins and the GNB3 C825T polymorphism was significantly increased on the multiplicative scale (synergy index: 1.67, 95% CI: 1.06-2.65). |
Does α-Enolase play a catalytically independent role in doxorubicin-induced cardiomyocyte apoptosis and mitochondrial dysfunction? | α-Enolase is a glycolytic enzyme with "second jobs" beyond its catalytic activity. However, its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the role of α-enolase in doxorubicin (Dox)-induced cardiomyopathy as well as the underlying mechanisms. The expression of α-enolase was detected in rat hearts and primary cultured rat cardiomyocytes with or without Dox administration. An adenovirus carrying short-hairpin interfering RNA targeting α-enolase was constructed and transduced specifically into the heart by intramyocardial injection. Heart function, cell apoptosis and mitochondrial function were measured following Dox administration. In addition, by using gain- and loss-of-function approaches to regulate α-enolase expression in primary cultured rat cardiomyocytes, we investigated the role of endogenous, wide type and catalytically inactive mutant α-enolase in cardiomyocyte apoptosis and ATP generation. Furthermore, the involvement of α-enolase in AMPK phosphorylation was also studied. The mRNA and protein expression of cardiac α-enolase was significantly upregulated by Dox. Genetic silencing of α-enolase in rat hearts and cultured cardiomyocytes attenuated Dox-induced apoptosis and mitochondrial dysfunction. In contrast, overexpression of wide-type or catalytically inactive α-enolase in cardiomyocytes mimicked the detrimental role of Dox in inducing apoptosis and ATP reduction. AMPK dephosphorylation was further demonstrated to be involved in the proapoptotic and ATP-depriving effects of α-enolase. | To explore the possibility of identifying skull fracture, with or without clinical signs, as a predictor of positive CT scans in mild traumatic brain injury (mTBI). Prospective cohort study, matched 1:1 for five potential confounding variables (age, sex, symptoms, mechanism of injury and extracranial trauma severity). The study was performed on patients with mTBI (Glasgow Coma Scale 15-14), with or without radiologically demonstrated skull fracture. The cohort with skull fracture included 155 patients selected from a sample of 5097 mTBI patients treated during 1998 at the Critical Care and Emergency Department of the Trauma Centre. The cohort without skull fracture was prospectively recruited from patients with mTBI treated in the same department from 2002-2005. The percentage of patients with intracranial lesion (IL) was significantly higher in mTBI patients with skull fracture than in those without. The risk of requiring neurosurgery was 5-fold higher when skull fracture was present. Of mTBI patients with skull fracture and IL, 63.2% showed no clinical signs of bone injury. |
Is television news exposure related to fear of breast cancer? | This study assessed the relationship between exposure to breast cancer content in television news programs and fear of breast cancer. A quantitative standardized Health and Media Interview Survey was administered to a random sample of 500 Flemish women aged 18-85 years in 2007. The survey contained closed measures on demographics, breast cancer fear, television exposure and potential confounding variables such as trait anxiety, perceived risk and experience with breast cancer. 80.6% of the women were moderately to very afraid of being diagnosed with breast cancer. Multinomial logistic regression results showed that women who had occasionally been exposed to breast cancer content in television news were 1.9 times more likely to be very afraid of breast cancer (95% CI 1.1-3.4). Women who had frequently been exposed were 3.3 times more likely to be moderately afraid (95% CI 1.1-10), and 7.5 times more likely to be very afraid of breast cancer (95% CI 2.4-23.8). | Renal ischemia-reperfusion (I/R) injury is a major cause of acute renal failure (ARF). The transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated as a key mediator of reperfusion injury. Activation of NF-kappaB is dependent upon the phosphorylation of its inhibitor, IkappaB, by the specific inhibitory kappaB kinase (IKK) subunit, IKKbeta. We hypothesized that ischemic preconditioning (IPC) reduces acute renal damage following I/R injury by inhibiting activation of IKKbeta. As neutrophil gelatinase-associated lipocalin (NGAL), an early predictive biomarker of acute kidney injury, is regulated by NF-kappaB, we approached the relationship between NGAL and IKKbeta. Thirty male Sprague-Dawley rats were randomly divided into 3 groups after right kidney nephrectomy. Group A rats were sham-operated controls. Group B rats were 45-min ischemic in the left renal artery while Group C rats were pre-treated with 3 cycles of 2-min ischemia and 5-min reperfusion. All the rats were sacrificed at 24 h after reperfusion. We harvested kidneys and serum to do further analysis, including histological and functional parameters, expressions of NGAL and IKKbeta in renal tissues. Compared with rats subjected to I/R injury, pre-treated rats had a significant decrease in serum creatinine level (Scr) and tubulointerstitial injury scores (Scr, 86.79 +/- 12.98 vs. 205.89 +/- 19.16 mircomol/l, p < 0.01; tubulointerstitial injury scores, 1.3 +/- 0.48 vs. 3.8 +/- 0.79, p < 0.01). In addition, expressions of IKKbeta (0.95 +/- 0.21 vs. 1.74 +/- 0.17, p < 0.05) and NGAL (1.71 +/- 0.032 vs. 2.66 +/- 0.078, p < 0.05) at renal tubule in pre-treated rats were attenuated significantly compared with rats subjected to ischemia-reperfusion injury. Moreover, our study showed that IKKbeta and NGAL were in positive correlation (R = 0.965 > R(0.01)(30) = 0.448, p < 0.01). |
Does tanshinone II a protect against lipopolysaccharides-induced endothelial cell injury via Rho/Rho kinase pathway? | To test whether tanshinone II A (Tan II A), a highly valued herb derivative to treat vascular diseases in Chinese medicine, could protect endothelial cells from bacterial endotoxin (lipopolysaccharides, LPS)-induced endothelial injury. Endothelial cell injury was induced by treating human umbilical vein endothelial cells (HUVECs) with 0.2 μg/mL LPS for 24 h. Y27632 and valsartan were used as positive controls. The effects of tanshinone II A on the LPS-induced cell viability and apoptosis rate of HUVECs were tested by flow cytometry, cell migration by transwell, adhesion by a 96-well plate pre-coated with vitronectin and cytoskeleton reorganization by immunofluorescence assay. Rho/Rho kinase (ROCK) pathway-associated gene and protein expression were examined by microarray assay; quantitative real-time polymerase chain reaction and Western blotting were used to confirm the changes observed by microarray. Tan II A improved cell viability, suppressed apoptosis and protected cells from LPS-induced reductions in cell migration and adhesion at a comparable magnitude to that of Y27632 and valsartan. Tan II A, Y27632 and valsartan also normalized LPS-induced actomyosin contraction and vinculin protein aggregation. A microarray assay revealed increased levels of fibronectin, integrin A5 (ITG A5), Ras homolog gene family member A (RhoA), myosin light chain phosphatase, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K, or PIP2 in Western blotting), focal adhesion kinase, vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in the damaged HUVECs, which were attenuated to different degrees by Tan II A, Y27632 and valsartan. | Low plasma IgG levels have long been reported as an important complication of the nephrotic syndrome. Few studies in vivo have evaluated IgG synthesis in nephrotic patients and no data are available on the effect of dietary protein restriction on the rate of IgG synthesis. We compared the IgG synthesis rates of seven nephrotic patients who assumed, for 4 weeks, either a normal protein diet (NPD) (1.20+/-0.06 g/kg/day) or a low-protein diet (LPD) (0.66+/-0.04 g/kg/day) with those of seven normal subjects (matched for age and body mass index). The post-absorptive fractional synthesis rate (FSR) and absolute synthesis rate (ASR) of IgG were evaluated during the last 120 min of a 5 h 5,5,5-D3-l-leucine infusion. Compared with controls, in nephrotic patients the plasma IgG levels and pool were significantly reduced (P<0.05), while IgG FSR and ASR were increased by 4- and 2.5-fold, respectively (P<0.05). The LPD regimen did not affect plasma IgG FSR, ASR, circulating concentrations and intravascular pool (P = NS). There was a significant negative correlation between plasma IgG FSR and the IgG intravascular pool in nephrotic patients evaluated during both the NPD (r = -0.828; P<0.05) and LPD (r = -0.861; P<0.05) regimens. |
Is palmitate-Induced MMP-9 Expression in the Human Monocytic Cells Mediated through the TLR4-MyD88 Dependent Mechanism? | 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. | To present a novel method for analyzing the voltage waveform from high-frequency X-ray generators for radiographic systems. The output signal of the actual voltage across the tube of a high-frequency generator was measured using the built-in voltage sense taps that are used for voltage regulation feedback in X-ray generators. The output signal was stored in an analyzing recorder, and the waveforms were analyzed using FFT analysis. The FFT analysis of high-frequency generators consisted of obtaining the power spectrum, comparing the major frequency components in the tube voltage waveforms, and examining the intensity of each frequency component. FFT analysis enables an objective comparison of the complex tube voltage waveforms in high-frequency X-ray generators. FFT analysis detected the change in the X-ray tube voltage waveform that occurred when there were problems with the high-frequency generator. |
Do axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties? | Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies associated with mutations or copy number variations in over 70 genes encoding proteins with fundamental roles in the development and function of Schwann cells and peripheral axons. Here, we used iPSC-derived cells to identify common pathophysiological mechanisms in axonal CMT. iPSC lines from patients with two distinct forms of axonal CMT (CMT2A and CMT2E) were differentiated into spinal cord motor neurons and used to study axonal structure and function and electrophysiological properties in vitro. iPSC-derived motor neurons exhibited gene and protein expression, ultrastructural and electrophysiological features of mature primary spinal cord motor neurons. Cytoskeletal abnormalities were found in neurons from a CMT2E (NEFL) patient and corroborated by a mouse model of the same NEFL point mutation. Abnormalities in mitochondrial trafficking were found in neurons derived from this patient, but were only mildly present in neurons from a CMT2A (MFN2) patient. Novel electrophysiological abnormalities, including reduced action potential threshold and abnormal channel current properties were observed in motor neurons derived from both of these patients. | Enhanced processing of emotional stimuli after stress exposure is reported to be associated with stress-induced cortisol. Because enhanced emotional information processing could make cognitive emotion regulation more difficult, it was hypothesized that stress-induced cortisol would be associated with non-negative interpretation generation associated with the cognitive reappraisal processes. A total of 36 participants (Mean age = 21.3 years, SD = 1.8) watched video clips of depression-related stressful situations before and after the administration of a stress induction task. They were then asked to generate as many non-negative interpretations as possible to reduce the depressive mood. Saliva samples were obtained before and after the stress induction task to measure change in the cortisol level. Participants were allocated post-hoc to either a responder (n = 19) or non-responder group (n = 17) based on the cortisol response to the stress induction task. The number of non-negative interpretations generated following the stress induction task was reduced only in the cortisol responders. The number of post-stress non-negative interpretations was fewer in the responder group when compared by sex, baseline cortisol level, and the number of pre-stress non-negative interpretations, statistically controlled. |
