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Is cross-section perimeter a suitable parameter to describe the effects of different baffle geometries in shaken microtiter plates? | Biotechnological screening processes are performed since more than 8 decades in small scale shaken bioreactors like shake flasks or microtiter plates. One of the major issues of such reactors is the sufficient oxygen supply of suspended microorganisms. Oxygen transfer into the bulk liquid can in general be increased by introducing suitable baffles at the reactor wall. However, a comprehensive and systematic characterization of baffled shaken bioreactors has never been carried out so far. Baffles often differ in number, size and shape. The exact geometry of baffles in glass lab ware like shake flasks is very difficult to reproduce from piece to piece due to the hard to control flow behavior of molten glass during manufacturing. Thus, reproducibility of the maximum oxygen transfer capacity in such baffled shake flasks is hardly given. As a first step to systematically elucidate the general effect of different baffle geometries on shaken bioreactor performance, the maximum oxygen transfer capacity (OTRmax) in baffled 48-well microtiter plates as shaken model reactor was characterized. This type of bioreactor made of plastic material was chosen, as the exact geometry of the baffles can be fabricated by highly reproducible laser cutting. As a result, thirty different geometries were investigated regarding their maximum oxygen transfer capacity (OTRmax) and liquid distribution during shaking. The relative perimeter of the cross-section area as new fundamental geometric key parameter is introduced. An empirical correlation for the OTRmax as function of the relative perimeter, shaking frequency and filling volume is derived. For the first time, this correlation allows a systematic description of the maximum oxygen transfer capacity in baffled microtiter plates. | To examine personal and environmental correlates of exercise among Mexican Americans living in the Texas-Mexico border region. The study was based on data from a community health assessment conducted in 2 counties at the Texas-Mexico border region. A random-digit-dialed community survey was used in this cross-sectional study (n=933). A majority of border Mexican Americans (52%) did not exercise at all. Gender, age, and self-rated health were statistically significant correlates to exercise. |
Do adolescent girls ' personal experience with Baby Think It Over infant simulator? | To explore adolescent girls' personal experience with an infant simulator that had to be cared for over a period of 1 to 2 weeks. This qualitative study employed the phenomenological approach and utilized Colaizzi's method of analysis. Participants were nine adolescent high school girls who were interviewed and audiotaped. Interview data were coded using NUD*IST 4 software. Three themes emerged from the data. They were (1) a parenting journey incorporating intellectual, emotive, and physical faculties; (2) recognizing the illusionary nature of previously held ideas about parenting an infant; and (3) offering counsel based on the BTIO experience. | Neoadjuvant chemotherapy (NACT) improves the prognosis of patients with esophageal cancer who respond, but it is not effective in nonresponders. Therefore, it is crucial to establish a reliable method of predicting response before initiation of chemotherapy. Hypercoagulability, which is thought to be because of upregulation of tissue factor (TF) in cancer cells, was reported to be associated with chemoresistance. The aim of this study was to investigate the association between TF expression and response to NACT in esophageal cancer. In 67 patients with advanced esophageal cancer, TF expression in pretreatment biopsy samples was evaluated immunohistochemically and correlated with clinicopathologic factors and response to chemotherapy. TF was expressed by 43.3% of the tumors, but there were no correlations observed with any clinicopathologic parameters examined. Clinical and histologic responses to chemotherapy were significantly worse in TF-positive patients compared with TF-negative patients. Multivariate analysis revealed that TF expression was significantly associated with a poor clinical response (P = 0.0431). TF expression was also independently associated with poor progression-free survival (P = 0.0353). |
Does amifostine reduce the toxicity of the fludarabine and cyclophosphamide regimen in patients with chronic lymphocytic leukemia? | Amifostine is an organic thiophosphate that may selectively protect normal tissues from the toxicities of chemotherapy. The combination of fludarabine and cyclophosphamide (FC) is highly active in patients with chronic lymphocytic leukemia (CLL). Infection is a serious toxicity of the FC regimen. Amifostine was added to the FC regimen in a phase II study of 46 patients with CLL. Patients received FCA (fludarabine 30 mg/m(2) i.v. daily for 3 days, cyclophosphamide 300 mg/m(2) i.v. daily for 3 days, and amifostine 500 mg i.v. over 15 min daily for 3 days starting 30 min before cyclophosphamide) at intervals of 4-6 weeks for a maximum of six courses. Patients receiving FCA had equivalent rates of sepsis, early death, objective response and survival to those observed in a prior series of 78 patients treated with FC. Amifostine-associated toxicities included nausea, vomiting, and hypotension. | Maternal pre-pregnancy obesity may increase the risk of childhood obesity but it is unknown whether other metabolic factors in early pregnancy such as lipid profile and hypertension are associated with offspring cardiometabolic traits. Our objective was to investigate whether fasting lipid, glucose, and insulin levels during early pregnancy and maternal pre-pregnancy weight status, are associated with offspring adiposity measures, lipid levels and blood pressure at preschool age. The study included 618 mother-child pairs of the pregnancy cohort "Rhea" study in Crete, Greece. Pregnant women were recruited at the first prenatal visit (mean: 12 weeks, SD: 0.7). A subset of 348 women provided fasting serum samples for glucose and lipid measurements. Outcomes measures were body mass index, abdominal circumference, sum of skinfold thickness, and blood pressure measurements at 4 years of age. A subsample of 525 children provided non-fasting blood samples for lipid measurements. Pre-pregnancy overweight/obesity was associated with greater risk of offspring overweight/obesity (RR: 1.83, 95%CI: 1.19, 2.81), central adiposity (RR: 1.97, 95%CI: 1.11, 3.49), and greater fat mass by 5.10 mm (95%CI: 2.49, 7.71) at 4 years of age. These associations were more pronounced in girls. An increase of 40 mg/dl in fasting serum cholesterol levels in early pregnancy was associated with greater skinfold thickness by 3.30 mm (95%CI: 1.41, 5.20) at 4 years of age after adjusting for pre-pregnancy BMI and several other confounders. An increase of 10 mmHg in diastolic blood pressure in early pregnancy was associated with increased risk of offspring overweight/obesity (RR: 1.22, 95%CI: 1.03, 1.45), and greater skinfold thickness by 1.71 mm (95% CI: 0.57, 2.86) at 4 years of age. |
Does comprehensive analysis suggest simple processes underlying EEG/ERP - demonstration with the go/no-go paradigm in ADHD? | Current basic or more advanced methods for analysis of averaged EEG/ERP are based on assumptions on the underlying processes, which are not necessarily precise. In this work we present the findings of a method which obviates such assumptions and aims at a comprehensive analysis of the averaged EEG/ERP signal. For the sake of demonstration we chose the established go/no-go paradigm in the context of ADHD. Our analysis method characterized two spatiotemporally distinct neurophysiologic processes which underlie the sampled signal: one which may be related to attention and the other which may be more related to perception. | Whilst gastrin has been found to be trophic for some colorectal cancer cell lines, and gastrin receptor antagonists are able to block this phenomenon, their potency has been modest. The effect of a new, potent and selective CCK B receptor antagonist, CI-988 on the growth of LoVo, a human colon cancer cell line both in vitro and in vivo was instigated. Basal growth of LoVo in vitro was inhibited by up to 58.93 +/- 7.30% with concentrations of CI-988 as low as 1 X 10(-11) mol/L whereas the addition of gastrin (G17) at 0.5 nmol/L had no effect. LoVo was also grown in vivo for 10 days in nude mice subsequently treated with CI-988 at 10 mg/kg per day orally for 20 days. CI-988 inhibited the growth of xenografts by 53%. |
Are hepatitis C virus core , NS3 , NS4B and NS5A the major immunogenic proteins in humoral immunity in chronic HCV infection? | The viral genome of hepatitis C virus constitutes a 9.6-kb single-stranded positive-sense RNA which encodes altogether 11 viral proteins. In order to study the humoral immune responses against different HCV proteins in patients suffering from chronic HCV infection, we produced three structural (core, E1 and E2) and six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) in Sf9 insect cells by using the baculovirus expression system. The recombinant HCV core, E1, E2, NS2, NS3, NS4A, NS4B, NS5A and NS5B proteins were purified and used in Western blot analysis to determine antibody responses against individual HCV protein in 68 HCV RNA and antibody positive human sera that were obtained from patients suffering from genotype 1, 2, 3 or 4 infection. These sera were also analysed with INNO-LIA Score test for HCV antibodies against core, NS3, NS4AB and NS5A, and the results were similar to the ones obtained by Western blot method. Based on our Western blot analyses we found that the major immunogenic HCV antigens were the core, NS4B, NS3 and NS5A proteins which were recognized in 97%, 86%, 68% and 53% of patient sera, respectively. There were no major genotype specific differences in antibody responses to individual HCV proteins. A common feature within the studied sera was that all except two sera recognized the core protein in high titers, whereas none of the sera recognized NS2 protein and only three sera (from genotype 3) recognised NS5B. | The aim of this study was to evaluate whether there is any relationship between in-stent late loss (ISLL) and the risk of stent thrombosis (ST) in patients treated with drug eluting stents (DES). The benefit of DES in reducing binary angiographic restenosis and the need for new revascularisation procedures is due to a reduction on ISLL. It has been hypothesised, however, that neointimal hyperplasia could preclude ST, and thus a very low ISLL could increase the risk of ST. We selected 26 randomised clinical trials comparing bare metal stents and DES or different DES types, and including clinical and angiographic follow-up. In order to evaluate the association between risk of ST and ISLL, meta-regression analyses were conducted, weighting for the number of patients of each study. Twenty-six studies were included, retrieving 36 subgroups for analysis and 8,971 patients treated with DES. The incidence for ST and LST was 0.81% and 0.17%. Using meta-regression techniques, neither the risk of ST nor the risk of LST were found to be significantly associated with ISLL, accounting for -0.82 and -0.002 meta-regression estimates respectively (IC 95%: -1.92 to 0.28 for ST and -0.008 to 0.003 for LST). |
Does transvaginal ultrasound after first-trimester uterine evacuation reduce the incidence of retained products of conception? | To assess the incidence of retained products of conception (RPOC) in relation to transvaginal ultrasound performed after first-trimester uterine evacuation. This was a prospective randomized study involving 809 women undergoing first-trimester uterine evacuation. The study group included 404 women in whom transvaginal sonography was performed at the end of the surgical procedure and the control group contained 405 women who did not undergo ultrasound examination. Initially, in the study group, recurettage was immediately performed if the endometrium appeared irregular but latterly only if endometrial thickness was > or = 8 mm. The patients were followed up by gynecological and ultrasound examinations 5-8 days following the surgical procedure. The total complication rate was 4.3%. RPOC presented in three women in the study group (0.7%) and in 15 women in the control group (3.7%, P < 0.05). Vaginal bleeding requiring hospitalization occurred in two women in the study group (0.5%) vs. seven in the control group (1.7%, P = 0.2). Endometritis was diagnosed in one woman in the study group (0.2%) vs. six in the control group (1.5%) and uterine perforation occurred in one woman in the control group vs. none in the study group. There were no cases of RPOC in women who had an endometrial thickness of < 8 mm as demonstrated by ultrasound at the end of the surgical procedure. | Age-related decline in muscle strength is an important public health issue for older adults. Dietary protein has been associated with maintenance of muscle mass, yet its relation to muscle strength remains unclear. We determined the association of dietary protein (total, animal, and plant) intake, measured by food frequency questionnaire, with change in grip strength over 6 years in 1,746 men and women from the Framingham Offspring cohort. Mean age at baseline was 58.7 years (range: 29-85), and mean total, animal, and plant protein intakes were 79, 57, and 22 g/d, respectively. Adjusted baseline mean grip strength did not differ across quartiles of energy-adjusted total, animal or protein intake. Greater protein intake, regardless of source, was associated with less decrease in grip strength (all p for trend ≤.05): participants in the lowest quartiles lost 0.17% to 0.27% per year while those in the highest quartiles gained 0.52% to 0.60% per year. In analyses stratified by age, participants aged 60 years or older (n = 646) had similar linear trends on loss of grip strength for total and animal (all p for trend <.03) but not plant protein, while the trends in participants younger than 60 years (n = 896) were not statistically significant. |