Do progesterone 's effects to reduce anxiety behavior of aged mice require actions via intracellular progestin receptors? | Aging is associated with reduced secretion of, and down-regulation of receptors for, progesterone (P); yet, P's effects when administered to younger and older animals have not been systematically investigated. Some of P's antianxiety effects may be due to its conversion to 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) and its subsequent actions as a positive modulator at GABAA receptor complexes (GBRs). We investigated whether P administration can decrease anxiety behavior of progestin receptor (PR) knockout (PRKO) or wild-type control mice. P (10 mg/kg) or vehicle (propylene glycol) were administered subcutaneously to intact, female or male wild-type or PRKO mice that were either 9-12 or 18-24 months of age. Behavior in tasks that assess spontaneous activity (activity monitor and roto-rod), free exploration of a novel environment (open field, elevated plus maze, and elevated zero maze), and conflict behavior (mirror chamber, dark-light transition, and punished drinking) were examined 1 h after injection. P significantly decreased anxiety behavior of both PRKO and wild-type mice. P did not alter motor behavior but increased central entries in the open field, time in the open quadrants of the elevated zero maze, time in the mirrored chamber, time in the light compartment of the dark-light transition, and punished drinking in young and old mice. P-administered mice had higher levels of hippocampal 3alpha,5alpha-THP and GABA-stimulated chloride flux than did vehicle-administered PRKO or wild-type mice. | Tuberculous pericarditis is considered to be a paucibacillary process; the large pericardial fluid accumulation is attributed to an inflammatory response to tuberculoproteins. Mortality rates are high. We investigated the role of clinical and microbial factors predictive of tuberculous pericarditis mortality using the artificial intelligence algorithm termed classification and regression tree (CART) analysis. Patients were prospectively enrolled and followed in the Investigation of the Management of Pericarditis (IMPI) registry. Clinical and laboratory data of 70 patients with confirmed tuberculous pericarditis, including time-to-positive (TTP) cultures from pericardial fluid, were extracted and analyzed for mortality outcomes using CART. TTP was translated to log10 colony forming units (CFUs) per mL, and compared to that obtained from sputum in some of our patients. Seventy patients with proven tuberculous pericarditis were enrolled. The median patient age was 35 (range: 20-71) years. The median, follow up was for 11.97 (range: 0·03-74.73) months. The median TTP for pericardial fluid cultures was 22 (range: 4-58) days or 3.91(range: 0·5-8·96) log10CFU/mL, which overlapped with the range of 3.24-7.42 log10CFU/mL encountered in sputum, a multi-bacillary disease. The overall mortality rate was 1.43 per 100 person-months. CART identified follow-up duration of 5·23 months on directly observed therapy, a CD4 + count of ≤ 199.5/mL, and TTP ≤ 14 days (bacillary load ≥ 5.53 log10 CFU/mL) as predictive of mortality. TTP interacted with follow-up duration in a non-linear fashion. |
Do [ CHL prevent colon neoplasms in mice and its selective inhibition on COX-2 ]? | Chlorophyllin (CHL) was proved to have strong anti-inducement effect toward many mutagens and epicarcinogens. This study was to explore effect of CHL in preventing colon neoplasms in mice induced by dimethylhydrazine (DMH), and the selective inhibition on cyclooxygenase 2(COX-2). The colorectal neoplasms were induced with DMH in mice and the different dose of CHL were administered in different phases, then the prevention of colorectal neoplasms by CHL was examined; The IC50 and growth curve of HT29 cells were measured with MTT method after treated with CHL; The effect of CHL on the expression of COX-1 mRNA and COX-2 mRNA in HT29 cells were measured with RT-PCR method; The effect of CHL on the expression of COX-2 protein and NF-kappaB protein were measured with western blot and immunohistochemistry methods. The incidence of colon cancer, average tumor amount, and percentage of carcinoma in CHL group were significantly lower than those in DMH group (P< .05); CHL could inhibit the growth of HT29 cells. The effects were dose dependent; CHL could selectively inhibit the expression of COX-2mRNA in HT29 cells,the expression of COX-2 protein in colon neoplasms and HT29 cells, and the expression of NF-kappaB protein in colon neoplasms. | For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the "preclinical" (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD. We investigated the relation between structural neuroimaging measures (whole-brain volume) and levels of CSF amyloid-beta (Abeta)(40), Abeta(42), tau, and phosphorylated tau(181) (ptau(181)), and plasma Abeta(40) and Abeta(42) in well-characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age-matched, cognitively normal control subjects (n = 69). Levels of CSF tau and ptau(181), but not Abeta(42), correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Abeta(42), but not tau or ptau(181), were positively correlated with whole-brain volume in nondemented control subjects. |
Is a high-performance liquid chromatography method for the serotonin release assay equivalent to the radioactive method? | The serotonin release assay (SRA) is considered the gold standard laboratory test for heparin-induced thrombocytopenia (HIT). The historic SRA method uses platelets loaded with radiolabeled serotonin to evaluate platelet activation by HIT immune complexes. However, a nonradioactive method is desirable. We report the performance characteristics of a high-performance liquid chromatography (HPLC) SRA method. We validated the performance characteristics of an HPLC-SRA method, including correlation with a reference laboratory using the radioactive method. Serotonin released from reagent platelets was quantified by HPLC using fluorescent detection. Results were expressed as % release and classified as positive, negative, or indeterminate based on previously published cutoffs. Serum samples from 250 subjects with suspected HIT were tested in the HPLC-SRA and with the radioactive method. Concordant classifications were observed in 230 samples (92%). Sera from 41 healthy individuals tested negative. Between-run imprecision studies showed standard deviation of <6 (% release) for positive, weak positive, and negative serum pools. Stability studies demonstrated stability after two freeze-thaw cycles or up to a week of refrigeration. | Dacts are multi-domain adaptor proteins. They have been implicated in Wnt and Tgfβ signaling and serve as a nodal point in regulating many cellular activities. Dact genes have so far only been identified in bony vertebrates. Also, the number of Dact genes in a given species, the number and roles of protein motifs and functional domains, and the overlap of gene expression domains are all not clear. To address these problems, we have taken an evolutionary approach, screening for Dact genes in the animal kingdom and establishing their phylogeny and the synteny of Dact loci. Furthermore, we performed a deep analysis of the various Dact protein motifs and compared the expression patterns of different Dacts. Our study identified previously not recognized dact genes and showed that they evolved late in the deuterostome lineage. In gnathostomes, four Dact genes were generated by the two rounds of whole genome duplication in the vertebrate ancestor, with Dact1/3 and Dact2/4, respectively, arising from the two genes generated during the first genome duplication. In actinopterygians, a further dact4r gene arose from retrotranscription. The third genome duplication in the teleost ancestor, and subsequent gene loss in most gnathostome lineages left extant species with a subset of Dact genes. The distribution of functional domains suggests that the ancestral Dact function lied with Wnt signaling, and a role in Tgfβ signaling may have emerged with the Dact2/4 ancestor. Motif reduction, in particular in Dact4, suggests that this protein may counteract the function of the other Dacts. Dact genes were expressed in both distinct and overlapping domains, suggesting possible combinatorial function. |
Is fragmented QRS associated with frequency of premature ventricular contractions in patients without overt cardiac disease? | In this study, we aimed to demonstrate whether the presence of fragmented QRS (fQRS) is associated with the frequency of premature ventricular contractions (PVCs). We retrospectively analyzed 282 cases by 24-hour Holter monitorings (HMs) between August 2012 and February 2013. Firstly, the patients were divided into 2 groups with respect to presence of fQRS and then divided into 3 groups with respect to frequency of PVCs as Group 1: seldom PVC (<120 PVCs/day), Group 2: moderate-frequency PVC (120-720 PVCs/day), and Group 3: frequent PVC (>720 PVCs/day). We investigated the predictors of frequent PVCs by using multinomial logistic regression analysis. Ninety-eight patients had fQRS. There was no difference between the 2 groups with respect to body mass index, gender, hypertension, and diabetes mellitus. Patients with fQRS were older (54.9±15.6 vs. 47.0±16.3, p<0.001) and had more family history of coronary artery disease (25% vs. 13%, p=0.012). Patients with fQRS was more likely to be on aspirin therapy (28.6% vs. 10.4%, p<0.001) and have a larger left atrium diameter (33.5±5.7 vs. 30.4±5.8, p=0.001). Presence of fQRS was significantly associated with the frequency of PVCs (for frequent PVC 27.7% vs. 7.6%, p<0.001; for moderate-frequency PVC 18.4% vs. 11.4%, p=0.012); 26.2% of Group 1 (n=202) had fQRS, 46.2% of Group 2 (n=39) had fQRS, and 65.9% of Group 3 (n=41) had fQRS. In the multinomial regression analysis, only age (odds ratio: 4.24, 95% confidence interval 2.08-8.64, p=0.001) and fQRS (odds ratio: 2.11, 95% confidence interval 1.00-4.45, p=0.05) were predictors of frequent PVCs. | Much research effort has been focused on investigating new compounds derived from low-cost sources, such as natural products, for treating leishmaniasis. Oleuropein derived from numerous plants, particularly from the olive tree, Olea europaea L. (Oleaceae), is a biophenol with many biological activities. Our previous findings showed that oleuropein exhibits leishmanicidal effects against three Leishmania spp. in vitro, and minimizes the parasite burden in L. donovani-infected BALB/c mice. The aim of the present study is to investigate the possible mechanism(s) that mediate this leishmanicidal activity. We determined the efficacy of oleuropein in elevating ROS and NO production in L. donovani-infected J774A.1 macrophages and in explanted splenocytes and hepatocytes obtained from L. donovani-infected BALB/c mice. We also assessed the expression of genes that are related to inflammation, T-cell polarization and antioxidant defense, in splenocytes. Finally, we determined the ratios of specific IgG2a/IgG1 antibodies and DTH reactions in L. donovani-infected BALB/c mice treated with oleuropein. Oleuropein was able to elevate ROS production in both in vitro and in vivo models of visceral leishmaniasis and raised NO production in ex vivo cultures of splenocytes and hepatocytes. The extensive oxidative stress found in oleuropein-treated mice was obviated by the upregulation of the host's antioxidant enzyme (mGCLC) and the simultaneous downregulation of the corresponding enzyme of the parasite (LdGCLC). Moreover, oleuropein was able to mount a significant Th1 polarization characterized by the expression of immune genes (IL-12β, IL-10, TGF-β1, IFN-γ) and transcription factors (Tbx21 and GATA3). Moreover, this immunomodulatory effect was also correlated with an inhibitory effect on IL-1β gene expression, rather than with the expression of IL-1α, IL-1rn and TNF-α. Furthermore, oleuropein-treated BALB/c mice mounted a delayed-type hypersensitivity (DTH) response and an elevated Leishmania-specific IgG2a/IgG1 ratio that clearly demonstrated an in vivo protective mechanism. |
Is soluble interleukin-2 receptor alpha elevated in sera of patients with benign ovarian neoplasms and epithelial ovarian cancer? | Previous studies have established that soluble interleukin-2 receptor alpha (sIL-2R alpha) levels are elevated in ascites and sera from individuals with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] Stage III/IV). This study was undertaken to evaluate sIL-2R alpha levels in individuals with benign ovarian neoplasms and early stage ovarian cancer (FIGO Stage I/II). Comparison with CA 125 levels was performed to assess screening potential. Sera from 92 healthy individuals, 61 with benign adnexal masses, 12 patients with FIGO Stage I/II ovarian cancers, and 27 patients with FIGO Stage III/IV ovarian cancers were assayed for sIL-2R alpha by enzyme-linked immunosorbent assay and CA 125 by radioimmunoassay. The mean serum sIL-2R alpha levels for benign pelvic masses, and Stage I/II and Stage III/IV epithelial ovarian cancer were 1507 +/- 82, 1631 +/- 274, and 2596 +/- 384 U/ml, respectively. The difference between mean serum sIL-2R alpha levels in individuals with benign adnexal masses and Stage III/IV epithelial ovarian cancer was statistically significant (P < 0.05). In addition, of the four individuals with FIGO Stage I/II ovarian cancer who had CA125 levels below 35 U/ml, the accepted upper limit of normal, three patients had elevated serum sIL-2R alpha levels. Eleven of 12 patients (92%) with potentially curable Stage I/II disease had elevated serum levels of either sIL-2R alpha or CA125 and 8 of 12 (67%) had elevations of both sIL-2R alpha and CA125. Sensitivity and specificity of a combination of CA 125 and soluble IL-2R alpha were 88.5% and 27.1%, respectively. | To investigate the effect of stimulation of toss simulated at sea on shock in severe burn rabbits. One hundred and thirty-two rabbits were randomly divided into normal control group (NC group, n = 6), toss group (T group, with treatment of continuous toss, n = 42), burn group (B group, with treatment of burn, n = 42), burn and toss (BT group, with treatment of continuous toss after burn, n = 42). The level of Cr, BUN, HCT and LA from blood samples in T, BT, B groups were observed at 2, 6, 8, 12, 24, 36, 48 post treatment hour (PTH). The changes in urinary volume was measured during 48 PTH. The histopathologic changes in kidney were observed at above-mentioned time points. The above indices in NC group were also observed. The mean urinary volume in B group during the first and second 24 PTH was (2.59 +/- 0.23) and (2.86 +/- 0.29) mL/h, while that in BT group was (1.61 +/- 0.13) and (1.66 +/- 0.16) mL/h respectively, which were all lower than those in NC group (6.06 +/- 0.18 mL/h, P < 0.01). The levels of HCT and LA in BT group were obviously higher than those in B group at each time point. The levels of Cr and BUN in BT group at 24, 36, 48 PTH were significantly higher than those in B group. The histopathological observation showed the capillary vessels and mesenchymal cells of kidney glomerulus were congestive, epithelial cells in kidney tubules were swollen. The infiltration degree of inflammatory cells in kidney tubule, and the pathological changes of erythrocyte cast in BT group were more serious than those in B group. |
Does hyperintense cortical signal on magnetic resonance imaging reflect focal leukocortical encephalitis and seizure risk in progressive multifocal leukoencephalopathy? | To determine the frequency of hyperintense cortical signal (HCS) on T1-weighted precontrast magnetic resonance (MR) images in progressive multifocal leukoencephalopathy (PML) patients, its association with seizure risk and immune reconstitution inflammatory syndrome (IRIS), and its pathologic correlate. We reviewed clinical data including seizure history, presence of IRIS, and MR imaging scans from PML patients evaluated at our institution between 2003 and 2012. Cases that were diagnosed either using cerebrospinal fluid JC virus (JCV) polymerase chain reaction, brain biopsy, or autopsy, and who had MR images available were included in the analysis (n=49). We characterized pathologic findings in areas of the brain that displayed HCS in 2 patients and compared them with isointense cortex in the same individuals. Of 49 patients, 17 (34.7%) had seizures and 30 (61.2%) had HCS adjacent to subcortical PML lesions on MR images. Of the 17 PML patients with seizures, 15 (88.2%) had HCS compared with 15 of 32 (46.9%) patients without seizures (p=0.006). HCS was associated with seizure development with a relative risk of 4.75 (95% confidence interval=1.2-18.5, p=0.006). Of the 20 patients with IRIS, 16 (80.0%) had HCS compared with 14 of 29 (49.3%) patients without IRIS (p=0.04). On histological examination, HCS areas were associated with striking JCV-associated demyelination of cortical and subcortical U fibers, significant macrophage infiltration, and a pronounced reactive gliosis in the deep cortical layers. | Maritime pine (Pinus pinaster Aiton) grows in a range of different climates in the southwestern Mediterranean region and the existence of a variety of latitudinal ecotypes or provenances is well established. In this study, we have conducted a deep analysis of the transcriptome in needles from two P. pinaster provenances, Leiria (Portugal) and Tamrabta (Morocco), which were grown in northern Spain under the same conditions. An oligonucleotide microarray (PINARRAY3) and RNA-Seq were used for whole-transcriptome analyses, and we found that 90.95% of the data were concordant between the two platforms. Furthermore, the two methods identified very similar percentages of differentially expressed genes with values of 5.5% for PINARRAY3 and 5.7% for RNA-Seq. In total, 6,023 transcripts were shared and 88 differentially expressed genes overlapped in the two platforms. Among the differentially expressed genes, all transport related genes except aquaporins were expressed at higher levels in Tamrabta than in Leiria. In contrast, genes involved in secondary metabolism were expressed at higher levels in Tamrabta, and photosynthesis-related genes were expressed more highly in Leiria. The genes involved in light sensing in plants were well represented in the differentially expressed groups of genes. In addition, increased levels of hormones such as abscisic acid, gibberellins, jasmonic and salicylic acid were observed in Leiria. |
Does two-hour insulin determination improve the ability of abdominal fat measurement to identify risk for the metabolic syndrome? | Visceral obesity is shown to be a predictor of morbidity and mortality. We evaluated the association of measurements of generalized adiposity and visceral fat area (VFA), with abnormalities of metabolic syndrome (MS). Seventy-six women (47.9 +/- 9.2 years) with BMI of 38.7 +/- 5.4 kg/m(2) underwent anthropometric measurements, laboratory procedures, bioeletrical impedance, and abdominal computed tomography (CT) scan. Diagnosis of MS was based on the presence of abdominal obesity and at least two of the following components: hypertension, dyslipidemia, and glucose intolerance and/or hyperinsulinemia. BMI was correlated with both components of adipose tissue--subcutaneous (r = 0.66, P < 0.01) and VFA (r = 0.33, P < 0.02)--and leptin levels (r = 0.38, P < 0.01). In contrast, VFA was correlated with 2-h glucose and insulin levels (r = 0.32 and 0.35, P < 0.05, respectively), triglyceride, HDL cholesterol, and uric acid (r = 0.33, -0.34 and 0.24, P < 0.05, respectively). Subjects with high VFA, matched for BMI, showed greater plasma glucose area under the curve (621 +/- 127 vs. 558 +/- 129 mg x h(-1) x dl(-1), P < 0.05), 2-h insulin (804 +/- 599 vs. 579 +/- 347 pmol/l, P < 0.05), and uric acid levels (0.33 +/- 0.07 vs. 0.26 +/- 0.06 mmol/l, P < 0.05) than subjects with low VFA. In logistic regression analysis, waist circumference, VFA, and 2-h insulin were identified as independent predictors of MS. Receiver operating characteristic curve analysis pointed out the values of 104 cm for waist circumference (58.1% specificity, 84.1% sensitivity), 158.5 cm(2) for VFA (78.1% specificity, 52.3% sensitivity), and 559.8 pmol/l for 2-h insulin (71.9% specificity, 69.8% sensitivity); the presence of at least two of the three variables resulted in a degree of concordance of 76%. | Inosine, a naturally occurring purine nucleoside, has been shown to stimulate axonal growth in cell culture and promote corticospinal tract axons to sprout collateral branches after stroke, spinal cord injury and TBI in rodent models. To explore the effects of inosine on the recovery of motor function following cortical injury in the rhesus monkey. After being trained on a test of fine motor function of the hand, monkeys received a lesion limited to the area of the hand representation in primary motor cortex. Beginning 24 hours after this injury and continuing daily thereafter, monkeys received orally administered inosine (500 mg) or placebo. Retesting of motor function began on the 14th day after injury and continued for 12 weeks. During the first 14 days after surgery, there was evidence of significant recovery within the inosine-treated group on measures of fine motor function of the hand, measures of hand strength and digit flexion. While there was no effect of treatment on the time to retrieve a reward, the treated monkeys returned to asymptotic levels of grasp performance significantly faster than the untreated monkeys. Additionally, the treated monkeys evidenced a greater degree of recovery in terms of maturity of grasp pattern. |
Are thyroid antibodies associated with stenotic lesions in the terminal portion of the internal carotid artery? | Several studies have reported moyamoya syndrome associated with thyroid disease, and the mechanism involved in this relationship is unknown. This study aimed to clarify the involvement of thyroid antibodies and thyroid function in intracranial arterial stenosis. The study included 30 patients <65 years of age with intracranial arterial steno-occlusion. Patients with definitive moyamoya disease were excluded. Thyroid function and thyroid antibody levels were evaluated. The steno-occlusive site and the presence of moyamoya vessels were evaluated using digital subtraction angiography. The characteristics of intracranial arterial lesions were compared between patients with and without elevated thyroid antibody levels, and between patients with increased thyroid function and those with normal thyroid function. Five patients had increased thyroid function and seven had elevated thyroid antibody levels. Four were diagnosed with Graves' disease, 13 with atherosclerotic intracranial stenosis, two with intracranial arterial dissection, one with vasculitis syndrome and 10 with intracranial stenosis of unknown cause. All patients with Graves' disease and patients with elevated antithyroid peroxidase antibody levels had steno-occlusion in the terminal portion of the internal carotid arteries, whereas most of the patients with normal thyroid function or without elevated thyroid antibody levels had stenosis in the middle cerebral arteries. | Hepatocyte-like cells, differentiated from different stem cell sources, are considered to have a range of possible therapeutic applications, including drug discovery, metabolic disease modelling, and cell transplantation. However, little is known about how stem cells differentiate into mature and functional hepatocytes. Using transcriptomic screening, a transcription factor, liver X receptor α (NR1H3), was identified as increased during HepaRG cell hepatogenesis; this protein was also upregulated during embryonic stem cell and induced pluripotent stem cell differentiation. Overexpressing NR1H3 in human HepaRG cells promoted hepatic maturation; the hepatocyte-like cells exhibited various functions associated with mature hepatocytes, including cytochrome P450 (CYP) enzyme activity, secretion of urea and albumin, upregulation of hepatic-specific transcripts and an increase in glycogen storage. Importantly, the NR1H3-derived hepatocyte-like cells were able to rescue lethal fulminant hepatic failure using a non-obese diabetic/severe combined immunodeficient mouse model. |