Does stimulation of osteoblasts with Emdogain increase the expression of specific mineralization markers? | The purpose of this study was to determine the effects of enamel matrix derivative on mRNA expression of markers related to periodontal healing. Murine osteoprogenitor cells (MC3T3-E1) were grown for 12 and 16 days in mineralization media and stimulated with 100 microg/mL Emdogain (EMD). Cell cultures treated with 2% and 10% fetal calf serum (FCS) served as control. The mRNA expression of bone sialoprotein (BSP), osteopontin (OPN), and runt-related protein 2 (Runx2) was analyzed by real-time polymerase chain reaction. One-way analysis of variance was used for statistical analysis. Stimulation with EMD significantly (P < .01) enhanced mRNA expression of BSP up to 13.9-fold and of OPN up to 3.2-fold at day 16 compared with the 2% FCS control. The expression of mRNA for transcription factor Runx2 was not significantly changed. | The purpose of this study was to determine the effectiveness of laparoscopic cholecystectomy in children with biliary dyskinesia. Reports of children with an abnormal cholecystokinin (CCK)-stimulated HIDA scan between January 2001 and July 2006 who underwent laparoscopic cholecystectomy were reviewed. Postoperatively, a 23-item Likert scale, symptom questionnaire was administered to parents. Sixty-four children with chronic abdominal pain and no gallstones on ultrasound had an abnormal CCK-HIDA scan. Twenty-three children (median age, 14 years; 16 girls), with mean (SD) ejection fraction of 17% (8), underwent laparoscopic cholecystectomy and were further analyzed. Preoperatively, these children had right upper quadrant/epigastric pain (78%), nausea (52%), vomiting (43%), and generalized abdominal pain (22%) lasting for a median of 3 months (range, 1 month to 2.5 years). Median postoperative follow-up was 2.7 years. Sixteen (70%) parents completed the questionnaire. Of those who responded, 63% indicated that their children had no abdominal pain, 87% had no vomiting, and 69% had no nausea in the month preceding the questionnaire. Overall, 67% of parents indicated that their children's symptoms were completely relieved after cholecystectomy, whereas 7% indicated that the symptoms were not relieved. |
Does a histone deacetylase inhibitor enhance adenoviral infection of renal cancer cells? | Coxsackie and adenovirus receptor is a high affinity receptor for adenovirus type 5. To our knowledge the expression profile of coxsackie and adenovirus receptor in renal cancer has not been described. We evaluated the expression of coxsackie and adenovirus receptor in human renal cancer specimens and determined whether the histone deacetylase inhibitor FK-228 (Astelas Pharmaceutical, Osaka, Japan) increases the efficiency of adenoviral infections in renal carcinoma cells in vivo and in vitro. We used randomly selected renal cancer specimens. Specimens were analyzed for coxsackie and adenovirus receptor expression using reverse transcriptase-polymerase chain reaction and immunohistochemistry. In vitro experiments on cytotoxicity were performed to determine a nontoxic dose of FK-228 for renal cancer cells. The level of coxsackie and adenovirus receptor expression was determined by fluorescence activated cell scanning and/or reverse transcriptase-polymerase chain reaction in FK-228 treated renal cancer cells. The effect in vivo on adenoviral gene expression was investigated in athymic mice. In several human renal cancer specimens a loss of or decreased coxsackie and adenovirus receptor expression was detected by reverse transcriptase-polymerase chain reaction based analysis and immunohistochemistry. The nontoxic dose of FK-228 for renal carcinoma cells was 0.5 ng/ml. Treatment of cancer cells with 0.5 ng/ml FK-228 increased levels of coxsackie and adenovirus receptor RNA and acetylated histone H3. This increase was associated with an approximately 10-fold increase in adenoviral infection, as evidenced by increased transgene expression from a beta-galactosidase containing adenoviral vector. Intravenous administration of FK-228 enhanced coxsackie and adenovirus receptor expression in athymic mice. The combination of beta-galactosidase adenovirus and FK-228 was significantly more effective than adenovirus only in A498 cells 3 weeks after treatment in vivo. The combination of p21 adenovirus and FK-228 resulted in significant tumor inhibition in vitro and in vivo. | Recent studies found that microembolic signals (MESs) could be detected by transcranial Doppler in patients with moyamoya disease. However, the clinical significance of MESs in moyamoya disease remains unclear. Our aim was to investigate whether the MESs could predict cerebral ischaemic events in patients with moyamoya disease. Fifty-four consecutive patients with moyamoya disease were recruited. MESs were monitored by transcranial Doppler for 30 min in the bilateral middle cerebral arteries of each patient on admission. Patients were followed up for 1 year. The primary end-point was cerebral ischaemic events including stroke and transient ischaemic attack (TIA). MESs were detected in 11 (20.4%) patients, with a frequency of 11 (10.2%) in 108 hemispheres. Logistic regression analysis revealed that previous ischaemic events within 3 months were associated with the presence of MESs (odds ratio 4.41, 95% CI 1.11-17.59). During a median follow-up of 384 days, 14 (13.0%) hemispheres had ischaemic events (seven strokes and seven TIAs). Cox regression showed that the hazard ratio for the risk of new ischaemic stroke and TIA in the hemispheres with MESs was 6.84 (95% CI 1.82-25.66) compared with those without, and 10.61 (95% CI 1.66-67.70) for ischaemic stroke alone, after controlling for age, sex, presence of ischaemic events at baseline, Suzuki stages and revascularization surgery. |
Are red cell and plasma plant sterols related during consumption of plant stanol and sterol ester spreads in children with hypercholesterolemia? | To show whether the ratios of squalene and cholesterol precursor sterols to cholesterol and cholestanol and plant sterols to cholesterol change differently in plasma and especially in the red cells of hypercholesterolemic children during consumption of plant stanol and sterol ester spreads. In a randomized, double-blind, crossover study, hypercholesterolemic children (n = 23) consumed low-fat plant stanol and sterol ester spreads for 5-week periods separated by a 5-week washout period. Plasma and red cell lipids, squalene, and noncholesterol sterols were measured before and at the end of each period. The plant stanol and sterol ester spreads lowered plasma total (-9% and -6%, respectively) and low-density lipoprotein (-12% and -9%) cholesterol but had no effect on red cell cholesterol, high-density lipoprotein cholesterol, or plasma triglycerides. The ratios of plasma and red cell sitosterol and campesterol to cholesterol decreased by 32% to 36% (P <.001) with the plant stanol ester and increased by 40% to 52% (P <.001) with the sterol ester spread. | Several risk factors have been claimed to predict the progression of clinically high grade T1 bladder tumors. However, these factors are not specific enough to define which patients should be treated immediately with radical cystectomy. Therefore, it is critical to identify molecular markers that can help provide individualized, risk stratified decision making. Our main goal was to evaluate the role of total p63, p53 and ΔNp63 expression in cases of clinically high grade T1 bladder cancer progression. Total p63, p53 and ΔNp63 expression was analyzed by immunohistochemistry in 134 clinically high grade T1 tumors. We assessed clinical progression to muscle invasive disease or radical cystectomy as a patient outcome end point. Survival analysis was done for recurrence-free, progression-free, disease specific and overall survival. A total of 132 patients (98.5%) underwent repeat transurethral resection. Cases of early progression (less than 3 months) were excluded from study to avoid under staging. Of the tumors 90 (67.2%) showed ΔNp63 expression loss. During a median followup of 62.1 months 19 patients (14.2%) progressed to muscle invasive disease. The progression rate was 21.1% in patients with tumors characterized by ΔNp63 loss but no progression was observed in those with tumors with ΔNp63 expression (p <0.001). There was no difference in the number of patients who underwent repeat transurethral resection, had associated carcinoma in situ, showed lymphovascular invasion or received followup intravesical bacillus Calmette-Guérin courses. |
Is gastroesophageal reflux disease with proton pump inhibitor use associated with an increased risk of osteoporosis : a nationwide population-based analysis? | Gastroesophageal reflux disease (GERD) with proton pump inhibitor (PPI) use is associated with an increased risk of osteoporosis. The risk of hip fracture is not increased in GERD patients with PPI use. The relationship between GERD with PPI treatment and the risk of osteoporosis is unclear. We aimed to determine the risk of developing osteoporosis in patients diagnosed with GERD. Patients diagnosed with GERD and received PPI treatment between 2000 and 2010 were identified from the Longitudinal Health Insurance Database as the study cohort (n = 10,620), which was frequency matched with the comparison cohort (n = 20,738) sampled from the general population according to age, sex, index year, and comorbidities. Both cohorts were followed until the end of 2011. The risk of osteoporosis was evaluated in both groups by using Cox proportional hazards regression models. The GERD patients with PPI treatment had a greater incidence (31.4 vs 20.7 per 1000 person-year; crude hazard ratio [cHR] 1.51; 95 % confidence interval [CI] 1.40-1.63) and a higher risk (adjusted HR [aHR] 1.50; 95 % CI 1.39-1.62) of osteoporosis than that of the comparison cohort. However, the overall incidence of hip fracture was not different between the GERD with PPI use and the control cohorts (aHR 0.79; 95 % CI 0.53-1.18). | Complement protein C4d has been used as a marker of antibody mediated rejection in kidney allografts. C4d has been shown to be deposited also in chronic kidney allograft rejection, and frequently in acute liver allograft rejection. In chronic liver allograft rejection there is limited data of C4d positivity. 7 liver allografts explanted at retransplantation due to chronic rejection were examined for expression of C4d. Immunoperoxidase technique on frozen sections was used. The "zero" biopsies of the same livers at the first transplantation served as controls. Expression of C4d was significantly increased in portal and central veins as well as in the portal stroma of the grafts with chronic rejection when compared to the expression at implantation of the graft. |
Do protein kinase C inhibitors sensitize GNAQ mutant uveal melanoma cells to ionizing radiation? | Uveal melanoma (UM) tumors require large doses of radiation therapy (RT) to achieve tumor ablation, which frequently results in damage to adjacent normal tissues, leading to vision-threatening complications. Approximately 50% of UM patients present with activating somatic mutations in the gene encoding for G protein αq-subunit (GNAQ), which lead to constitutive activation of downstream pathways, including protein kinase C (PKC). In this study, we investigated the impact of small-molecule PKC inhibitors bisindolylmaleimide I (BIM) and sotrastaurin (AEB071), combined with ionizing radiation (IR), on survival in melanoma cell lines. Cellular radiosensitivity was determined by using a combination of proliferation, viability, and clonogenic assays. Cell-cycle effects were measured by flow cytometry. Transcriptomic and proteomic profiling were performed by quantitative real-time PCR, reverse-phase protein array analysis, and immunofluorescence. We found that the PKC inhibitors combined with IR significantly decreased the viability, proliferation, and clonogenic potential of GNAQ(mt), but not GNAQ(wt)/BRAF(mt) cells, compared with IR alone. Combined treatment increased the antiproliferative and proapoptotic effects of IR in GNAQ(mt) cells through delayed DNA-damage resolution and enhanced induction of proteins involved in cell-cycle arrest, cell-growth arrest, and apoptosis. | The objective was to evaluate the effect of dexamethasone and platelet transfusion treatment on recovery in patients with class 1 hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. All women with class 1 HELLP syndrome (true HELLP syndrome) who were seen at the hospital Complejo Hospitalario de la Caja de Seguro Social de Panama, Panama between July 1996 and June 2004 took part in a retrospective, comparative study. They were divided into two groups. One group received dexamethasone and the other group received dexamethasone plus platelet transfusion. True HELLP syndrome was defined as hemolysis, elevated liver enzymes, and maternal platelet nadir < or =50,000 platelets/microl. The primary endpoint was resolution of the HELLP syndrome as recognized by normalization of the platelet count (> or =150,000/microl) and the mean length (measured in days) of the postpartum stay in hospital. Forty-six women with true HELLP syndrome were studied. Twenty-six patients received dexamethasone and 20 received dexamethasone plus platelet transfusion. The normalization of the platelet count was significantly more rapid in the dexamethasone group (p<0.004) and the postpartum hospital stay was significantly more prolonged in the dexamethasone plus platelet transfusion group (p<0.02). There was no maternal death. |