Does over-expression of small ubiquitin-like modifier proteases 1 predict chemo-sensitivity and poor survival in non-small cell lung cancer? | Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors. Despite the advances in therapy over the years, its mortality remains high. The aim of this study was to evaluate the expression of small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) in NSCLC tissues and its role in the regulation of vascular endothelial growth factor (VEGF) expression. We also investigated the association between the expression level of SENP1 and the clinicopathological features and survival of the patients. A SENP1 small interfering RNA (siRNA) was constructed and transfected into the NSCLC cells. VEGF gene expression was analyzed by real-time polymerase chain reaction (RT-PCR). Immunohistochemistry staining was used to assess the expression of SENP1 in 100 NSCLC patients and its association with the clinicopathological features and survival was analyzed. VEGF expression was significantly higher in NSCLC tissues than in normal lung tissues. Inhibition of SENP1 by siRNA was associated with decreased VEGF expression. SENP1 was over-expressed in 55 of the 100 NSCLC samples (55%) and was associated with a moderate and low histological tumor grade (3.6%, 38.2%, and 58.2% in high, moderate and low differentiated tumors, respectively, P = 0.046), higher T stage (10.9% in T1, and 89.1% in T2 and T3 tumor samples, P < 0.001) and TNM stage (10.9% in stage I, and 89.1% in stages II and III tumor samples, P < 0.001). The rate of lymph node metastasis was significantly higher in the SENP1 over-expression group (76.4%) than that in the SENP1 low expression group (33.3%, P < 0.001). Sixty three patients received postoperative chemotherapy, including 34 with SENP1 over-expression and 29 with SENP1 low expression. Among the 34 patients with SENP1 over-expression, 22 (64.7%) patients developed recurrence or metastasis, significantly higher than those in the low expression group 27.6% (8/29) (P = 0.005). Multivariate Cox regression analysis showed that lymph node metastasis (P = 0.015), TNM stage (P = 0.001), and SENP1 expression level (P = 0.002) were independent prognostic factors for the survival of NSCLC patients. | Selfish genetic elements that distort the sex ratio are found widely. Notwithstanding the number of records of sex ratio distorters, their incidence is poorly understood. Two factors can prevent a sex ratio distorter from invading: inability of the sex ratio distorter to function (failure of mechanism or transmission), and lack of drive if they do function (inappropriate ecology for invasion). There has been no test to date on factors causing variation in the incidence of sex ratio distorting cytoplasmic bacteria. We therefore examined whether absence of the male-killing Wolbachia infection in D. bifasciata in Hokkaido island of Japan, in contrast to the presence of infection on the proximal island of Honshu, was associated with failure of the infection to function properly on the Hokkaido genetic background. The male-killer both transmitted and functioned well following introgression to each of 24 independent isofemale inbred lines carrying Hokkaido genetic backgrounds. This was maintained even under stringent conditions of temperature. We therefore reject the hypothesis that absence of infection is due to its inability to kill males and transmit on the Hokkaido genetic background. Further trap data indicates that D. bifasciata may occur at different densities in Hokkaido and Honshu populations, giving some credence to the idea that ecological differentiation could be important. |
Does focal adhesion kinase overexpression induce enhanced pathological retinal angiogenesis? | Focal adhesion kinase (FAK) is involved in processes integral to angiogenesis, such as cell growth, survival, and migration. FAK is activated by angiogenic growth factors, such as insulin-like growth factor (IGF)-I, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF). The study was conducted to determine whether overexpression of FAK or FAK-related nonkinase (FRNK), an inhibitor of FAK, could influence human retinal endothelial cell (HREC) migration and in vivo angiogenesis. Migration in response to a combination of growth factors was examined in transfected HRECs overexpressing FAK or FRNK. The effect of FAK or FRNK overexpression on preretinal neovascularization was examined in a mouse model of oxygen-induced retinopathy. Overexpression of FAK in HRECs resulted in a 102% +/- 13% increase (P = 1.4 x 10(-4)) in cell migration, whereas overexpression of FRNK resulted in a 20% +/- 8% decrease (P = 0.01). Overexpression of FAK in mouse eyes led to formation of numerous large vascular tufts resembling glomeruli and a 57% +/- 7% increase in preretinal neovascularization (P = 3 x 10(-9)), whereas FRNK resulted in a 55% +/- 15% reduction (P = 5 x 10(-5)). | We examined the effect of prior heating, by exercise and warm-water immersion, on core cooling rates in individuals rendered mildly hypothermic by immersion in cold water. There were seven male subjects who were randomly assigned to one of three groups: 1) seated rest for 15 min (control); 2) cycling ergometry for 15 min at 70% Vo2 peak (active warming); or 3) immersion in a circulated bath at 40 degrees C to an esophageal temperature (Tes) similar to that at the end of exercise (passive warming). Subjects were then immersed in 7 degrees C water to a Tes of 34.5 degrees C. Initial Tes cooling rates (initial approximately 6 min cooling) differed significantly among the treatment conditions (0.074 +/- 0.045, 0.129 +/- 0.076, and 0.348 +/- 0.117 degrees C x min(-1) for control, active, and passive warming conditions, respectively); however, secondary cooling rates (rates following initial approximately 6 min cooling to the end of immersion) were not different between treatments (average of 0.102 +/- 0.085 degrees C x min(-1)). Overall Tes cooling rates during the full immersion period differed significantly and were 0.067 +/- 0.047, 0.085 +/- 0.045, and 0.209 +/- 0.131 degrees C x min(-1) for control, active, and passive warming, respectively. |
Does virgin olive oil reduce blood pressure in hypertensive elderly subjects? | Hypertension is one of the most important risk factors for coronary heart disease. Recent studies have pointed out the possibility that virgin olive oil (VOO) may lower blood pressure in hypertensive (HT) subjects. However, until the date there is scarce information regarding elderly people. The present study was designed to assess the effect of dietary VOO on blood pressure in medically treated hypertensive elderly patients. 31 medically treated HT elderly patients and 31 normotensive (NT) elderly volunteers participated in a randomized sequential dietary intervention. Subjects consumed diets enriched in sunflower oil (SO) or VOO for 4 weeks each with a 4-week washout period between them. VOO reduced total and LDL-cholesterol in NT but not in HT (P < 0.01) and the concentrations were lower than in the group consuming SO. In contrast, no significant differences were found in the levels of tocopherols among the groups studied. Iron-induced oxidation of LDL resulted in a complete loss of monoacylglycerols (MG) and diacylglycerols (DG) and a reduction in triacylglycerols (TG) (60-80%), which was found to be greater in HT (P < 0.01) with no effect of diet. VOO consumption normalized systolic pressure in the HT group (136 +/- 10 mmHg) compared to SO (150 +/- 8 mmHg). | This study was conducted to gain insight into the relationship between expression profiles and underlying genetic changes, which are known to be important for the pathogenesis of lung cancers. Expression profiles of 18,175 unique genes and three major targets for genetic changes, p53, epidermal growth factor receptor (EGFR), and K-ras, were investigated in 149 patients with non-small-cell lung cancer, including 90 patients with adenocarcinoma to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms. This study successfully established a basis for expression profile-defined classification, which can classify adenocarcinomas into two major types, terminal respiratory unit (TRU) type and non-TRU type. Our GO term-based identifier of particular biologic processes, molecular functions, and cellular compartments clearly showed characteristic retention of normal peripheral lung features in TRU type, in sharp contrast to the significant association of non-TRU type with cell cycling and proliferation-related features. While significantly higher frequency of EGFR mutation was observed in TRU type, we found that the presence of EGFR mutations was a significant predictor of shorter postoperative survival for TRU type, independent of disease stage. We were also able to identify a set of genes in vivo with significant upregulation in the presence of EGFR mutations. |
Is flat-footedness a disadvantage for athletic performance in children aged 11 to 15 years? | Because the controversy about the relation of foot morphology and foot function is still present, we find it surprising that there are no studies published dealing with motor skills and athletic performance in flat-footed school children. Our aim in this study was to determine if there is an association between the degree of foot flatness and several motor skills that are necessary for sport performance. The feet of 218 children aged 11 to 15 years were scanned, and the arch index was determined. The value of the arch index was corrected for the influence of age, and then the entire sample was categorized into 4 groups according to the flatness of their feet. The children were tested for eccentric-concentric contraction and hopping on a Kistler force platform, speed-coordination polygon (Newtest system), balance (3 tests), toe flexion (textile crunching), tiptoe standing angle, and repetitive leg movements. Altogether, 17 measures of athletic performance were measured. No significant correlations between the arch height and 17 motor skills were found. Categorizing the sample into 4 groups did not reveal any differences between the groups in athletic performance. Also, several multivariate analysis of variance sets of multiple independent variables referring to a particular motor ability were not found to be significant. The differences were not found even after comparing only the 2 extreme groups, meaning children with very low and children with very high arches. | Lipolysis of triglyceride-rich lipoproteins (TGRLPs) generates phospholipid-rich surface remnants and induces cytotoxic effects in adjacent vascular cells. We hypothesized that by integrating surface remnants into HDL, phospholipid transfer protein (PLTP) alleviates cytotoxicity. To test this hypothesis and gain insight into cytotoxicity during the postprandial phase in vivo, we injected normo-TG and hyper-TG human volunteers after a standardized fat meal (postprandial sample) with heparin, thereby stimulating lipolysis (postprandial heparinized sample). Incubation of (primary) human macrophages and primary human endothelial cells with postprandial heparinized hyper-TG plasma induced pronounced cytotoxic effects that were dose dependent on the TG content of the sample. No such effects were seen with normo-TG and postprandial hyper-TG plasma. In vitro lipolysis of VLDL and chylomicrons indicated that both lipoprotein fractions can cause cytotoxicity. Interestingly, in experiments with THP-1-derived macrophages stably transfected with PLTP, PLTP substantially augmented both net phospholipid uptake and apoptotic cell death due to postprandial heparinized hyper-TG plasma. We observed that activation of caspase-3/7, poly-ADP-ribose polymerase, and enhanced bioactivity of acid sphingomyelinase may all contribute to this augmented apoptosis. |
Does downregulation of the glucocorticoid-induced leucine zipper ( GILZ ) promote vascular inflammation? | Glucocorticoid-induced leucine zipper (GILZ) represents an anti-inflammatory mediator, whose downregulation has been described in various inflammatory processes. Aim of our study was to decipher the regulation of GILZ in vascular inflammation. Degenerated aortocoronary saphenous vein bypass grafts (n = 15), which exhibited inflammatory cell activation as determined by enhanced monocyte chemoattractrant protein 1 (MCP-1, CCL2) and Toll-like receptor 2 (TLR2) expression, showed significantly diminished GILZ protein and mRNA levels compared to healthy veins (n = 23). GILZ was also downregulated in human umbilical vein endothelial cells (HUVEC) and macrophages upon treatment with the inflammatory cytokine TNF-α in a tristetraprolin (ZFP36, TTP)- and p38 MAPK-dependent manner. To assess the functional implications of decreased GILZ expression, we determined NF-κB activation after GILZ knockdown by siRNA and found that NF-κB activity and inflammatory gene expression were significantly enhanced. Importantly, ZFP36 is induced in TNF-α-activated HUVEC as well as in degenerated vein bypasses. When atheroprotective laminar shear stress was employed, GILZ levels in HUVEC increased on mRNA and protein level. Laminar flow also counteracted TNF-α-induced ZFP36 expression and GILZ downregulation. MAP kinase phosphatase 1 (MKP-1, DUSP1), a negative regulator of ZFP36 expression, was distinctly upregulated under laminar shear stress conditions and downregulated in degenerated vein bypasses. | Clinical studies have shown that performance on the serial digit learning test (SDLT) is dependent upon the mesial temporal lobes, which are responsible for learning and its consolidation. However, an effective SDLT performance is also dependent upon sequencing, temporal ordering, and the utilization of mnemonic strategies. All of these processes are among the functions of the frontal lobes; in spite of this, the relationship between SDLT performance and the frontal lobes has not been demonstrated with previously used mapping techniques. The aim of this study was to investigate the areas of the brain that are activated by SDLT performance. Ten healthy, right handed volunteers (mean age, 20.1 years; SD: 3.3) who had 12 years of education were studied with a 1.0 T MR imaging scanner. BOLD (blood oxygen level dependent) contrast and a modified SDLT were used. Activated loci were automatically mapped using a proportional grid. In learning, the most consistent activation was observed in B-a-7 of the right (80%) and the left hemispheres (50%). In recall, the most consistent activation was observed in B-a-7 of the right hemisphere (60%). Activations were observed in 2.5+/-0.97 Talairach volumes in learning, whereas they encompassed 1.7+/-0.95 volumes in recall. The difference between both phases (learning and recall) regarding total activated volume was significant (p < 0.05). |
Does shaoYao decoction ameliorate colitis-associated colorectal cancer by downregulating proinflammatory cytokines and promoting epithelial-mesenchymal transition? | Shaoyao decoction (SYD) is a traditional Chinese medicine prescription formulated by Liu Wan-Su, a master of traditional Chinese medicine in Jin-Yuan Dynasty. SYD is effective in treating ulcerative colitis. Paeonol, a component of SYD, inhibits colorectal cancer (CRC) cell proliferation and induces CRC cell apoptosis. In this study, azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated CRC (caCRC) model and CRC cell lines were used to examine the effects of SYD on CRC in vivo and in vitro. A translational medicine strategy based on phytomics quality control was adopted. Liquid chromatography was employed for the chemical characterization and chemical fingerprinting of SYD. Protein expression and macrophage existence were determined by immunohistochemistry and western blot. Serum cytokines were quantified by Luminex assay. AOM/DSS-induced caCRC phenotypically resembled human caCRC. SYD significantly increased the survival rate of the mice, ameliorated the general well-being of the mice, and reduced the incidence and multiplicity of colonic neoplasms. SYD inhibited epithelial-mesenchymal transition (EMT), as indicated by upregulated epithelia cadherin and downregulated neuronal cadherin, fibronectin, vimentin, and transcription factor Snail. SYD reduced the expression levels of serum interleukin 1β, interleukin-6, tumor necrosis factor α, tumor-associated macrophages, and p65. These results showed that SYD can attenuate proinflammatory cytokines and inhibit EMT. | Behavioral studies of spatial navigation in aging indicate that orientation using an allocentric reference frame (object-centered orientation) is impaired, whereas orientation using egocentric processes (self-centered orientation) is not. It has been proposed that navigational deficits may result from more general alterations of perception and attention or executive functions. The purpose of this study is to assess allocentric and egocentric representation in elderly individuals, and to determine if age-related deficits in spatial navigation are related to an attentional decline. We assessed encoding of the position of geometrical shapes, depending specifically on an allocentric or egocentric reference frame, during ERP recording in young and old subjects. Aging was associated with a performance decline in allocentric, but not egocentric, encoding. Both allocentric and egocentric conditions elicited parietal early components P1 and N1, reflecting top-down modulation, and components P2 and N2, reflecting selective attention and stimulus categorization. We observed age-associated effects on N1 and N2 amplitudes and on N2 latency in both spatial conditions. Moreover, impaired allocentric performance in older subjects was associated with a greater P2 amplitude and delayed P2 latency compared with younger subjects. |
Do humeral stress remodelling locations differ in Thoroughbred racehorses training and racing on dirt compared to synthetic racetrack surfaces? | Veterinarians have observed a putative change in the location of humeral stress remodelling in Thoroughbred racehorses with change from dirt to synthetic racetrack surfaces. To determine whether the location and severity of humeral stress remodelling differs between Thoroughbred racehorses exercising on dirt and synthetic racetrack surfaces, the potential significance of different locations of stress remodelling, and the potential usefulness of scintigraphy for prevention of complete humeral fracture. Scintigraphic images of humeri from 841 Thoroughbred racehorses at 3 racetracks during 2 years before and after conversion from dirt to synthetic surfaces were evaluated for location and severity of lesions. The effects of surface on lesion distributions were examined using Chi-square or Fisher's exact tests. Archived fractured humeri were examined to determine the location and severity of stress remodelling associated with complete fracture. Databases were queried to determine whether racehorses with scintigraphic lesions suffered humeral fracture and whether racehorses with a complete humeral fracture had had a scintigraphic examination. Horses at synthetic racetracks had a greater proportion of distal humeral lesions, whereas horses at dirt racetracks had a greater proportion of caudoproximal lesions (P<0.001). Proximal lesions were more likely to be severe than distal lesions (P<0.001). Most complete fractures were associated with caudoproximal lesions, which were more often severe than distal lesions (P = 0.002). None of the horses with a scintigraphic lesion had a complete humeral fracture. None of the horses with a complete humeral fracture underwent scintigraphic examination. | Cytokine activity and polymorphisms have been associated with sleep outcomes in prior animal and human research. The purpose of this study was to determine whether circulating plasma cytokines and cytokine polymorphisms are associated with the poor sleep maintenance commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Cross-sectional descriptive study. HIV clinics and community sites in the San Francisco Bay area. A convenience sample of 289 adults (193 men, 73 women, and 23 transgender) living with HIV/AIDS. None. A wrist actigraph was worn for 72 h to estimate the percentage of wake after sleep onset (WASO%) and total sleep time (TST), plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1B, IL1R2, IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor-alpha (TNFA). Controlling for demographic variables such as race and sex, and clinical variables such as CD4+ count and medications, higher WASO% was associated with single nucleotide polymorphisms (SNPs) of IL1R2 rs11674595 and TNFA rs1041981 and less WASO% was associated with IL2 rs2069776. IL1R2 rs11674595 and TNFA rs1041981 were also associated with short sleep duration. |
Is rapid increase of bile salt secretion associated with bile duct injury after human liver transplantation? | Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. In 28 liver transplant recipients, bile samples were collected daily posttransplantation for determination of bile composition. Hepatic expression of bile transporters was studied before and after transplantation. Histopathological criteria as well as biliary concentrations of alkaline phosphatase (ALP) and gamma-glutamyltransferase (gamma-GT) were used to quantify bile duct injury. Early after transplantation, bile salt secretion increased more rapidly than phospholipid secretion, resulting in high biliary bile salt/phospholipid ratio (BA/PL). In parallel with this, mRNA levels of the bile salt transporters NTCP and BSEP increased significantly after transplantation, whereas phospholipid translocator MDR3 mRNA levels remained unchanged. Bile duct injury correlated significantly with bile salt secretion and was associated with a high biliary BA/PL ratio. | Excessive daytime sleepiness, one of the most frequent sleep complaints in the elderly, may affect survival, but inconsistent results have been observed in that population so far. We therefore estimated the risk of mortality for excessive daytime sleepiness (EDS) in community-dwelling elderly participating in the Three City Study. The Three City Study is a French population-based multicenter prospective study including 9294 subjects (60% women) aged >or=65 years at recruitment between 1999 to 2001. At baseline, 8269 subjects rated EDS and nocturnal sleep complaints as never, rare, regular, and frequent in response to an administered questionnaire and provided information on medication use for sleep or anxiety. Hazard ratios (HR) of EDS (regular or frequent) for mortality over 6 years were estimated by a Cox proportional hazard model. At baseline, 18.7% of the study participants had regular or frequent EDS. After 6 years of follow-up, 762 subjects had died including 260 from cancer and 196 from cardiovascular disease. EDS was associated with a significant 33% increased risk of mortality (95% CI: 1.13 to 1.61) after adjustment for age, gender, study center, body mass index, previous cardiovascular disease, Mini Mental State Examination score, and cardiovascular risk factors. Further adjustment for current use of medication for sleep and for depressive symptoms slightly diminished the HRs. EDS was equally predictive of mortality in those who snored loudly and in those who did not. EDS was related to cardiovascular mortality but not to mortality attributable to cancer. |