Does the BCL11A-XL expression predict relapse in squamous cell carcinoma and large cell carcinoma? | The B cell leukemia 11A (BCL11A) gene was identified as a proto-oncogene in hematopoietic cell malignancies and breast cancer. Alternative RNA splicing generates three main transcripts designated as Extra-long (XL; 5.9 kb/125 kD), Long (L; 3.8 kb/100 kD) and Short (S; 2.4 kb/35 kD). Our previous study results demonstrated that BCL11A expression levels were specifically upregulated in non-small cell lung cancer (NSCLC) tissues, especially in squamous cell carcinoma (SCC) and large cell carcinoma (LCC). In this study, we detected the BCL11A protein isoforms with immunohistochemistry (IHC) method in NSCLC with in a cohort (n=40) of BCL11A overexpression NSCLC patients. All 40 cases were BCL11A overexpression including 27 SCCs, 8 LCCs and 5 adenocarcinomas (ACs). Relationship between BCL11A isoforms and the clinicopathological parameters were also analyzed. Compare to the BCL11A-L and S isoforms, the BCL11A-XL isoform was specifically expressed in SCC and LCC (P=0.006). There were 19 (19/40, 47.5%) cases positive for BCL11A-XL expression, SCC accounted for 63.2% (12/19) and LCC accounted for 36.8% (7/19). The survival analysis indicated that BCL11A-XL expression was an independent prognostic factor for disease-free survival (DFS) [hazards ratio (HR) 0.246; 95% confidence interval (CI), 0.065-0.939, P=0.040] but not for overall survival (OS) in patients with SCC and LCC. | Intestinal distention induces perception and gut reflexes via sympathetic and vagal pathways, but the modulatory mechanisms of such responses remain obscure. The aim of this study was to determine the effects of sympathetic nervous activity on sympathetic and vagal reflexes as well as on intestinal and somatic perception. In 9 healthy volunteers, proximal duodenal distentions were produced in 4-mL increments and hand transcutaneous electrical nerve stimulation was produced in 3-mA increments. Increasing stimuli of 1-minute duration were randomly performed at 10-minute intervals both with and without sympathetic activation (induced by means of lower body negative pressure). Intestinal and somatic perception was scored by specific questionnaires; vagal enterogastric and sympathetic intestinointestinal relaxatory reflexes were simultaneously measured by gastric and distal duodenal barostats. Sympathetic activation significantly heightened perception of intestinal distention without modifying perception of somatic stimuli (perception scores increased by 41% and -2%, respectively). The reflex responses to duodenal distention significantly increased during sympathetic activation both in the stomach and in the intestine (relaxation increased by 91% and 69%, respectively; P < 0.05 for both). |
Is mYC a metastasis gene for non-small-cell lung cancer? | Metastasis is a process by which cancer cells learn to form satellite tumors in distant organs and represents the principle cause of death of patients with solid tumors. NSCLC is the most lethal human cancer due to its high rate of metastasis. Lack of a suitable animal model has so far hampered analysis of metastatic progression. We have examined c-MYC for its ability to induce metastasis in a C-RAF-driven mouse model for non-small-cell lung cancer. c-MYC alone induced frank tumor growth only after long latency at which time secondary mutations in K-Ras or LKB1 were detected reminiscent of human NSCLC. Combination with C-RAF led to immediate acceleration of tumor growth, conversion to papillary epithelial cells and angiogenic switch induction. Moreover, addition of c-MYC was sufficient to induce macrometastasis in liver and lymph nodes with short latency associated with lineage switch events. Thus we have generated the first conditional model for metastasis of NSCLC and identified a gene, c-MYC that is able to orchestrate all steps of this process. | The aim of the present study was to evaluate whether thyroid hormonal changes during menopause may affect the development and the course of major depressive disorder. Thirty-nine female patients (n = 17 in pre-menopause; n = 22 in post-menopause) with major depressive disorder based on Diagnostic Statistical Manual of Mental Disorders (4th edition) criteria and who were euthyroid and not on hormonal replacement therapy, participated in a prospective, 6-week, open-label naturalistic study. The Hamilton Depression Rating Scale-17 item, the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression scale and the Cognitive Failure Questionnaire were administered at baseline, week 1, week 3, and week 6. Levels of thyroid stimulating hormone, total thyroxine and total triiodothyronine were collected at baseline visit. In the whole sample, particularly in pre-menopausal women, levels of thyroid stimulating hormone-potential markers of subclinical hypothyroidism were correlated with those of less severe but more resistant depressive form. Conversely, total thyroxine levels were correlated with a more severe depression, but high levels of this hormone favored the response to antidepressants. Overall, a diagnosis of subclinical hypothyroidism was associated with a poor response to antidepressant treatment. Finally, total triiodothyronine levels were associated with better cognitive functioning, though they did not influence improvement occurring with recovery. |
Is the glucocorticoid receptor heterocomplex gene STIP1 associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids? | Corticosteroids exert their anti-inflammatory action by binding and activating the intracellular glucocorticoid receptor heterocomplex. We sought to evaluate the genes HSPCB, HSPCA, STIP1, HSPA8, DNAJB1, PTGES3, FKBP5, and FKBP4 on corticosteroid response. White asthmatic subjects (n = 382) randomized to once-daily flunisolide or conventional inhaled corticosteroid therapy were genotyped. Outcome measures were baseline FEV1, percent predicted FEV1, and percent change in FEV1 after corticosteroid treatment. Multivariable analyses adjusted for age, sex, and height were performed, fitting the most appropriate genetic model based on the quantitative mean derived from ANOVA models to determine whether there was an independent effect of polymorphisms on change in FEV1 independent of baseline level. Positive recessive model correlations for STIP1 single nucleotide polymorphisms were observed for baseline FEV1 (rs4980524, P = .009; rs6591838, P = .0045; rs2236647, P = .002; and rs2236648; P = .013), baseline percent predicted FEV1 (rs4980524, P = .002; rs6591838, P = .017; rs2236647, P = .003; and rs2236648, P = .008), and percent change in FEV1 at 4 weeks (rs4980524, P = .044; rs6591838, P = .016; and rs2236647, P = .01) and 8 weeks (rs4980524, P = .044; rs6591838, P = .016; and rs2236647; P = .01) or therapy. Haplotypic associations were observed for baseline FEV1 and percent change in FEV1 at 4 weeks of therapy (P = .05 and P = .01, respectively). Significant trends toward association were observed for baseline percent predicted FEV1 and percent change in FEV1 at 8 weeks of therapy. Positive correlations between haplotypes and percent change in FEV1 were also observed. | Increased concentrations of metalloproteinases are associated with the invasive and metastatic behavior of several human malignant tumors. Normally, enzymatic activity is tightly regulated by nonspecific mechanisms and specific inhibitors. The aim of the study was to determine the potential of a synthetic metalloproteinase inhibitor, batimastat, to show its in vitro effect on MatLyLu cancer cells and its in vivo effect on tumor growth in orthotopic cancer (R3327 Dunning tumor) in rats. In vitro, a dose response curve of batimastat was generated over 4 days using the MTT assay. Prostate cancer was injected in vivo in male Copenhagen rats by inoculating R3327 Dunning tumor cells (MatLyLu) into the ventral prostatic lobe of 30 rats. Each of 10 rats received batimastat (30 mg/kg body weight) or vehicle administered once a day by i.p. application beginning the day of cell inoculation. Ten rats remained untreated. The effect on local tumor growth was evaluated by measuring tumor weights 20 days after tumor cell inoculation. Significant inhibition of tumor cell proliferation in vitro occurred at 400 and 4,000 ng/ml batimastat. After orthotopic cell inoculation, tumors grew to mean weights of 18.9 g in the control group without treatment, to 22.3 g in the vehicle group, and to 11.1 g in the treated group. In comparison to the control group and to the vehicle group, tumor weights increased significantly less under treatment with batimastat. |
Is c-Jun NH2-terminal kinase activity in subcutaneous adipose tissue but not nuclear factor-kappaB activity in peripheral blood mononuclear cells an independent determinant of insulin resistance in healthy individuals? | Chronic low-grade activation of the immune system (CLAIS) predicts type 2 diabetes via a decrease in insulin sensitivity. Our study investigated potential relationships between nuclear factor-kappaB (NF-kappaB) and c-Jun NH(2)-terminal kinase (JNK) pathways-two pathways proposed as the link between CLAIS and insulin resistance. Adiposity (dual-energy X-ray absorptiometry), waist-to-hip ratio (WHR), and insulin sensitivity (M, hyperinsulinemic-euglycemic clamp) were measured in 22 healthy nondiabetic volunteers (aged 29 +/- 11 years, body fat 28 +/- 11%). NF-kappaB activity (DNA-binding assay) and JNK1/2 activity (phosphorylated JNK) were assessed in biopsies of the vastus lateralis muscle and subcutaneous adipose tissue and in peripheral blood mononuclear cell (PBMC) lysates. NF-kappaB activities in PBMCs and muscle were positively associated with WHR after adjustment for age, sex, and percent body fat (both P < 0.05). NF-kappaB activity in PBMCs was inversely associated with M after adjustment for age, sex, percent body fat, and WHR (P = 0.02) and explained 16% of the variance of M. There were no significant relationships between NF-kappaB activity and M in muscle or adipose tissue (both NS). Adipose-derived JNK1/2 activity was not associated with obesity (all P> 0.1), although it was inversely related to M (r = -0.54, P < 0.05) and explained 29% of its variance. When both NF-kappaB and JNK1/2 were examined statistically, only JNK1/2 activity in adipose tissue was a significant determinant of insulin resistance (P = 0.02). | We have previously reported changes in retinal function and histopathology in rabbits treated with vigabatrin. The purpose of the present study was to evaluate retinal function and histopathology of retina in rabbits 4-5 months after terminating vigabatrin medication. Five rabbits were treated with a daily per oral dose of vigabatrin during 12-13 months. After terminating treatment an observation period of 4-5 months followed. Six rabbits receiving water served as controls. Standardized full-field electroretinograms were performed every 6-8 weeks, using a Burian-Allen bipolar contact lens. After 18 months the rabbits were sacrificed and the morphology of the sectioned retina was studied. The antibodies used for staining were GABA, GFAP, GAD, and vimentin. After 12-13 months of treatment the full-field ERG was reduced in all rabbits treated with vigabatrin. There was a statistically significant difference in the dark adapted cone b-wave amplitude between treated animals and controls (Wilcoxon signed-rank test, p = 0.043). This difference was consistent also 4-5 months after terminating treatment. Immunohistology of the sectioned retina demonstrated no significant difference in immunoreactivity between treated animals and controls. All treated rabbits demonstrated elevated serum concentration of the drug during medication. |
Does ataxia Severity correlate with White Matter Degeneration in Spinocerebellar Ataxia Type 7? | There is a scarcity of information on the effect of white matter degeneration in patients with spinocerebellar ataxia type 7. Therefore, we investigated the WM integrity in a large group of patients with spinocerebellar ataxia type 7 by using Tract-Based Spatial Statistics. Thirty-three patients with a molecular diagnosis of spinocerebellar ataxia type 7 and their age- and sex-matched healthy controls participated in this study. The patients' ataxia severity was evaluated with the Scale for the Assessment and Rating of Ataxia. Voxelwise analyses of diffusion metrics, including fractional anisotropy and mean diffusivity, were performed with Tract-Based Spatial Statistics. The correlation between WM abnormalities and ataxia severity was then calculated. Tract-Based Spatial Statistics analysis revealed WM abnormalities in the cerebellum and the cerebellar peduncles, as well as in other major cortical and subcortical pathways. Further analysis between the Scale for the Assessment and Rating of Ataxia score and WM mean diffusivity showed significant associations only in key areas related to motor control and visuospatial processing, including the cerebellar WM, the middle occipital WM, the superior cerebellar peduncle, and bilateral anterior thalamic radiation. No significant associations between fractional anisotropy and the Scale for the Assessment and Rating of Ataxia were found. | Childhood asthma morbidity remains significant, especially in low-income children. Most often, asthma management is provided by the child's primary care provider. We sought to evaluate whether enhancing primary care management for persistent asthma with telephone-based peer coaching for parents reduced asthma impairment and risk in children 3 to 12 years old. Over 12 months, peer trainers provided parents with asthma management training by telephone (median, 18 calls) and encouraged physician partnership. The intervention was evaluated in a cluster-randomized trial of 11 intervention and 11 usual care pediatric practices (462 and 486 families, respectively). Patient outcomes were assessed by means of telephone interviews at 12 and 24 months conducted by observers blinded to intervention assignment and compared by using mixed-effects models, controlling for baseline values and clustering within practices. In a planned subgroup analysis we examined the heterogeneity of the intervention effect by insurance type (Medicaid vs other). After 12 months, intervention participation resulted in 20.9 (95% CI, 9.1-32.7) more symptom-free days per child than in the control group, and there was no difference in emergency department (ED) visits. After 24 months, ED visits were reduced (difference in mean visits/child, -0.28; 95% CI, -0.5 to -0.02), indicating a delayed intervention effect. In the Medicaid subgroup, after 12 months, intervention participation resulted in 42% fewer ED visits (difference in mean visits/child, -0.50; 95% CI, -0.81 to -0.18) and 62% fewer hospitalizations (difference in mean hospitalizations/child, -0.16; 95% CI, -0.30 to -0.014). Reductions in health care use endured through 24 months. |
Does synergy of interferon-alpha and 5-fluorouracil in human renal cell carcinoma require p53 activity? | Immunochemical therapy combining cytokines and chemotherapeutic agents is expected to be effective for treating advanced renal cell carcinoma (RCC). We investigated the mechanism underlying the synergism of interferon-alpha (IFN-alpha) and 5-fluorouracil (5-FU) and the effect of p53 status on the synergy of the combined therapy in RCC cell lines. The synergy of IFN-alpha and 5-FU was analyzed by isobolographic analysis in five RCC cell lines. The effect of combined treatment on apoptosis induction was measured by flow cytometric analysis, Hoechst staining, and caspase activity assay; PCNA expression was investigated by Western blotting to examine the effect of combined treatment on the antiproliferative effect. We demonstrated synergy of IFN-alpha and 5-FU in five RCC cell lines with wild-type p53. IFN-alpha suppressed the proliferation of RCC cells via G1 or G2/M cell cycle arrest without inducing apoptosis, whereas 5-FU induced apoptosis in a dosage-dependent manner. IFN-alpha enhanced the apoptosis of RCC cells induced by 5-FU, whereas 5-FU did not increase the antiproliferative effect of IFN-alpha. However, the synergistic inhibition by IFN-alpha and 5-FU was abolished when the cell lines were transfected with p53 dominant-negative vector. | Adiponectin is a recognized protective risk marker for cardiovascular disease in adults and is associated with an optimal lipid profile. The role of adiponectin at birth is not well understood, and its relationship with the neonatal lipid profile is unknown. Because ethnic disparities in cardiovascular risk have been attributed to low adiponectin and its associated low high-density lipoprotein cholesterol (HDL-C), investigation at birth may help determine the etiology of these risk patterns. Our objective was to investigate the relationship between neonatal adiponectin and lipid profile at birth in two ethnic groups in cord blood. Seventy-four healthy mothers and their newborns of South Asian and White European origin were studied in this cross-sectional study at St. Mary's Hospital, Manchester, United Kingdom. Serum adiponectin, total cholesterol, HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels were measured in umbilical venous blood at birth and in maternal blood collected at 28 wk gestation. Cord adiponectin was significantly inversely associated with cord LDL-C (r = -0.32; P = 0.005) but not HDL-C. In a multiple regression analysis, cord LDL-C remained the most significant association of cord adiponectin (beta = -0.13; P < 0.001). We did not find any significant ethnic differences in cord adiponectin or lipids with the exception of triglycerides, which were significantly lower in South Asian newborns (P < 0.05). |
Do neutrophil serine proteases mediate inflammatory cell recruitment by glomerular endothelium and progression towards dysfunction? | Neutrophil recruitment into glomerular tissues and reduced capillary wall integrity has been implicated in the development of vasculitic glomerulonephritis (VGN). This study investigated the stages and mechanisms through which neutrophil serine proteases (SPs), proteinase 3 (PR3) or elastase contribute to endothelial dysfunction. Protease-induced damage to endothelium and adhesion molecule upregulation was measured by viability assays and ELISA. Neutrophil/platelet adhesion to human glomerular and umbilical vein endothelium was assessed using in vitro adhesion assays. PR3 and elastase (1 µg/mL, 2 h) significantly induced neutrophil adhesion to endothelial cells (EnC) whilst PR3 also enhanced platelet-EnC interactions. This neutrophil adhesion was associated with enhanced P-selectin expression and required CXCL8 receptor involvement, and could be inhibited by blocking the P-selectin ligand PSGL-1. SPs induced damage in a time- and dose-dependent fashion, decreasing cell monolayer integrity followed by cell membrane integrity, inducing caspase-3 activation and p21 cleavage. However, SPs caused significant EnC damage with increasing concentrations and prolonged exposures. | Numerous factors influence the development of gastrointestinal (GI) cancer. The insulin-like growth factor (IGF) axis plays a role in embryonic and postnatal growth and tissue repair. Elevated levels of IGFs, low levels of IGF binding proteins (IGFBPs) and over-expression of IGF receptor (IGFR-I) were associated with several stages of cancer. Here, the prevalence of the single nucleotide polymorphisms (SNPs) rs6214 in the IGF type I (IGF-I) gene and rs6898743 in the growth hormone receptor (GHR) gene in patients with GI cancer and controls was studied. In this Dutch case-control study, DNA isolated from blood of 1,457 GI cancer patients; 438 patients with head and neck cancer (HNC), 475 with esophageal cancer (EC) and 544 with colorectal cancer (CRC) and 1,457 matched controls, was used to determine the rs6214 and rs6898743 genotypes by polymerase chain reaction. The association between these SNPs and GI cancer, HNC, esophageal adenocarcinoma (EAC), esophageal squamous-cell carcinoma (ESCC) and proximal or distal CRC was studied. Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated via unconditional logistic regression. Overall for GI cancer, the ORs for SNPs rs6214 and rs6898743 were approximately 1.0 (p-value>0.05), using the most common genotypes GG as reference. An OR of 1.54 (95% CI, 1.05-2.27) was found for EC for genotype AA of rs6214. The ORs for EAC were 1.45 (95% CI, 1.04-2.01) and 1.71 (95% CI, 1.10-2.68), for genotypes GA and AA, respectively. Genotype GC of rs6898743 showed an OR of 0.47 (95% CI, 0.26-0.86) for ESCC. |
Is postprandial walking better for lowering the glycemic effect of dinner than pre-dinner exercise in type 2 diabetic individuals? | In prior studies of exercise done before or after breakfast and lunch, postprandial activity generally reduces glycemia more than pre-meal. This study sought to examine the effects of exercise before or after an evening meal. Examined the differing effects of a single bout of pre- or postprandial moderate exercise or no exercise on the glycemic response to an evening (dinner) meal in individuals with type 2 diabetes. Community-dwelling participants tested at a research university in Virginia. Twelve men and women subjects (mean age of 61.4+/-2.7 years) with type 2 diabetes treated with diet and/or oral medications. Three trials conducted on separate days consisting of a rest day when subjects consumed a standardized dinner with a moderate glycemic effect and 2 exercise days when they undertook 20 minutes of self-paced treadmill walking immediately before or 15 to 20 minutes after eating. Blood samples taken every 30 minutes over a 4-hour period and later assayed for plasma glucose; from these data both absolute and relative changes in glucose levels were determined, as well as the total glucose area under the curve (AUC) of the 4-hour testing period. Initial samples were additionally assayed for glycated hemoglobin and lipid levels. Twenty minutes of self-paced walking done shortly after meal consumption resulted in lower plasma glucose levels at the end of exercise compared to values at the same time point when subjects had walked pre-dinner. Total glucose AUC over 4-hours was not significantly different among trials. | Receptor down-regulation by the multivesicular body (MVB) pathway is critical for many cellular signaling events. MVB generation is mediated by the highly conserved ESCRT (0, I, II, and III) protein complexes. Chmp1 is an ESCRT-III component and a putative tumor suppressor in humans. However, published data on Chmp1 activity are conflicting and its role during tissue development is not well defined. We investigated the function of Drosophila Chmp1 and found that it is an essential gene. In the wing, loss of Chmp1 activity causes a cell fate change from intervein to vein, and interactions between Chmp1 and Drosophila Epidermal Growth Factor Receptor (DER) regulators suggest that Chmp1 negatively regulates DER signaling. Chmp1 knockdown also decreases Blistered expression, which is repressed by DER signaling. We find that Chmp1 protein localizes to the late endosome in Drosophila embryos, which is consistent with its effects on DER signaling resulting from its function in the ESCRT-III complex. |
Does cerebellar stroke impair temporal but not spatial accuracy during implicit motor learning? | Numerous studies have demonstrated cerebellar activity during implicit motor learning, but few have addressed its specific role. The purpose of this study was to determine if specific components (spatial or temporal) of an implicit motor-tracking task were affected by cerebellar stroke. The authors studied the performance of individuals with unilateral cerebellar stroke (n = 7)and a control group (n = 10) across 3 acquisition days and at a delayed retention test as they practiced a unimanual tracking task with the contralesional upper extremity. After cerebellar stroke, participants demonstrated reduced tracking errors for repeating sequences compared to random sequences; however, decomposition of tracking performance into temporal and spatial components revealed persistent deficits in tracking time lag despite improved spatial accuracy. A lesion analysis showed that the dentate nucleus was the only common region affected by all cerebellar strokes. | Elevation of serum proinflammatory advanced glycation end products (AGEs) is involved in the pathogenesis of polycystic ovary syndrome (PCOS). The soluble receptor for AGEs (sRAGE) acts as a decoy by binding circulating AGEs. Vitamin D supplementation attenuates the deposition of AGEs in the vascular system of diabetic animals and improves some metabolic aspects of vitamin D-deficient women with PCOS. Additionally, serum anti-Mullerian hormone (AMH) is elevated in women with PCOS, reflecting abnormal ovarian folliculogenesis. The objective of the study was to evaluate the effect of 1,25 dihydroxyvitamin D3 (vit D3) supplementation on serum sRAGE and AMH in vitamin D-deficient women with PCOS. DESIGN, SETTINGS, PARTICIPANTS, AND INTERVENTION: Sixty-seven women with (n = 22) or without (control; n = 45) PCOS who were diagnosed with vitamin D deficiency were enrolled. Fifty-one women were replaced with oral vit D3 for 8 weeks (16 with PCOS and 35 controls) and 16 women were not treated (six with PCOS and 10 controls). Serum 25-hydroxyvitamin D (25 OH-D), sRAGE, and AMH concentrations were measured at baseline and after vit D3 supplementation in the treated group and 8 weeks apart in the nontreated group. Changes in serum sRAGE and AMH concentrations after vit D3 replacement were measured. In all participants, there was a negative correlation between body mass index and serum sRAGE levels (r = -0.3, P = .01). In women with PCOS, but not in controls, vit D3 increased serum sRAGE (P = .03) and decreased serum AMH levels (P < .001). The increase in serum sRAGE positively correlated with the increase in serum 25 OH-D after supplementation in women with PCOS (r = 0.6, P = .01). |
Does single-dose local simvastatin injection improve implant fixation via increased angiogenesis and bone formation in an ovariectomized rat model? | Statins have been reported to promote bone formation. However, taken orally, their bioavailability is low to the bones. Implant therapies require a local repair response, topical application of osteoinductive agents, or biomaterials that promote implant fixation. The present study evaluated the effect of a single local injection of simvastatin on screw fixation in an ovariectomized rat model of osteoporosis. Dual-energy X-ray absorptiometry, micro-computed tomography, histology, and biomechanical tests revealed that 5 and 10 mg simvastatin significantly improved bone mineral density by 18.2% and 22.4%, respectively (P<0.05); increased bone volume fraction by 51.0% and 57.9%, trabecular thickness by 16.4% and 18.9%, trabeculae number by 112.0% and 107.1%, and percentage of osseointegration by 115.7% and 126.3%; and decreased trabeculae separation by 34.1% and 36.6%, respectively (all P<0.01). Bone mineral apposition rate was significantly increased (P<0.01). Furthermore, implant fixation was significantly increased (P<0.05), and bone morphogenetic protein 2 (BMP2) expression was markedly increased. Local injection of a single dose of simvastatin also promoted angiogenesis. Vessel number, volume, thickness, surface area, and vascular volume per tissue volume were significantly increased (all P<0.01). Vascular endothelial growth factor (VEGF), VEGF receptor-2, von Willebrand factor, and platelet endothelial cell adhesion molecule-1 expression were enhanced. | Primary sclerosing cholangitis (PSC) is commonly associated with inflammatory bowel disease (IBD) and characterized by fibrosing inflammatory destruction of biliary ducts. The pathogenesis of PSC remains unknown, but immunological, bacterial, viral, and toxic factors play a role in a genetically susceptible host. We hypothesized that CC-type chemokine receptor 5 (CCR5) would be an interesting candidate gene for susceptibility to PSC from its chromosomal location within the IBD susceptibility locus on 3p21, as well as from a functional perspective. We therefore investigated the role of the functional 32-bp deletion in this gene (CCR5-Delta32) with regard to susceptibility to PSC. A total of 110 patients with PSC, 56 with concomitant IBD (23 with Crohn's disease, 28 with ulcerative colitis, 5 with indeterminate colitis), were collected. All of the subjects were genotyped for CCR5-Delta32 with polymerase chain reaction amplification, followed by detection on ethidium bromide-stained agarose gel. Genotypes and allele frequencies were compared with a cohort of IBD patients without PSC (n = 400) and healthy control subjects (n = 362). The frequency of the CCR5-Delta32 mutation in PSC (6.8%) was significantly lower compared with IBD (12.6%; P = 0.016) and healthy control subjects (12.2%, P = 0.026), suggesting a protective effect of this mutation on PSC. None of the PSC patients with severe disease necessitating liver transplantation (n = 17) carried CCR5-Delta32. |