Are small increases in extravascular lung water accurately detected by transpulmonary thermodilution? | Detection of small (10-20%) increases in lung water may be relevant to detect incipient pulmonary edema but no clinically usable method has demonstrated this capability to date. In six pigs weighing 28 to 35 kg, we performed 18 determinations of extravascular lung water (EVLW; transpulmonary thermodilution method) before and immediately after the intratracheal introduction of 50 mL of saline solution. Six determinations were performed in normal lung and 12 in edematous lung. In normal lung, the mean of EVLW increased from 245 +/- 18 mL to 288 +/- 19 mL (p < 0.001) after the intratracheal introduction of 50 mL of saline solution; therefore, 43 of the 50 mL (84%) were detected (range, 37-48 mL). In edematous lung, the EVLW increased from 491 +/- 106 mL to 530 +/- 108 mL after the introduction of 50 mL of saline solution; therefore, 39 of the 50 mL (77%) were detected (range, 15-67 mL). | Dentofacial deformities are dys-morpho-functional disorders involving the temporomandibular joints (TMJ). Many authors have reported a TMJ improvement in dysfunctional subjects with malocclusion after orthodontic or combined orthodontic and surgical treatment particularly for the relief of pain. In particular, few studies have highlighted the demographic and clinical predictors of response to surgical treatment. To date, no genetic factor has yet been identified as a predictor of response to surgical treatment. The aim of this cohort study is therefore to identify single-nucleotide polymorphisms associated with postoperative temporomandibular disorders (TMD) or with TMJ symptoms after orthognathic surgery. Here, we found the AA genotype of SNP rs1643821 (ESR1 gene) as a risk factor for dysfunctional worsening after orthognathic surgery. In addition, we have identified TT genotype of SNP rs858339 (ENPP1 gene) as a protective factor against TMD in a population of patients with dentofacial deformities. Conversely, the heterozygous genotype AT was identified as a risk factor of TMD with respect to the rest of our population. All these elements are particularly important to bring new screening strategies and tailor future treatment. |
Is beta amyloid in Alzheimer 's disease : increased deposition in brain reflected in reduced concentration in cerebrospinal fluid? | A decreased concentration of beta amyloid (1-42) (Abeta42) has consistently been found in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and is considered a diagnostic biomarker. However, it is not clear to which extent CSF Abeta42 levels are reflective of cerebral pathology in AD. The aim of the study was to determine the association between cerebral amyloid plaque load, as measured by means of the positron emission tomography (PET) tracer carbon-11-labeled Pittsburgh Compound B ([11C]PiB) and CSF Abeta42 in AD. A group of 30 patients with probable AD, as defined by established clinical criteria and by an AD-typical pattern of tracer uptake in fluorine-18-labeled fluorodeoxyglucose ([18F]FDG) PET, were included. In all patients, [11C]PiB PET and CSF analysis were performed. The association between amyloid load and CSF Abeta42 levels was examined in three different ways: by linear regression analysis using an overall [11C]PiB value for the entire cerebrum, by correlation analyses using [11C]PiB measurements in anatomically defined regions of interest, and by voxel-based regression analyses. All patients showed a positive [11C]PiB scan demonstrating amyloid deposition. Linear regression analysis revealed a significant inverse correlation between the overall [11C]PiB uptake and CSF Abeta42 levels. Voxel-based regression and regional correlation analyses did not attain statistical significance after correction for multiple comparisons. Numerically, correlation coefficients were higher in brain regions adjacent to CSF spaces. | To investigate the incidence of acute kidney injury after cardiac surgery and its association with mortality in a patient population receiving ibuprofen and gentamicin perioperatively. Retrospective study with Cox regression analysis to control for possible preoperative, intraoperative and postoperative confounders. University hospital-based single-center study. All patients who underwent coronary artery bypass grafting ± valve surgery during 2012. None. Acute surgery within 24 hours of coronary angiography, previous nephrectomy, preoperative sCr >2.26 mg/dL and selective cerebral perfusion during cardiopulmonary bypass were used as exclusion criteria. Acute kidney injury was defined, using the Acute Kidney Injury Network (AKIN) criteria. Six hundred eight patients were included in the study. Mean age was 68.2 ± 9.7 years, and 81% were males. Acute kidney injury was seen in 28.1% of the patients. Overall mortality at one year was 7% and 3% in the no-AKI group. At one year, mortality was 15% in patients with AKIN stage 1 and AKIN stage 2 compared to 70% in AKIN stage 3. A hazard ratio of 2.34 (95% CI: 1.21-4.51, p = 0.011) and 5.62 (95% CI: 2.42-13.06), p<0.0001) were found for AKIN stage 1 and 2/3 combined, respectively. |
Do temporal and other factors that influence the time doctors take to prescribe using an electronic prescribing system? | A computerized physician order entry (CPOE) system with embedded clinical decision support can reduce medication errors in hospitals, but might increase the time taken to generate orders. We aimed to quantify the effects of temporal (month, day of week, hour of shift) and other factors (grade of doctor, prior experience with the system, alert characteristics, and shift type) on the time taken to generate a prescription order. A large university teaching hospital using a locally developed CPOE system with an extensive audit database. We retrospectively analyzed prescription orders from the audit database between August 2011 and July 2012. The geometric mean time taken to generate a prescription order within the CPOE system was 11.75 s (95% CI 11.72 to 11.78). Time to prescribe was most affected by the display of high-level (24.59 s (24.43 to 24.76); p<0.001) or previously unseen (18.87 s (18.78 to 18.96); p<0.001) alerts. Prescribers took significantly less time at weekends (11.29 s (11.23 to 11.35)) than on weekdays (11.88 s (11.84 to 11.91); p<0.001), in the first (11.25 s (11.16 to 11.34); p<0.001) and final (11.56 s (11.47 to 11.66); p<0.001) hour of their shifts, and after the first month of using the system. | Deficiency of the antiprotease alpha-1-antitrypsin (AAT) and exposure to cigarette smoke (CS) contribute to the development of early onset emphysema. CS-induced apoptosis of alveolar cells including endothelial cells plays critical role in the lung destruction. AAT deficiency is associated with increased lung tissue destruction as well. We hypothesize that AAT protects lung alveoli from noxious environmental stimuli such as CS-induced apoptosis. Porcine pulmonary artery endothelial cells (PAEC) were exposed to CS in the presence or absence of AAT (20 microM). AAT internalization and markers for apoptosis were assessed by confocal microscopy. Flow cytometry was performed in parallel to quantify the number of AAT-loaded and apoptotic cells. We demonstrated that exogenous AAT accumulated in PAEC and protected cells from CS-induced apoptosis. AAT-loaded CS-exposed cells exhibited increased amounts of chaperone HSP-70 in their cytosol and less apoptosis inducing factor in their nuclei compared to AAT-untreated, CS-exposed cells. |
Does intrinsic Visual-Motor Synchrony correlate With Social Deficits in Autism? | Imitation, which is impaired in children with autism spectrum disorder (ASD) and critically depends on the integration of visual input with motor output, likely impacts both motor and social skill acquisition in children with ASD; however, it is unclear what brain mechanisms contribute to this impairment. Children with ASD also exhibit what appears to be an ASD-specific bias against using visual feedback during motor learning. Does the temporal congruity of intrinsic activity, or functional connectivity, between motor and visual brain regions contribute to ASD-associated deficits in imitation, motor, and social skills? We acquired resting-state functional magnetic resonance imaging scans from 100 8- to 12-year-old children (50 ASD). Group independent component analysis was used to estimate functional connectivity between visual and motor systems. Brain-behavior relationships were assessed by regressing functional connectivity measures with social deficit severity, imitation, and gesture performance scores. We observed increased intrinsic asynchrony between visual and motor systems in children with ASD and replicated this finding in an independent sample from the Autism Brain Imaging Data Exchange. Moreover, children with more out-of-sync intrinsic visual-motor activity displayed more severe autistic traits, while children with greater intrinsic visual-motor synchrony were better imitators. | The optimal treatment of acute cholecystitis is urgent laparoscopic cholecystectomy. Most reports suggest that a delay of 72 or 96 h from onset of symptoms leads to a higher conversion rate. This study assessed the conversion rate in relation to the timing of urgent laparoscopic cholecystectomy for acute cholecystitis. During a 12 month period, 112 patients received laparoscopic cholecystectomy for acute cholecystitis at a tertiary care university hospital in central Taiwan. Data were collected prospectively. The overall conversion rate was 3.6% (4/112). Of 62 procedures performed within 72 h from onset of symptoms, 2 were converted, as compared with 2 of 50 procedures after 72 h. Of 76 procedures performed within 96 h from onset of symptoms, 3 were converted, as compared with 1 of 36 procedures after 96 h. There were no mortalities or common bile duct injuries. |
Does the ileal bile acid transporter inhibitor A4250 decrease serum bile acids by interrupting the enterohepatic circulation? | Reabsorption of bile acids from the intestine by ileal bile acid transporter is pivotal for the enterohepatic circulation of BAs and sterol homoeostasis. To assess tolerability and study, bile acid metabolism in a phase 1 trial with the selective ileal bile acid transporter inhibitor A4250. A randomised double-blind, single-ascending dose (SAD) and multiple-ascending-dose study consisting of five cohorts comprising 40 individuals with a single administration of A4250 (0.1, 0.3, 1, 3, or 10 mg) or placebo and three cohorts comprising 24 individuals with a 1-week administration of A4250 (1 or 3 mg once daily or 1.5 mg twice daily) or placebo. For the multiple-ascending-dose study, bile acids were measured by HPLC-MS in plasma and faeces, and fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) were measured in plasma. No serious adverse events occurred and all participants finished the trial per protocol. At the end of the multiple-ascending-dose study, plasma total bile acids and FGF19 decreased by 47% and 76%, respectively, at 3 mg/day (P < 0.01), and by 15% and 16%, respectively, at 1.5 mg twice daily (P < 0.05). Plasma C4 and faecal bile acids increased at all dose regimens, by 555%, 664%, 292% and 338%, 421%, 420%, respectively (P < 0.01-0.05). The primary bile acids cholic and chenodeoxycholic acids constituted the majority of faecal bile acids in the A4250-treated groups. | Prion protein (PrP) predominantly localized at synapses can modulate neuronal excitability. The prion protein gene (PRNP) has been considered one of the candidate genes that play a role in seizure susceptibility. A recent study demonstrated that the 129V allele in the PRNP gene was associated with susceptibility to temporal lobe epilepsy (TLE) in female patients in an Italian population. We screened variations in the open-reading frame (ORF) of the PRNP gene and also replicated the association of the M129V polymorphism with TLE in a Han Chinese population. The M129V polymorphism was genotyped in 320 MTLE patients and 558 non-epilepsy controls. All subjects were Han Chinese. No novel polymorphism in the ORF of the PRNP gene was detected. Differences in the genotype distributions and allele frequencies of this polymorphism between cases and controls were insignificant (P = 0.24). Further analysis with stratification of the results by gender or age and analysis of clinical features in relation to M129V genotypes also yielded negative findings. |