Does oligonucleotide-mediated retroviral RNase H activation lead to reduced HIV-1 titer in patient-derived plasma? | The retroviral RNase H is essential for viral replication. This component has not yet been extensively studied for antiviral therapy. It can be activated by an oligodeoxynucleotide (ODN) resulting in self-destruction of the virions. To examine antiviral potential of ODN in clinical samples using plasma of HIV-1-infected patients. Plasma of 19 HIV-1-infected patients from Zurich and 10 HIV-1 isolates from Africa and drug-resistant strains were processed for ex-vivo treatment. Cell-free virions were treated with ODN in the plasma and HIV RNA was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, infectivity of the treated virions was tested on primary human peripheral blood mononuclear cells. Cell-free virions in plasma contained significantly less intact HIV RNA upon treatment with ODN (P = 0.0004), and their infectivity was decreased 52-fold (P = 0.0004). In 39% of the Zurich samples, infectivity was reduced more than 10-fold, in 33% more than 100-fold, and in 28% more than 1000-fold. Also, the isolates from Africa exhibited a 63-fold reduction in infectivity (P = 0.0069) with 80% of the isolates responding more than 10-fold, 40% more than 100-fold, and 10% more than 1000-fold. | Considerable interest has been focused on angiogenic factors and angiogenic imbalance in the field of pre-eclampsia (PE), owing to its gaining role in the development of PE. This study was addressed to investigate the associations of sFlt-1-to-PlGF plasma ratios with oxidative stress assessed by the level of 8-isoprostane, and inflammation measured by the level of high-sensitive C-reactive protein (hs-CRP), and adipocytokines. A total of 83 patients with PE including 47 mild PE (MPE) and 36 severe PE (SPE) and 50 age-matched normotensive subjects in the third trimester of pregnancy were examined. Measurements included body mass index (BMI), systolic and diastolic blood pressure (BP) levels, plasma concentrations of hs-CRP, 8-isoprostane, adiponectin, and leptin. Subjects with PE had higher levels of sFlt-1/PlGF (P < 0.01), hs-CRP (P < 0.01), 8-isoprostane and leptin (both P < 0.01) and lower adiponectin (P < 0.01) than did normotensive control subjects. Significant positive correlations were found between plasma sFlt-1/PlGF and hs-CRP (r = 0.437, P < 0.01) or leptin (r = 0.656, P < 0.01). A weak inverse correlation emerged between sFlt-1/PlGF and adiponectin (r = -0.306, P < 0.01). When a multiple regression analysis was performed, with sFlt-1/PlGF as a dependent variable and all the other parameters as independent variables, sFlt-1/PlGF maintain a significant relationship with leptin (beta = 0.219, P < 0.05) and with hs-CRP (beta = 0.295, P < 0.01) as well as with systolic BP(beta = 0.446, P < 0.05). |
Does treatment of AG129 mice with antisense morpholino oligomers increase survival time following challenge with dengue 2 virus? | To determine the antiviral activity of phosphorodiamidate morpholino oligomers (PMO) and peptide-conjugated PMO (PPMO) in AG129 mice infected with dengue 2 virus (DENV-2). Antisense PMO and PPMO were designed against the 5' terminal region (5'SL) or the 3'-cyclization sequence region (3'CS) of DENV genomic RNA and administered to AG129 mice before and/or after infection with DENV-2. In addition, cell culture evaluations designed to determine optimum PPMO length, and pharmacokinetic and toxicity analysis of PPMO were also carried out. Mock-treated AG129 mice lived for 9-17 days following intraperitoneal (ip) infection with 10(4)-10(6) pfu of DENV-2 (strain New Guinea C). Intraperitoneal administration of 5'SL or 3'CS PPMO before and after DENV infection produced an increase in the average survival time of up to 8 days. Animals receiving only post-infection PPMO treatment did not benefit significantly. Cell culture studies showed that PPMO of 22-24 bases long produced substantially higher DENV titre reductions than did PPMO that were either shorter or longer. Pharmacokinetic and toxicology analysis with non-infected animals showed that nine consecutive once-daily ip treatments of 10 mg/kg PPMO resulted in high concentrations of PPMO in the liver and caused little impact on overall health. | The LAP Mentor is a procedural simulator that provides a stepwise training for laparoscopic cholecystectomy. This study addresses its "construct" validity that is present when a simulator is able to discriminate between persons with known differences in performance level on the laparoscopic cholecystectomy in real life. Three groups with different skill levels performed 2 trials of 4 distinct parts of the cholecystectomy procedure (cholecystectomy exercises) and 1 full procedure on the LAP Mentor. Assessment parameters concerning the quantity and the quality of performance were compared between groups using the Kruskal-Wallis and Mann-Whitney U tests. The entire research was performed in the Center for Surgical Technologies, Leuven, Belgium. For study purposes, 5 expert abdominal laparoscopists (>100 laparoscopic cholecystectomies performed), 11 surgical residents (10-30 cholecystectomies performed), and 10 novices (minimal laparoscopic experience) were recruited. With regard to the quantity of performance (time needed and number of movements), the experts showed significantly better results compared with the novices in the cholecystectomy exercises. Only in the full procedure, the results of all the parameters (except speed) were significantly different between the 3 groups, with the best results observed for the experts and worst for the novices. With respect to quality of performance, only the parameter "accuracy rate of dissection" in exercise 3 showed significantly better performance by the experts. |
Does interleukin-8 induce the endothelial cell migration through the Rac 1/RhoA-p38MAPK pathway? | Endothelial cell migration is essential for tumor angiogenesis, and interleukin-8 (IL-8) has been shown to play an important role in tumor growth, angiogenesis, and metastasis. The objective of this study was to investigate the molecular mechanism of IL-8 induced endothelial cell migration in vitro. Fluorescence microscope was used to study the distribution of cytoskeleton. The expression of Rac1 and RhoA protein was detected by western blotting. After endothelial cells were transfected by lipofectamine 2000 reagent, the Transwell chamber motility assay was applied to observe the migration of endothelial cells induced by IL-8. The active p38MAPK (mitogen-activated protein kinase) was evaluated by the p38MAPK activation assay. We demonstrated that IL-8 activated cell migration can be impaired by p38MAPK inhibitor, suggesting the participation of p38MAPK in the cell migration. Our results indicated that p38MAPK signaling is required for membrane ruffles, lamellipodia extensions, and actin stress fibers formation induced by IL-8. Furthermore, p38MAPK inhibitor led to increased Rac1 and RhoA expression in IL-8 treated EA.hy926 cells. In addition, IL-8 induced p38MAPK activation was suppressed by dominant-negative mutant for Rac1 and RhoA. | Gestational diabetes mellitus (GDM), defined by two abnormal glucose values on a 3-h oral glucose tolerance test (OGTT), is associated with insulin resistance and a low serum concentration of adiponectin. The metabolic implications of impaired glucose tolerance (IGT) of pregnancy (i.e., a single abnormal value on an OGTT), however, are not well established. We sought to evaluate the metabolic phenotype of pregnant women with IGT in relation to the timing of their isolated hyperglycemia. A cross-sectional study was performed in pregnant women undergoing a 3-h, 100-g OGTT. The OGTT stratified participants into four groups: 1) GDM (n = 48), 2) 1-h IGT (single elevated value at 1 h) (n = 15), 3) 2-h/3-h IGT (single elevated value at either 2 or 3 h) (n = 23), and 4) normal glucose tolerance (NGT) (n = 93). Insulin sensitivity was measured by the validated insulin sensitivity index (IS(OGTT)) of Matsuda and DeFronzo. Measures of severity of glycemia (fasting glucose, area under the glucose curve from the OGTT, and glucose challenge test result) were highest in the GDM group, followed by the 1-h IGT, 2-h/3-h IGT, and NGT groups, respectively (each trend P < 0.0001). Consistent with this finding, IS(OGTT) was highest in the NGT group (5.1), followed by the 2-h/3-h IGT (4.6), 1-h IGT (3.8), and GDM (3.2) groups (trend P < 0.0001). Furthermore, on multiple linear regression analysis of IS(OGTT), both GDM and 1-h IGT were independently associated with reduced insulin sensitivity (whereas 2-h/3-h IGT was not). Mean adjusted adiponectin was highest in the NGT group (15.7 microg/ml), followed by the 2-h/3-h IGT (15.6 microg/ml), 1-h IGT (13.7 microg/ml), and GDM (12.0 microg/ml) groups (trend P = 0.0024). |
Does a simple noninvasive score predict gastroesophageal varices in patients with chronic viral hepatitis? | Guidelines recommend upper endoscopic screening of cirrhotic patients for gastroesophageal varices. Cirrhosis is not always distinguishable from chronic hepatitis. To identify low-risk patients who can be spared upper endoscopy irrespective of a diagnosis of cirrhosis. We evaluated 13 nonendoscopic variables as predictors of esophagogastric varices in 254 patients with hepatitis B or hepatitis C-related chronic liver disease who underwent upper endoscopy. Any size varices occurred in 30.3% (77/254), and large varices in 12.2% of patients (31/254). Age >50 years [odds ratio (OR): 11.29; 95% confidence interval (CI): 2.33-54.67], platelet count <150,000/mmc (OR: 4.40; 95% CI: 1.85-10.45), albumin <3.6 g/dL (OR: 2.99; 95% CI: 1.31-6.79), and aspartate aminotransferase/alanine aminotransferase ratio >1 (OR: 2.83; 95% CI: 1.26-6.34) independently predicted varices by logistic regression. Using a score based on age >50 years, platelets <150,000/mmc, and aspartate aminotransferase/alanine aminotransferase ratio >1 (1 point/predictor), only 3.2% of patients with a score <2 had varices, all small. | Autologous cell transplantation has been proposed as a possible therapeutic approach for Duchenne dystrophy. In this approach, patients' muscle precursor cells (mpcs) obtained from muscle biopsies would be expanded ex vivo, genetically modified to restore dystrophin expression and then reimplanted in the original donor. Such strategy would have the advantage of bypassing the immune response problem, but on the other hand, it would require a large number of cells because of the poor viability and mobility of transplanted myoblasts. Besides, extensive multiplication of mpcs is difficult and can affect their myogenic ability. Given the key role of inflammation in muscle regeneration, we set out to verify if factors secreted by inflammatory cells could be used to improve in vitro expansion of DMD-mpcs. We have previously shown that a murine macrophage conditioned medium (mMCM) could increase the in vitro proliferation rate of rat and mouse mpcs. Here we tested the effect of mMCM on cultures of human, dystrophin-deficient mpcs (DMD-mpcs). In the presence of mMCM, DMD-mpcs displayed an increased proliferation rate, while at the same time, maintaining their myogenicity after many in vitro passages. Expanded cells were also injected in muscles of immuno-deficient mice, showing that they were also able to participate in muscle regeneration within recipient muscles. |
Is increased time from neoadjuvant chemoradiation to surgery associated with higher pathologic complete response rates in esophageal cancer? | The interval between neoadjuvant chemoradiation treatment and surgery has been described as an important predictor of pathologic response to therapy in nonesophageal cancer sites. We retrospectively reviewed our experience with patients who underwent neoadjuvant chemoradiation and esophagectomy to better understand the impact of the timing of surgery on pathologic complete response rates in esophageal cancer. Two hundred thirty-one sequentially treated patients from 2000 to 2011 were identified for this study; 88 of these patients completed neoadjuvant chemoradiation followed by esophagectomy at our institution. The interval between completion of chemoradiation and surgery was calculated for each patient. The patients were categorized into quartiles and also into 3-week interval groups. Treatment factors and surgical morbidity data, including the estimated blood loss and length of operative stay, were also assessed. Quartiles for the neoadjuvant chemoradiation to surgery interval were less than 45 days, 46 to 50 days, 51 to 63 days, and 64+ days. Corresponding pathologic complete response rates were 12.5%, 20.0%, 22.7%, and 40.9% (p = 0.03). Results for 3-week intervals were similar (p = 0.02). There was no association between increasing time interval between the ending of neoadjuvant chemoradiation to surgery and length of stay longer than 2 weeks. | Innate immune inflammatory response is suggested to have a role in the pathogenesis of major depressive disorder (MDD). Interleukin (IL)-10 family cytokines IL-10, IL-19, IL-20, and IL-24 are all implicated in the inflammatory processes and polymorphisms in respective genes have been associated with various immunopathological conditions. This study was carried out to investigate whether single-nucleotide polymorphisms (SNPs) in these genes are also associated with MDD. Case-control association study was performed with seven SNPs from the IL10 gene cluster. 153 patients with MDD and 277 healthy control individuals were recruited. None of the selected SNPs were individually associated with MDD. The linkage disequilibrium (LD) analysis indicated the existence of two recombination sites in the IL10 gene cluster, thus confirming the formerly established LD pattern of this genomic region. This also created two haplotype blocks, both consisting of three SNPs. Additionally, the haplotype analysis detected a significantly higher frequency of block 2 (IL20 and IL24 genes) haplotype TGC in the patients group compared to healthy control individuals (P = 0.0097). |
Is loss of CO2 reactivity of cerebral blood flow associated with severe brain damage in mechanically ventilated very low birth weight infants? | Early detection of pathophysiological factors associated with permanent and severe brain damage in preterm infants requiring intensive care is a major issue in neonatal neurology. The aim of this study was to investigate if an abnormal CO2 reactivity of cerebral blood flow in high risk very low birth weight infants is associated with severe brain injury demonstrated at autopsy or by neurodevelopment examination at 18 months. The CO2 reactivity of cerebral blood flow (xenon-133) was measured in 18 mechanically ventilated, severely ill, very low birthweight infants (gestational age 26-32 weeks, birthweight: 630-1360 g) during the first 36 hours of life. Cerebral outcome was assessed on autopsy findings (n = 8) or at the age of 18 months using Bayley developmental scales (n = 10). Eight infants with normal development at 18 months (within mean +/- 2.5 SD of reference group) and two infants with normal cerebral autopsy findings had a median CO2 reactivity of 24.4%/kPa CO2 (interquartile range 14.7-41.2). Two infants with abnormal development (> 2.5 SD below mean) and six infants with hypoxic-ischaemic encephalopathy at autopsy has a median CO2 reactivity of 3.4%/kPa CO2 (interquartile range 8.0-11.7). | Human papillomavirus (HPV) is a common sexually transmitted infection that causes anal, penile, and oropharyngeal cancers in men. Men who have sex with men (MSM) are at particularly high risk for HPV infection and HPV-related disease. Human papillomavirus vaccination is currently recommended for all MSM in the United States through age 26 years, yet little is known about HPV vaccine uptake in this population. The purpose of this study was to identify predictors of HPV vaccine uptake and barriers and facilitators to HPV vaccination that may be unique to young MSM. Men aged 18 to 26 years (n = 336) were recruited via advertisements placed on a geospatial smartphone dating application designed for MSM. Participants completed an online survey. Correlates of vaccine uptake and provider recommendation for HPV vaccine were identified using logistic regression. In total, 21% of participants had received at least 1 dose of HPV vaccine. Provider recommendation was the strongest predictor of uptake such that MSM with a recommendation were more than 40 times more likely to have been vaccinated. Additional predictors of uptake included age and HPV vaccine attitudes. Predictors of provider recommendation included sexual identity, race/ethnicity, condomless anal sex, and HIV status. Psychosocial correlates and barriers and facilitators to HPV vaccination among unvaccinated men were also identified. |
Is apoE-epsilon4 associated with reduced memory in long-standing intractable temporal lobe epilepsy? | To investigate the relationship between the apolipoprotein (ApoE) epsilon4 allele and memory performance (verbal and nonverbal) in patients with medically intractable temporal lobe epilepsy (TLE) who underwent temporal lobectomy. Presurgical and postsurgical memory performance was examined in 87 adult patients with TLE (epsilon4 = 22; non-epsilon4 = 65) to determine whether the expression of ApoE-epsilon4 may be associated with memory performance in this population and to examine how this relationship may be affected by duration of epilepsy. There was a significant interaction between ApoE-epsilon4 status and duration of epilepsy such that epsilon4 carriers with a long duration of epilepsy demonstrated the poorest memory performance on both verbal and nonverbal measures. This relationship was observed both before and after temporal lobectomy, with little change in test performance over time. | Statins have been reported to promote bone formation. However, taken orally, their bioavailability is low to the bones. Implant therapies require a local repair response, topical application of osteoinductive agents, or biomaterials that promote implant fixation. The present study evaluated the effect of a single local injection of simvastatin on screw fixation in an ovariectomized rat model of osteoporosis. Dual-energy X-ray absorptiometry, micro-computed tomography, histology, and biomechanical tests revealed that 5 and 10 mg simvastatin significantly improved bone mineral density by 18.2% and 22.4%, respectively (P<0.05); increased bone volume fraction by 51.0% and 57.9%, trabecular thickness by 16.4% and 18.9%, trabeculae number by 112.0% and 107.1%, and percentage of osseointegration by 115.7% and 126.3%; and decreased trabeculae separation by 34.1% and 36.6%, respectively (all P<0.01). Bone mineral apposition rate was significantly increased (P<0.01). Furthermore, implant fixation was significantly increased (P<0.05), and bone morphogenetic protein 2 (BMP2) expression was markedly increased. Local injection of a single dose of simvastatin also promoted angiogenesis. Vessel number, volume, thickness, surface area, and vascular volume per tissue volume were significantly increased (all P<0.01). Vascular endothelial growth factor (VEGF), VEGF receptor-2, von Willebrand factor, and platelet endothelial cell adhesion molecule-1 expression were enhanced. |
Is recent Decrease in Colorectal Cancer Mortality Rate Affected by Birth Cohort in Korea? | Colorectal cancer mortality has started to decrease in several developed countries in Asia. The current study aimed to present the long-term trends in colorectal cancer mortality in Korea using joinpoint analysis and age-period-cohort modeling. The number of colorectal cancer deaths and the population for each 5-year age group were obtained from Statistics Korea for the period 1984-2013 for adults 30 years and older. Joinpoint regression analysis was conducted to determine changes in trends in age-standardized mortality rates, and age-period-cohort analysis was performed to describe trends in colorectal cancer mortality using the intrinsic estimator method. In men, the age-standardized mortality rate for colorectal cancer increased from 1984 to 2003, and the mortality rates stabilized thereafter, whereas the mortality rate of colorectal cancer in women has decreased since 2004. The age-specific mortality rate of colorectal cancer increased in both men and women over time, whereas decreases in the age-specific mortality rate in younger cohorts were observed. In the age-period-cohort analysis, old age and recent period were associated with higher mortality for both men and women. The birth cohort born after 1919 showed reduced colorectal cancer mortality in both men and women. | Soluble type I interleukin-1 receptor is a competitive inhibitor of interleukin-1 and may reduce its proinflammatory actions. The objective of this experiment was to demonstrate that endobronchial gene transfer of soluble type I interleukin-1 receptor IgG to donor lung grafts reduces posttransplant ischemia-reperfusion injury. All experiments utilized an orthotopic left lung isograft transplant model. Donors were divided into three groups (n = 6 each) for endobronchial transfection: group I received 2 x 10(7) plaque-forming units of adenovirus encoding soluble type I interleukin-1 receptor IgG; group II received 2 x 10(7) plaque-forming units of nonfunctional control adenovirus encoding beta-galactosidase; and group III received 0.1 mL of saline. Left lungs were harvested 24 hours after transfection and stored for 18 hours before transplantation. Graft function was assessed 24 hours after reperfusion using three measurements: isolated graft oxygenation, wet-to-dry lung weight ratio, and tissue myeloperoxidase activity. Transgene expression of soluble type I interleukin-1 receptor IgG was also evaluated using enzyme-linked immunosorbent assay and immunohistochemistry. Isolated graft arterial oxygenation was significantly improved in group I compared with groups II and III (281.8 +/- 134.8 versus 115.7 +/- 121.5 and 88.0 +/- 58.9 mm Hg, p = 0.0197 and p = 0.0081, respectively). Myeloperoxidase activity was also significantly reduced in group I compared with groups II and III (0.083 +/- 0.044 versus 0.155 +/- 0.043 and 0.212 +/- 0.079 optical density units per minute per milligram protein, p = 0.0485 and p = 0.0016, respectively). Expression of soluble type I interleukin-1 receptor IgG was detected only in lungs from group I. |
Does eGR1 support the osteogenic differentiation of dental stem cells? | To evaluate whether and how the transcription factor early growth response gene 1 (EGR1) affects the osteogenic differentiation of dental stem cells. Dental stem cells from apical papilla (SCAPs) and from the dental follicle (DFCs) were transfected with EGR1-specific siRNA or EGR-1 expression plasmid. Gene regulation was verified at protein level by Western blotting. The expression of the transcription factors distal-less homeobox 3 (DLX3), alkaline phosphatase (ALP) and bone morphogenetic protein 2 (BMP2), which are all regulators and markers of the osteogenic differentiation in dental stem cells, was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). To investigate mineralization, SCAP long-term cultures were stained with alizarin red after EGR1 over-expression. EGR1 was induced in SCAPs during osteogenic differentiation. DLX3 and bone morphogenetic protein 2 (BMP2) were up-regulated after EGR1 over-expression and down-regulated after EGR1 depletion. The expression of ALP was also down-regulated after EGR1 depletion. The over-expression of EGR1 in SCAPs promoted mineralization after osteogenic differentiation. | Assess acceptance and attitudes regarding telemanagement (HAT) in patients with inflammatory bowel disease (IBD). Noncompliance is a barrier to successful outcomes in patients with IBD. Novel methods for monitoring and assessing compliance are needed. HAT consists of a laptop connected to a weight scale. HAT prompts patients to respond to questions about symptoms, medication side effects, and compliance. Ten consecutive adult patients with IBD were trained to use HAT. Attitudinal surveys and structured qualitative interviews were performed at the end of the session. Twenty percent of patients had never used a computer at home. All patients reported that use of the computer and self-testing was not complicated. All patients reported that the symptom diary and questions on side effects were easy to answer. All patients reported that self-testing took little time. Eighty percent said that testing would not interfere with usual activities, that they could comply with testing 3 times/wk, and that they would agree to use the system in the future. |
Does pre-oxygenation enhance induction with sevoflurane as assessed using bispectral index monitoring? | Several methods may enhance the inhalational induction of anesthesia. In this randomized double-blind study, we evaluated the speed of induction of anesthesia with sevoflurane with or without pre-oxygenation. Fifty-four patients scheduled for hysteroscopy received for 10 min air or 100% oxygen via a facemask followed by > or = 7% sevoflurane in 100% oxygen. During the first 300 s of sevoflurane administration, bispectral index (BIS) values were recorded every 30 s in all patients. In 14 patients, seven in each group, BIS, endtidal CO(2), tidal volume, respiratory rate, SpO(2), and heart rate were recorded every minute during the pre-induction period and every 30 s during the first 5 min of sevoflurane administration. The BIS, endtidal CO(2), tidal volume and respiratory rate did not differ between the oxygen or air breathing groups (P = 0.696, P = 0.999, P = 0.388, and P = 0.875, respectively), though the oxygen group exhibited lower tidal volumes by 16-20%. The SpO(2) and heart rates were higher in the oxygen breathing group (P < 0.001 and P = 0.042, respectively). During sevoflurane administration, BIS values were lower in the oxygen group vs. the group breathing air, in particular at 90, 120, 150, 180 and 210 s (P = 0.001, P = 0.001, P = 0.001, P = 0.001 and P = 0.030, respectively). The endtidal CO(2) and the tidal volumes between the groups did not differ. The two groups differed in the SpO(2) and the heart rates during induction (P = 0.004 and 0.003, respectively). | Dairy foods help achieve essential nutrient adequacy. This role may be conflicted where so-called chronic diseases prevail. We have examined associations between dairy intake and mortality where dairy foods have not been traditional. A representative Taiwanese cohort of 3810 subjects, aged 19-64 years, derived from the Nutrition and Health Survey in Taiwan (NAHSIT, 1993-1996) was linked to death registration (1993-2008). Participants were categorized by 4 dairy weekly intake frequencies from 0 to >7 times. Mortality hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional-hazards models. Nonconsumers of dairy products included 30.7% of the men and 22.1% of the women. Adverse sociodemographic and personal behaviors were generally significantly associated with lower dairy consumption. After adjustment for covariates, together with body mass index (BMI) and supplement use, those with 3-7 times/week intakes had an HR (95% CI) for all-cause mortality of 0.61 (0.39-0.96) with a significant dose-response trend (p = 0.043). Similarly, the HR for cardiovascular disease (CVD) mortality with dairy weekly intake frequency >7 was 0.14 (0.02-0.97) with a significant linear trend (p = 0.007). For stroke, the corresponding HR (95% CI) was 0.03 (0.00-0.28) with a linear trend. By age and with adjustment for dietary quality, food, and calcium or vitamin D intake, significance and dose-response relationships remained. Dairy intake and cancer mortality were not associated. |
Is serotonin 5-HT7 receptor critically involved in acute and chronic inflammation of the gastrointestinal tract? | Intestinal inflammation is often associated with an increased level of serotonin (5-HT), an important gastrointestinal signaling molecule involved in gut homeostasis through stimulation of specific receptors. In this study, we investigated the role of 5-HT7 receptor (5-HT7R) in the induction and development of intestinal inflammation using a mouse model of acute and chronic colitis and human patients with Crohn's disease (CD). Acute colitis was induced through administration of dextran sodium sulfate to wild-type, 5-HT7R-deficient mice and hematopoietic bone marrow chimera. Chronic colitis was induced in interleukin 10-deficient mice. The role of 5-HT7R in gut inflammation was assessed using agonist/antagonist treatment. We investigated expression and distribution of 5-HT7R, extent of gut inflammation with magnetic resonance imaging and histological analysis, survival rate, and disease activity index. Finally, biopsies from the large intestine of patients with CD were analyzed. Under basal conditions, 5-HT7R is expressed both in enteric neurons and CD11c cells of the large intestine. Expression of 5-HT7R significantly increased after induction of colitis in mice and in inflamed intestinal regions of patients with CD in CD11c/CD86 double-positive cells. Pharmacological blockade or genetic ablation of 5-HT7R resulted in increased severity of both acute and chronic dextran sodium sulfate-induced colitis, whereas receptor stimulation showed an anti-inflammatory effect. Analysis of bone marrow chimera indicated importance of 5-HT7R expressed by hematopoietic cells in intestinal inflammation. | To describe the long-term outcomes of cases of neovascular glaucoma drained by Molteno implants. A prospective study of 145 eyes (130 patients) followed up for a mean of 3.3 years (range, 0.02 year [5 days] to 18.1 years) in the province of Otago, New Zealand, from 1979 to 2002. Insertion of a Molteno implant controlled the intraocular pressure at 21 mm Hg or less with a probability (95% confidence interval) of 0.72 (0.64-0.80), 0.60 (0.51-0.69), and 0.40 (0.29-0.50) at 1, 2, and 5 years, respectively. Failure to control intraocular pressure at 1, 2, and 5 years was significantly correlated with persistent iris neovascularization (P<.001, P<.001, and P = .01, respectively). Visual acuity at final follow-up in nonenucleated eyes was maintained or improved in 56 eyes (39%) and deteriorated to light perception or better in 25 (17%) or no light perception in 47 (32%). Seventeen eyes (12%) were enucleated. |