Does neural stem cell transplantation rescue rectum function in the aganglionic rat? | Neural stem cell (NSC) transplantation is a promising tool for restoring the nervous system in a variety of neurodegenerative disorders. The aim of this study was to determine the potential of NSC transplantation as a therapeutic strategy for neuronal replacement of the enteric nervous system of the rectum in an aganglionic rat. Rat central nervous system-derived NSCs (CNS-NSCs) obtained from the cortex of the fetal brain (E16) were transplanted into the benzalkonium chloride (BAC)-induced rat aganglionic rectum. Survival and differentiation of the implanted cells were assessed at 8 weeks posttransplantation using immunostaining and Western blotting. The rectoanal inhibitory reflex (RAIR) was also be measured. Eight weeks following transplantation, grafted CNS-NSCs differentiated into neurons and glial cells in the aganglionic rectum. The protein expression of neuronal nitric oxide synthase (nNOS) and choline acetyltransferase (ChAT) were significantly increased and the RAIR restored after cell implantation. | The objective of this study was to determine the quantitative influence of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP 2C9) polymorphisms on warfarin dose requirements in Turkish patients. A total of 205 patients taking warfarin for >2 months were enrolled in the study. Deoxyribonucleic acid (DNA) samples from these patients were genotyped for polymorphisms in VKORC1 and CYP2C9 genes. A linear regression analysis was used to determine the independent effects of genetic and non-genetic factors on mean warfarin dose requirements. The VKORC1 promoter polymorphism (3673 G>A) was associated with differences in weekly mean varfarin dose: for GG genotype the dose was 43.18 mg/week, for GA genotype 33.78 mg/week and for AA genoype 25.83 mg/week (P < 0.0001). Patients who carried VKORC1 and CYP2C9 variants needed a 40% lower mean weekly warfarin dose compared to wild types. Variables associated with lower warfarin dose requirements were VKORC1 3673 AA or GA genotype (both P < 0.0001), one or two CYP2C9 variant alleles (both P < 0.0001), increasing age (P < 0.0001) and non-indication of venous thromboembolism for warfarin therapy (P = 0.002). |
Are full-length autonomous transposable elements preferentially targeted by expression-dependent forms of RNA-directed DNA methylation? | Chromatin modifications such as DNA methylation are targeted to transposable elements by small RNAs in a process termed RNA-directed DNA methylation (RdDM). In plants, canonical RdDM functions through RNA polymerase IV to reinforce pre-existing transposable element silencing. Recent investigations have identified a "non-canonical" form of RdDM dependent on RNA polymerase II expression to initiate and re-establish silencing of active transposable elements. This expression-dependent RdDM mechanism functions through RNAi degradation of transposable element mRNAs into small RNAs guided by the RNA-dependent RNA polymerase 6 (RDR6) protein and is therefore referred to as RDR6-RdDM. We performed whole-genome MethylC-seq in 20 mutants that distinguish RdDM mechanisms when transposable elements are either transcriptionally silent or active. We identified a new mechanism of expression-dependent RdDM, which functions through DICER-LIKE3 (DCL3) but bypasses the requirement of both RNA polymerase IV and RDR6 (termed DCL3-RdDM). We found that RNA polymerase II expression-dependent forms of RdDM function on over 20 % of transcribed transposable elements, including the majority of full-length elements with all of the domains required for autonomous transposition. Lastly, we find that RDR6-RdDM preferentially targets long transposable elements due to the specificity of primary small RNAs to cleave full-length mRNAs. | To determine the influence of ketamine on endotoxin-induced leukocyte adherence and venular microhemodynamics. Randomized, controlled trial. Experimental laboratory. Thirty male Wistar rats. The rats were pretreated with ketamine (10 mg/kg iv) or 0.9% saline, and both groups were given endotoxin (Escherichia coli lipopolysaccharide; 5 mg/kg iv). The control group received two doses of 0.9% saline. The rates of leukocyte adherence and changes in microhemodynamics were monitored in rat mesenteric venules, using in vivo video microscopy. The number of adherent leukocytes was determined on-line in 10-min intervals from 60 mins before until 2 hrs after endotoxin administration. Venular diameters, red blood cell velocity, volumetric blood flow, and the venular wall shear rate were monitored before and at 10, 30, and 60 mins after endotoxin exposure. A 6.3-fold increase in the number of adherent leukocytes was observed 10 mins after administration of endotoxin when compared with control animals (5.87 +/- 0.69 vs. 0.93 +/- 0.21 adherent cells/100 microns; p < .001). This increase remained unchanged for 120 mins. In ketamine-pretreated rats, a 2.6-fold increase in leukocyte adherence occurred during the first 20 mins after endotoxin exposure (2.40 +/- 0.46 vs. 0.93 +/- 0.21 adherent cells/100 microns; p < .01). However, no difference in the number of adherent leukocytes between ketamine-pretreated and control animals was found after this 20-min period. In animals of the control group, no increase in leukocyte adherence occurred during the entire observation time. Diameters of mesenteric venules did not change after endotoxin exposure in any of the groups. Red blood cell velocity and venular blood flow in the endotoxin-treated groups decreased 10 mins after the injection of endotoxin when compared with controls, but these values did not show any difference when they were compared between ketamine and saline-pretreated animals. Similarly, venular wall shear rate in the endotoxin-treated groups decreased 10 and 30 mins after injection of endotoxin. However, no significant difference occurred between ketamine and saline-pretreated animals. |
Does angiotensin II-induced cardiovascular load regulate cardiac remodeling and related gene expression in late-gestation fetal sheep? | Angiotensin II (ANG II) stimulates fetal heart growth, although little is known regarding changes in cardiomyocyte endowment or the molecular pathways mediating the response. We measured cardiomyocyte proliferation and morphology in ANG II-treated fetal sheep and assessed transcriptional pathway responses in ANG II and losartan (an ANG II type 1 receptor antagonist) treated fetuses. In twin-gestation pregnant sheep, one fetus received ANG II (50 μg/kg/min i.v.) or losartan (20 mg/kg/d i.v.) for 7 d; noninstrumented twins served as controls. ANG II produced increases in heart mass, cardiomyocyte area (left ventricle (LV) and right ventricle mononucleated and LV binucleated cells), and the percentage of Ki-67-positive mononucleated cells in the LV (all P < 0.05). ANG II and losartan produced generally opposing changes in gene expression, affecting an estimated 55% of the represented transcriptome. The most prominent significantly affected biological pathways included those involved in cytoskeletal remodeling and cell cycle activity. | Patients with skin of color demand treatment modality suitable for their skin. Salicylic acid peel has effectiveness for both of acne and postinflammatory hyperpigmentation that are common in patients with skin of color. To assess the whitening effect of salicylic acid peels in Asian patients with acne objectively by the colorimetric method. Twenty-four healthy adult patients with acne participated voluntarily in the study. Any other systemic and topical acne treatments were prohibited. They had undergone full-face peels with 30% salicylic acid in absolute ethanol bi-weekly for 3 months. Colorimetric changes of the face were recorded with reflectance spectrophotometer. Paired comparisons with pretreatment CIE L*a*b* showed abrupt descent of L* value after first peel (p=.0286). Then there was continued increase of mean L* value, even though the final L* value did not reach a statistically significant level. The mean a* value decreased continually, and the a* values recorded after the second, third, fourth, fifth, and final peel showed significantly lowered levels (p=.0027, .0005, <.0001, <.0001, <.0001). |
Is nociceptin/orphanin FQ receptor gene variation associated with smoking status in Japanese? | The endogenous opioid system has been reportedly implicated in tobacco/nicotine dependence. We examined the genetic effects of eight SNPs in opioid receptor-related genes on smoking status and smoking-related traits in Japanese. The genotypic and allelic variations of the rs2229205 SNP in the OPRL1 gene were significantly associated with smoking status, but no significant differences were found in the genetic variations of any of the SNPs with regard to smoking-related traits. The rs2229205 SNP did not show high linkage disequilibrium with the other SNPs in the linkage disequilibrium block that contained the SNP. | An experimental study of rabbit calvaria evaluated the suitability of porous beta-tricalcium phosphate (beta-TCP) block as a biomaterial for onlay bone grafting and determined whether the addition of platelet-rich plasma (PRP) can accelerate bone formation inside the pores of the beta-TCP block. In eight rabbits, the calvarium was exposed, and the marrow was penetrated. The beta-TCP blocks were made of Ca3(CO4)3 (porosity, 75%; diameter, 8 mm; thickness, 5 mm). For the experimental group, the blocks were treated with PRP; for the control group, the blocks were treated with venous blood only. Each block was placed in the bone, attached with a titanium screw, and covered with a cutaneous flap. The animals were sacrificed after 3 months, and the tissue ingrowth into the blocks was euthanized. Histologic and histomorphometric measurements demonstrated that there was no inflammatory infiltration around the blocks in either group. New bone formation inside the blocks originated from the parent bone in both groups. The mineralized bone generated tended to climb along the inner walls of the block. In addition, mineralized bone formation was noted around the titanium screw. Furthermore, there was no significant difference between the experimental and control groups in the relative amounts of newly generated tissue and mineralized bone generated in the blocks. |
Is plasma oligomeric alpha-synuclein associated with glucocerebrosidase activity in Gaucher disease? | The link between Parkinson's disease (PD) and Gaucher disease (GD), the most common lysosomal storage disease associated with loss of glucocerebrosidase (GBA) activity, can be explained by abnormal accumulation of oligomeric alpha-synuclein (α-Syn) species resulting from mutations in the GBA gene. However, in GD, the relationship between GBA activity and α-Syn accumulation in biological fluids has not been investigated. We analyzed plasma oligomeric α-Syn levels, leucocyte GBA activity, and plasma chitotriosidase activity in 21 patients with GD. Negative correlation between plasma oligomeric α-Syn levels, and leucocyte GBA activity was observed in patients with GD (R(2) = 0.487; P < 0.001). | Results in previous qualitative studies of the association of the apoptosis inhibitor survivin with prognosis of breast cancer patients have been contradictory. Survivin mRNA was measured by quantitative TaqMan reverse transcription-PCR in 275 breast cancer tissues from patients with operable tumors and was correlated with established clinicopathologic factors, relapse-free survival [(RFS); 102 events], and overall survival [(OS); 81 events]. High survivin mRNA concentrations were found mainly in tissues from younger patients and in high-grade cancer tissues. High survivin concentrations were most strongly associated with estrogen receptor- or progesterone receptor-negative tumors. In univariate Cox regression analysis for RFS, survivin concentrations were significantly associated with poor prognosis with a hazard ratio (HR) of 1.99 (95% confidence interval, 1.31-3.02; P = 0.001) for every 10-fold increase in expression. For OS, a significant contribution of survivin to poor prognosis was found with a HR of 2.76 (1.67-4.55; P <0.001). Multivariate analyses were performed including established clinicopathologic factors. For RFS, age (P = 0.027), nodal category (P <0.001), and survivin [HR = 1.78 (1.18-2.68); P = 0.006] contributed significantly to the model. For OS, only nodal category (P <0.001) and survivin [HR = 3.05 (1.83-5.10); P <0.001] were significant. |