Does the functional connectivity of different EEG bands move towards small-world network organization during sleep? | To analyze the functional connectivity patterns of the different EEG bands during wakefulness and sleep (different sleep stages and cyclic alternating pattern (CAP) conditions), using concepts derived from Graph Theory. We evaluated spatial patterns of EEG band synchronization between all possible pairs of electrodes (19) placed over the scalp of 10 sleeping healthy young normal subjects using two graph theoretical measures: the clustering coefficient (Cp) and the characteristic path length (Lp). The measures were obtained during wakefulness and the different sleep stages/CAP conditions from the real EEG connectivity networks and randomized control (surrogate) networks (Cp-s and Lp-s). We found values of Cp and Lp compatible with a small-world network organization in all sleep stages and for all EEG bands. All bands below 15Hz showed an increase of these features during sleep (and during CAP-A phases in particular), compared to wakefulness. | One of the major causes of death in severe acute pancreatitis (SAP) is severe infection owing to bacterial translocation. Some clinical studies suggested that ecoimmunonutrition (EIN) as a new strategy had better treatment effect on SAP patients. But the experiment studies on the precise mechanism of the effect of EIN were less reported. In this study, we mainly investigated the effects of EIN on bacterial translocation in SAP model of dogs. SAP was induced by retrograde infusion of 5% sodium taurocholate into the pancreatic duct in healthy hybrid dogs. The SAP dogs were supported with either parenteral nutrition (PN) or elemental enteral nutrition (EEN) or EIN. The levels of serum amylase, serum aminotransferase and plasma endotoxin were detected before and after pancreatitis induction. On the 7th day after nutrition supports, peritoneal fluid, mesenteric lymph nodes (MLN), liver, and pancreas were collected for bacterial culture with standard techniques to observe the incidence of bacterial translocation. Pathology changes of pancreas were analyzed by histopathologic grading and scoring of the severity of pancreas, and the degree of intestinal mucosal damage was assessed by measuring mucosal thickness, villus height, and crypt depth of ileum. Compared with PN and EEN, EIN significantly decreased the levels of serum amylase, serum aminotransferase, plasma endotoxin, and the incidence of bacterial translocation. Furthermore, compared with the others, the histology scores of inflammation in pancreas and the ileum injury (ileum mocosa thickness, villus height, and crypt depth) were significantly alleviated by EIN (P < 0.05). Moreover, concerning liver function, the serum levels of alanine aminotransferase, aspartate aminotransferase and albumin were ameliorating significantly in the EIN group. |
Does honokiol affect melanoma cell growth by targeting the AMP-activated protein kinase signaling pathway? | Malignant melanoma is an aggressive form of skin cancer with limited effective therapeutic options. Melanoma research concentrates on maximizing the effect on cancer cells with minimal toxicity to normal cells. AMP-activated protein kinase (AMPK) is an important regulator of cellular energy homeostasis and has been shown to control tumor progression regulating the cell cycle, protein synthesis, and cell growth and/or survival. Honokiol (HNK) is a biphenolic compound derived from Magnolia officinalis, a plant that has been used in traditional Chinese and Japanese medicine for the treatment of various pathological conditions. Recent studies have shown that HNK has antitumor activity with relatively low toxicity. In this study, we demonstrated that the growth inhibitory effects of HNK on melanoma and melanoma cancer stem cells were mediated through the activation of AMPK and hence AMPK signaling in melanoma cells. We determined the effects of HNK treatment on various melanoma cell lines. HNK-induced cell growth inhibitory effects were determined using hexosaminidase assay. Protein expression studies were done by immunoblotting. Primary spheroid assay was used to assess stemness by growing single suspension cells in ultralow attachment plates. HNK is highly effective in inhibiting melanoma cells by attenuating protein kinase B/mammalian target of rapamycin and AMPK signaling. HNK showed significant inhibition of the spheroid-forming capacity of melanoma cells and, hence, stemness. HNK significantly decreased the number and size of melanospheres in a dose-dependent manner. Western blot analyses showed enhanced phosphorylation of AMPK in melanoma cells. Furthermore, HNK decreased the cellular adenosine triphosphate pool in a dose-dependent manner with maximum effects observed at 48 hours. | Surgeon-performed ultrasonography is increasingly becoming part of the initial evaluation of patients after blunt or penetrating trauma. Currently, most institutions obtain a subxyphoid or subcostal view of the heart and pericardial space, and a three-view ultrasonogram of the abdomen to detect blood in the pericardial sac or in three dependent abdominal areas. A left parastemal standard transverse transthoracic view is described in addition to the aforementioned views. This facilitates the visualization of the pericardial sac when a subxyphoid or subcostal view cannot be obtained because of anatomical reasons (narrow subxyphoid space) or local factors (pain, fractures, subcutaneous emphysema, or chest wall contusion). The transthoracic view can be useful in patients where the subxyphoid view is difficult to obtain through the conventional approach. In most patients an excellent view of the pericardial sac and ventricles can be obtained and, therefore, expedites the diagnosis and treatment of patients with hemopericardium. |
Does the long-term use of soap affect the pH-maintenance mechanism of human skin? | The pH at the surface of healthy human skin is around 5. Cleansing the skin with soap increases the pH of the skin, which then returns to a more acidic pH within a few hours. However, the effects of skin cleansing with soap over a long time on the pH regulatory system is still unclear. We compared the pH of the skin between users of a soap-based cleanser and of a mild-acidic cleanser prior to and following the cleansing. This study had two groups of subjects, one group who had used a soap-based cleanser for more than 5 years and the other group who had used a mild-acidic cleanser for more than 5 years. The pH on the inner forearm of each subject was measured prior to and for 6 h after cleansing with a soap bar. There were no differences between the pH of the skin these two groups prior to cleansing, immediately after cleansing or in the pH recovery rate for 6 h. | Activating mutations of FLT3 have been identified in multiple myeloid malignancies. Two types of activating mutations have been described: (1) the internal tandem duplication (FLT3-ITD) and (2) point mutations within the activating loop (FLT3-ALM). Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative disorder of early childhood. Mutations and other genetic abnormalities of RAS, NF1, and PTPN11 have been implicated as causative events in JMML, but approximately 25% of JMML patients harbor none of these abnormalities. We investigated whether FLT3 mutations might also contribute to JMML pathogenesis, and if present, whether FLT3 status would correlate with disease natural history and prognosis. Genomic DNA was isolated from peripheral blood and bone marrow samples of 60 patients meeting international JMML diagnostic criteria. Samples were analyzed for FLT3-ITD and FLT3-ALM using polymerase chain reaction and restriction endonuclease digestion. FLT3-ALM was found in 1/60 (1.7%) patients analyzed. Direct sequencing confirmed a C836G mutation. Clinical and laboratory characteristics of the JMML patient with the FLT3-ALM did not differ from the remainder of the cohort. No FLT3-ITD mutations were detected. |
Is low percentage of free prostate-specific antigen ( PSA ) a strong predictor of later detection of prostate cancer among Japanese men with serum levels of total PSA of 4.0 ng/mL or less? | To investigate the effect of the percentage of free prostate-specific antigen (%fPSA) on future prostate cancer risk. We examined serum total PSA (tPSA) and %fPSA annually in a prostate cancer-screening cohort between July 2001 and June 2011. Men with tPSA >4.0 ng/mL or tPSA of 2.0-4.0 ng/mL with %fPSA ≤12% were screened as positive and were recommended to undergo a biopsy. The study population consisted of 6368 men, aged 40-79 years, who had tPSA ≤4.0 ng/mL at initial screening and who subsequently underwent 1 or more screenings. We calculated the cumulative risk and hazard ratio of prostate cancer stratified by the initial %fPSA groups as quartiles of prostate cancer patients. During a median follow-up of 36 months, 119 men were diagnosed with prostate cancer. The lowest quartile of %fPSA (<13.3%) was associated with a 21.2-fold higher risk of having prostate cancer compared with the highest quartile (>22.2%). For the subset with an initial tPSA ≤1.0 ng/mL, all men diagnosed with cancer had an initial %fPSA ≤33.3% (median). For the subset with tPSA >1.0 ng/mL, men with %fPSA ≤23.0% (median) had significantly higher risk for cancer than those with %fPSA >23.0% (P <.0001). Of the 114 men with prostate cancer in whom pathologic findings were available, 79 (69.3%) had a Gleason score ≥3 + 4 = 7. | Studies in rodents and carnivores have shown that orientation tuning width of single neurons does not change when stimulus contrast is modified. However, in these studies, stimuli were presented for a relatively long duration (e. g., 4 seconds), making it possible that contrast adaptation contributed to contrast-invariance of orientation tuning. Our first purpose was to determine, in marmoset area V1, whether orientation tuning is still contrast-invariant with the stimulation duration is comparable to that of a visual fixation. We performed extracellular recordings and examined orientation tuning of single-units using static sine-wave gratings that were flashed for 200 msec. Sixteen orientations and three contrast levels, representing low, medium and high values in the range of effective contrasts for each neuron, were randomly intermixed. Contrast adaptation being a slow phenomenon, cells did not have enough time to adapt to each contrast individually. With this stimulation protocol, we found that the tuning width obtained at intermediate contrast was reduced to 89% (median), and that at low contrast to 76%, of that obtained at high contrast. Therefore, when probed with briefly flashed stimuli, orientation tuning is not contrast-invariant in marmoset V1. Our second purpose was to determine whether contrast adaptation contributes to contrast-invariance of orientation tuning. Stationary gratings were presented, as previously, for 200 msec with randomly varying orientations, but the contrast was kept constant within stimulation blocks lasting >20 sec, allowing for adaptation to the single contrast in use. In these conditions, tuning widths obtained at low contrast were still significantly less than at high contrast (median 85%). However, tuning widths obtained with medium and high contrast stimuli no longer differed significantly. |
Does combination chemotherapy and radiation of human squamous cell carcinoma of the head and neck augment CTL-mediated lysis? | The combination of systemic multiagent chemotherapy (5-fluorouracil + cisplatin) and tumor irradiation is standard of care for head and neck squamous cell carcinoma (HNSCC). Furthermore, it has been shown that sublethal doses of radiation or chemotherapeutic drugs in diverse cancer types may alter the phenotype or biology of neoplastic cells, making them more susceptible to CTL-mediated cytotoxicity. However, little is known about the potential synergistic effect of drug plus radiation on CTL killing. Here, we examined whether the combination of two chemotherapeutics and ionizing radiation enhanced CTL-mediated destruction of HNSCC more so than either modality separately, as well as the basis for the enhanced tumor cell lysis. Several HNSCC cell lines with distinct biological features were treated with sublethal doses of cisplatin and 5-fluorouracil for 24 hours and with 10-Gy irradiation. Seventy-two hours postirradiation, tumor cells were exposed to an antigen-specific CD8+ CTL directed against carcinoembryonic antigen or MUC-1. In three of three tumor cell lines tested, enhanced CTL activity was observed when the two modalities (chemotherapy and radiation) were combined as compared with target cells exposed to either modality separately. CTL-mediated lysis was MHC restricted and antigen specific and occurred almost entirely via the perforin pathway. Moreover, the combination treatment regimen led to a 50% reduction in Bcl-2 expression whereas single modality treatment had little bearing on the expression of this antiapoptotic gene. | To assess pregnancy outcome in women with anaemia during pregnancy. The study design involved a retrospective chart review of all women registering for prenatal care in the area of Kuopio University Hospital between 1990 and 2000. A haemoglobin concentration below 100g/l was used as a cutoff for anaemia and affected women (N=597) were stratified by the trimester at which anaemia was diagnosed. Multiple regression analysis was used to compare obstetric outcomes in the study groups and in non-anaemic women (N=22,202). The frequency of anaemia was 2.6%, with 0.3% occurring in the first trimester. After controlling for confounding factors, anaemia detected in the first trimester was associated with low-birth-weight infants (OR=3.14, 95% CI: 1.35-7.28) whereas the mid- and third-trimester anaemia groups showed no significantly different outcomes when compared with the non-anaemic women. First trimester anaemia was not significantly associated with small birth weight for gestational age (OR=0.98, 95% CI: 0.41-2.17) or with premature delivery <37 weeks (OR=1.80, 95% CI: 0.72-4.49). |