Is high expression of GTPase regulator associated with the focal adhesion kinase ( GRAF ) a favorable prognostic factor in acute myeloid leukemia? | GRAF is a recognized tumor suppressor gene that was found inactivated in AML. However, the prognostic role of a GRAF transcript has not been studied in patients with AML. In this study, we investigated the expression of the GRAF transcript by real time quantitative PCR in 60 AML patients and 30 healthy age and sex matched controls. GRAF expression was significantly lower in patients with AML when compared to controls (P=0.008). There were no significant differences in clinical features, FAB subtypes and cytogenetic risk subgroups between patients with high and low GRAF expression levels. Kaplan-Meier analysis showed that patients with high GRAF expression had longer overall survival (OS). Multivariate analysis revealed that, besides WBC count, GRAF expression was also an independent prognostic factor for AML. | Weight gain is a common outcome of antipsychotics therapy in schizophrenic patients. However, the underlying neuronal mechanisms are unclear. The present study was undertaken to investigate the role of GABA(A) receptors within the framework of nucleus accumbens shell (AcbSh) in haloperidol-induced hyperphagia and body weight gain in sated rats. In acute studies, GABA(A) receptor agonists muscimol, diazepam or antagonist bicuculline were administered by AcbSh route, alone or in combination with haloperidol (intraperitoneal/ip). Immediately after these treatments, preweighed food was offered to the animals at commencement of dark phase. Cumulative food intake was measured at 2 and 6 h post-injection time-points. Furthermore, effects of subacute haloperidol treatment, alone or in combination with muscimol, diazepam or bicuculline, on food intake and body weight were investigated. While acute treatment with haloperidol, muscimol or diazepam dose dependently stimulated the food intake, bicuculline suppressed the same. Prior administration of muscimol (20 ng/rat, intra-AcbSh) and diazepam (5 microg/rat, intra-AcbSh) significantly potentiated, whereas bicuculline (40 ng/rat, intra-AcbSh) negated the hyperphagic effect of acute haloperidol (0.005 or 0.01 mg/kg/rat, ip). Subacute administration of haloperidol (0.01 mg/kg/rat/day, ip) for 15 days produced increase in food intake and body weight. Although, concomitant administration of muscimol (20 ng/rat/day, intra-AcbSh) or diazepam (5 microg/rat/day, intra-AcbSh) markedly enhanced, bicuculline (40 ng/rat/day, intra-AcbSh) prevented the subacute haloperidol-induced hyperphagia and weight gain. |
Is receipt of Care Discordant with Practice Guidelines Associated with Compromised Overall Survival in Nasopharyngeal Carcinoma? | It is unknown whether receiving treatment that is discordant with practice guidelines is associated with improved survival in patients with nasopharyngeal carcinoma. The objectives of this study were to characterise national treatment patterns, analyse whether treatment outside of practice guidelines is associated with overall survival, and identify variables associated with receiving guidelines-discordant care in the USA. This was a retrospective cohort study of 1741 nasopharyngeal carcinoma patients in the National Cancer Data Base (2003-2006). Treatment regimens were compared with the 2004-2006 National Comprehensive Cancer Network guidelines. Statistical analyses included chi-square, Kaplan-Meier, multivariable logistic, and Cox regression. Nearly 26% of our cohort received care discordant with practice guidelines. In multivariable analysis, patients with stage IVC disease (odds ratio 2.59, 95% confidence interval 1.66-4.04) were more likely to receive guidelines-discordant care when compared with those with stage II-IVB disease. The most common treatment deviation for those with stage I disease was overtreatment with chemoradiation therapy. Receiving guidelines-discordant care was associated with an increased risk of death (hazard ratio 1.46, 95% confidence interval 1.25-1.69). | We examined the possibility that tetanus toxin can prevent muscle atrophy associated with limb immobility in rats. While the knee and ankle joints were immobilized unilaterally, the tibialis anterior (TA) muscle on the immobilized side was injected with 1 μl saline or with 1 ng tetanus toxin. After 2 weeks, TA wet weights, contractile forces, and myofiber sizes from the immobilized sides were compared with those from body weight-matched normal animals. Saline group wet weights decreased and produced less absolute twitch and tetanic force and normalized tetanic force compared with the toxin or normal groups. Cross-sectional areas of saline group type I, IIa, and IId myofibers, and the masses of saline group IIa, IId, IIb, and toxin group IIb myofibers, were smaller compared with the normal group. |
Is elevated Fas expression related to increased apoptosis of circulating CD8+ T cell in patients with gastric cancer? | Extensive apoptosis of immune cells occurs in patients with cancer, and is possibly related to immune evasion by cancer cells. The present study was designed to investigate the correlation between apoptosis levels and Fas expression in CD8+ T lymphocytes in patients with gastric cancer. The expression of apoptosis markers (annexin V binding and caspase-3 activation) and the death receptor Fas in CD8+ T cells was evaluated by multicolor flow cytometry. Soluble Fas ligand (sFasL) in the sera was quantitated by enzyme-linked immunosorbent assay. In patients with gastric cancer, 18.7% +/- 10.5% (mean +/- SD) of CD8+ T cells bound annexin V compared with 11.7% +/- 7.9% in normal controls (P = 0.0282). Fas expression in CD8+ T cells was higher in patients with gastric cancer (69.2% +/- 15.3%) than normal controls (50.6% +/- 15.3%) (P = 0.0051). The proportion of apoptotic CD8+ T cells was significantly correlated with Fas expression in CD8+ T cells (r = 0.409, P = 0.0214). In patients, Fas+CD8+ T cells preferentially underwent apoptosis and showed high caspase-3 activation. Moreover, the proportion of apoptotic CD8+ T cells was inversely correlated with serum levels of soluble Fas ligand (r = -0.324, P = 0.0359). Fas expression in tumor infiltrating CD8+ T cells was significantly more frequent (80.3% +/- 13.4%) than in circulating CD8+ T cells (67.9% +/- 15.5%) (P = 0.0046). A decrease in the percentage of Fas+CD8+ T cells was observed after surgery (54.1% +/- 12.8%) compared with before surgery (65.9% +/- 17.0%) (P = 0.0284). | Hemiepiphysiodesis is a potential method to treat idiopathic juvenile scoliosis early. The purpose of the present study was to investigate a mechanism of curve creation in the pig thoracic model of spinal hemiepiphysiodesis by determining whether the structure of the vertebral growth plate varied with distance from the stapled, concave side of the spine. The hypotheses were that the heights of the hypertrophic zone, hypertrophic cells, and disc would be decreased on the treated side of the treated level as compared with both an unstapled control level and the side opposite the staple. Custom spine staples were implanted into six midthoracic vertebrae in each of five skeletally immature pigs. After eight weeks, the spines were harvested and histological sections were prepared. Hypertrophic zone height, hypertrophic cell height and width, and disc height were measured at discrete coronal plane locations at stapled and unstapled thoracic levels. Differences between stapled and unstapled levels and locations were compared with use of mixed linear modeling for repeated measures, followed by regression models to determine growth plate intercept and slope across the plane by thoracic level. Zone height, cell height, and cell width were lowest on the stapled side of the stapled level, with significant differences in the overall statistical model (p < 0.02). Disc heights were significantly reduced (p < 0.0001) at the stapled levels across the coronal plane. |
Is persistent hyperglycemia an independent predictor of outcome in acute myocardial infarction? | Elevated blood glucose values are a prognostic factor in myocardial infarction (MI) patients. The unfavourable relation between hyperglycemia and outcome is known for admission glucose and fasting glucose after admission. These predictors are single measurements and thus not indicative of overall hyperglycemia. Increased persistent hyperglycemia may better predict adverse events in MI patients. In a prospective study of MI patients treated with primary percutaneous coronary intervention (PCI) frequent blood glucose measurements were obtained to investigate the relation between glucose and the occurrence of major adverse cardiac events (MACE) at 30 days follow-up. MACE was defined as death, recurrent infarction, repeat primary coronary intervention, and left ventricular ejection fraction equal to or smaller than 30%. MACE occurred in 89 (21.3%) out 417 patients. In 17 patients (4.1%) it was a fatal event. A mean of 7.4 glucose determinations were available per patient. Mean +/- SD admission glucose was 10.1 +/- 3.7 mmol/L in patients with a MACE versus 9.1 +/- 2.7 mmol/L in event-free patients (P = 0.0024). Mean glucose during the first two days after admission was 9.0 +/- 2.8 mmol/L in patients with MACE compared to 8.1 +/- 2.0 mmol/L in event free patients (P < 0.0001). The area under the receiver operator characteristic curve was 0.64 for persistent hyperglycemia and 0.59 for admission glucose. Persistent hyperglycemia emerged as a significant independent predictor (P < 0.001). | Human epidermis provides the body a barrier against environmental assaults. To assume this function, the epidermis needs the renewal of keratinocytes allowed by constant mitosis, which replace the exfoliating corneocytes. Keratinocyte stem cells (KSCs) located in the basal epidermis are mitotically active, self-renewing and govern the epithelial stratification by producing renewed source of keratinocytes. Protein complex such as the chromosomal passenger complex (CPC) allows the correct development of this process. The CPC is composed of four members: INCENP, survivin, borealin and aurora kinase B, and the disruption of the CPC during cell division induces mitotic spindle defects and improper repartition of chromosomes. The aim of our study was to investigate the implication of CRM1 and survivin in the progress of mitosis in skin keratinocytes. Cultured human keratinocytes and skin biopsies were used in this study. KSCs-enriched population of keratinocytes was isolated from total keratinocytes by differential attachment to a type IV collagen matrix. Survivin and CRM1 expression levels were assessed by immunofluorescence and immunoblotting. Specific siRNAs for each CPC member and for CRM1 were used to determine the relationship between these proteins. Survivin-specific siRNA was used to induce the apparition of mitotic abnormalities in cultured keratinocytes. We demonstrated the ability of our compound 'IV08.009' to modulate the expression level of survivin and CRM1 in keratinocytes and in skin biopsies. We observed that members of the CPC are interdependent: siRNA-induced inhibition of one component caused a decrease in the expression of all other CPC members. Downregulation of survivin or CRM1 induced mitotic abnormalities in keratinocytes. However, decreased number of mitotic abnormalities was observed in keratinocytes after 'IV08.009' application. |
Subsets and Splits