Does severe neutrophil depletion by leucocyte filters or cytotoxic drug improve recovery of contractile function in stunned porcine myocardium? | The contribution of neutrophils to myocardial injury during stunning remains controversial because of conflicting results in neutropenic animals. The goal of this study was to compare the recovery of function in stunned myocardium using two distinct methods for inducing neutropenia in pigs. Three groups of pigs were studied: control (n = 6), and made neutropenic by either Leukopak blood filters (n = 7), or cyclophosphamide (n = 7, 50 mg.kg-1 intravenously 4 d prior to study). In anaesthetised open chest pigs, with the heart paced at 110 beats.min-1, the left anterior descending coronary artery was perfused with an extracorporeal circuit at controlled coronary pressure (CP) and the regional coronary blood flow was measured. Systolic wall thickening was determined by sonomicrometry in the left anterior descending and circumflex coronary artery regions. The protocol consisted of 15 min of low flow ischaemia (CP = 40 mm Hg), followed by a staged reperfusion over 10 min back to baseline (CP = 90 mm Hg), and continued for 2 h. Blood filtration was initiated prior to ischaemia and stopped after 90 min reperfusion. In both treated groups during ischaemia and the initial 60 min of reperfusion the neutrophil count was severely depleted to < 5% compared to the control group. Aortic pressure, coronary blood flow during ischaemia, area at risk, and systolic wall thickening in the circumflex region were similar between groups. Recovery of systolic wall thickening in the left anterior descending region after reperfusion was equivalent in all three groups. In the filter group, arrhythmias during ischaemia and reperfusion were significantly less. | To investigate the mutation status of growth differentiation factor 15 (GDF15) in patients with oral squamous cell carcinoma (OSCC), as well as the prognostic value of missense GDF15 mutations. Formalin-fixed paraffin-embedded biopsy samples from 46 OSCC patients were involved in this study. GDF15 and TP53 mutations were sequenced using the Ion Torrent Personal Genome Machine, GDF15 protein expression was detected using immunohistochemistry. Torrent Suite Software v.3.6, Integrative Genomics Viewer; v.2.3, statistical software SPSS18.0 for Windows were used for analysis. All hypothesis-generating tests were two-sided at a significance level of 0.05. Twenty-nine GDF15 mutations were identified in 19 out of 46 patients (41.3%), including eighteen missense mutations, two nonsense mutations and nine synonymous mutations. The patients with missense GDF15 mutations had poorer prognostic outcomes than those with wild-type GDF15, including overall survival (P = 0.035), disease-free survival (P = 0.032), locoregional recurrence-free survival (P = 0.015), and distant metastasis-free survival (P = 0.070). Missense GDF15mutations was an independent increased risk factor of overall survival (HR = 5.993, 95% CI:1.856-19.346, P = 0.003), disease-free survival (HR = 3.764, 95% CI:1.295-10.945, P = 0.015), locoregional recurrence-free survival (HR = 4.555, 95% CI:1.494-13.889, P = 0.008), and distant metastasis-free survival (HR = 4.420, 95% CI:1.145-13.433, P = 0.009). |
Do a single dose of fentanyl and midazolam prior to Cesarean section have no adverse neonatal effects? | Analgesia and sedation, routinely used as adjunct medications for regional anesthesia, are rarely used in the pregnant patient because of concerns about adverse neonatal effects. In an effort to obtain more information about maternal analgesia and sedation we studied neonatal and maternal effects of iv fentanyl and midazolam prior to spinal anesthesia for elective Cesarean section. In this double-blinded, randomized, placebo-controlled trial, 60 healthy women received either a combination of 1 microg x kg(-1) fentanyl and 0.02 mg x kg(-1) midazolam intravenously or an equal volume of iv saline at the time of their skin preparation for a bupivacaine spinal anesthetic. Sample size was based on a non-parametric power analysis (power > 0.80 and alpha = 0.05) for clinically important differences in Apgar scores. Fetal outcome measures included Apgar scores, continuous pulse oximetry for three hours, and neurobehavioural scores. Maternal outcomes included catecholamine levels, and recall of anesthesia and delivery. There were no between-group differences of neonatal outcome variables (Apgar score, neurobehavioural scores, continuous oxygen saturation). Mothers in both groups showed no difference in their ability to recall the birth of their babies. | To assess, in a retrospective cohort, urinary tract urothelial carcinoma (UT-UC) in patients with various stages of chronic kidney disease (CKD) and their clinicopathological features, as patients with end-stage renal disease (ESRD) have a higher incidence of UT-UC, but the relationship between early stages of CKD and characteristics of UT-UC are less well known. The study included 267 patients with pathologically confirmed UT-UC from January 1994 to December 2006; all had a physical examination (blood pressure), and measurements of laboratory data (serum creatinine, serum haemoglobin) and pathological data. The glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease equation. Patients were divided into three groups by individual GFR (mL/min), i.e. >60 (no/mild CKD), 30-60 (CKD stage 3) and <30 (CKD stage 4/5). The CKD stages included 81 (30.3%) patients with none/mild CKD, 121 (45.3%) with CKD stage 3 and 65 (24.3%) with CKD stage 4/5. There was a significant and parallel increase in the frequency of UT-UC as CKD severity increased from none/mild CKD to stage 3 (11% vs 55%), and from CKD stage 3 to 4/5 (55% vs 71%; P < 0.05). Pathologically, the frequency of high-grade and high T stage UT-UC in patients with CKD stage 3 (90% and 35%, respectively) and CKD stage 4/5 (91% and 29%, respectively) were significantly greater than in the group with none/mild CKD (P < 0.001). Advanced age and more distant metastasis were independent risk factors for patient survival. |
Is incidence of Type 1 Diabetes Increasing in a Population-Based Cohort in Olmsted County , Minnesota , USA? | To investigate the recent incidence of T1D in a US Midwestern county to determine whether this increase has been sustained and compare it with the incidence of celiac disease (CD) and also investigate the prevalence of CD, an associated autoimmune disease, within the cohort. A broad search strategy was used to identify all incident cases of T1D in Olmsted County, Minnesota, between January 1, 1994, and December 31, 2010, using the Rochester Epidemiology Project. Diagnosis and residency status were confirmed through the medical record. Incidence rates were directly standardized to the 2010 US population. Poisson regression was used to test for a change in incidence rate. Clinical charts were reviewed to confirm case status. There were 233 incident cases of T1D. Directly adjusting for age and sex with respect to the 2010 US white population, the overall annual incidence of T1D was 9.2 (95% CI, 8.0-10.4) per 100,000 people per year among all ages and 19.9 (95% CI, 16.6-23.2) per 100,000 people per year for those younger than 20 years. There was no significant increase in the incidence of T1D over time (P=.45). Despite the overall stability in annual incidence, there was an initial increasing trend followed by a plateau. Of the 109 patients with T1D (47%) tested for CD, 12% (13) had biopsy-proven CD. | Hypertension is closely associated with erectile dysfunction (ED) as it has been observed in many experimental models of hypertension. Additionally, epidemiological studies show that approximately a third of hypertensive patients have ED. To test the hypothesis that the two-kidney, one-clip (2K-1C) rat model of hypertension displays normal erectile function due to increased nitric oxide (NO) production in the penis. Ganglionic-induced increase in intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio was used as an index of erectile function in 2K-1C and in normotensive sham-operated (SHAM) anesthetized rats. Cavernosal strips from hypertensive and normotensive rats were used for isometric tension measurement. The contraction induced by alpha-adrenergic agonist phenylephrine and the relaxation induced by the NO donor sodium nitroprusside (SNP) and by the Rho-kinase inhibitor Y-27632 were performed in the absence and in the presence of the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA). Changes in ICP/MAP induced by ganglionic stimulation were not different between 2K-1C and SHAM rats. The contractile response induced by phenylephrine as well as the relaxation induced by SNP or the Y-27632 were similar in cavernosal strips from both groups. However, in the presence of L-NNA, the relaxation induced by Y-27632 was significantly impaired in 2K-1C compared to SHAM. |
Do increased levels of GALbeta1-4GLCNACalpha2-6 sialyltransferase pretransplant predict delayed graft function in kidney transplant recipients? | Galbeta1-4GlcNAcalpha2-6 sialyltransferase (ST6GalI) is an acute phase reactant whose release from cells can be induced by proinflammatory cytokines. Because patients with chronic renal failure have high circulating levels of proinflammatory cytokines, we hypothesized that patients on the renal transplant waiting list would have high circulating levels of ST6GalI, which might adversely affect post-transplant events. Levels of ST6GalI were measured in the serum of 70 patients immediately before renal transplant; these were correlated with posttransplant events, such as delayed graft function and rejection. The mean serum level of ST6GalI was significantly higher in the patients (3162+/-97 U) than in 19 controls (2569 +/- 125 U; P<0.003). Patients who required dialysis posttransplant for treatment of delayed graft function (n=20) had significantly higher levels of ST6GalI pretransplant (3735+/-228 U) than patients (n=50) who did not require dialysis (2933+/-83 U; P<0.0001). In a multivariate analysis the ST6GalI level and cold ischemic time were found to be independent risk factors for the development of delayed graft function. | The aims of this study were to review the literature on intraoral digital radiography in endodontic treatment with focus on technical parameters and to propose recommendations for improving the quality of reports in future publications. Two electronic databases were searched. Titles and abstracts were selected according to preestablished criteria. Data were extracted using a model of image acquisition and interpretation. The literature search yielded 233 titles and abstracts; 61 reports were read in full text. Recent reports presented technical parameters more thoroughly than older reports. Most reported important parameters for the x-ray unit, but for image interpretation only about one-half of the publications cited resolution of the display system and fewer than one-half bit depth of the graphics card. |
Is incidence of peptic ulcer in men inversely correlated with blood pressure : study in an apparently healthy Japanese population? | To study the role of autonomic nervous innervation in the etiology of peptic ulcer, we investigated the blood pressure in patients with peptic ulcer. In 100,085 Japanese adults who were undergoing health screening examinations, including barium meal study, there were endoscopic evaluation-confirmed diagnoses of gastric ulcer in 769 cases and of duodenal ulcer in 344 cases. The blood pressure in those patients was compared with that in 57,208 normal Japanese controls with no gastrointestinal abnormalities, as confirmed by barium meal study. The blood pressure of younger and middle-aged men with gastric and duodenal ulcer were lower than those of normal control men. In women, except for the diastolic pressure of those in their 50s, the blood pressure in patients with peptic ulcer and normal controls did not differ significantly. The incidence of duodenal ulcer or of gastric ulcer in men was inversely related to the systolic and diastolic pressure. No definite relationship in this respect was seen in women. | Scaffold Attachment Factor B1 (SAFB1) is a multifunctional protein which has been implicated in breast cancer previously. We recently generated SAFB1 knockout mice (SAFB1-/-), but pleiotropic phenotypes including high lethality, dwarfism associated with low IGF-I levels, and infertility and subfertility in male and female mice, respectively, do not allow for straightforward tumorigenesis studies in these mice. Therefore, we asked whether SAFB1 heterozygosity would influence tumor development and progression in MMTV-Wnt-1 oncomice or DMBA induced tumorigenicity, in a manner consistent with haploinsufficiency of the remaining allele. We crossed female SAFB1+/- (C57B6/129) mice with male MMTV-Wnt-1 (C57B6/SJL) mice to obtain SAFB1+/+/Wnt-1, SAFB1+/-/Wnt-1, and SAFB1+/- mice. For the chemical induced tumorigenesis study we treated 8 weeks old SAFB1+/- and SAFB+/+ BALB/c mice with 1 mg DMBA once per week for 6 weeks. Animals were monitored for tumor incidence and tumor growth. Tumors were characterized by performing H&E, and by staining for markers of proliferation and apoptosis. We did not detect significant differences in tumor incidence and growth between SAFB1+/+/Wnt-1 and SAFB1+/-/Wnt-1 mice, and between DMBA-treated SAFB1+/+ and SAFB1+/-mice. Histological evaluation of tumors showed that SAFB1 heterozygosity did not lead to changes in proliferation or apoptosis. There were, however, significant differences in the distribution of tumor histologies with an increase in papillary and cribriform tumors, and a decrease in squamous tumors in the SAFB1+/-/Wnt-1 compared to the SAFB1+/+/Wnt-1 tumors. Of note, DMBA treatment resulted in shortened survival of SAFB1+/- mice compared to their wildtype littermates, however this trend did not reach statistical significance. |
Does trop-2-targeting tetrakis-ranpirnase have potent antitumor activity against triple-negative breast cancer? | Ranpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, comprising four copies of Rap linked to the CH3 and CK termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC). The DNL-based immunoRNases, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, were characterized and tested for biological activities in vitro on a panel of breast cancer cell lines and in vivo in a MDA-MB-468 xenograft model. (Rap)2-E1-(Rap)2 was highly purified (>95%), exhibited specific cell binding and rapid internalization in MDA-MB-468, a Trop-2-expressing TNBC line, and displayed potent in vitro cytotoxicity (EC50 ≤ 1 nM) against diverse breast cancer cell lines with moderate to high expression of Trop-2, including MDA-MB-468, BT-20, HCC1806, SKBR-3, and MCF-7. In comparison, structural counterparts of (Rap)2-E1-(Rap)2, generated by substituting hRS7 with selective non-Trop-2-binding antibodies, such as epratuzumab (anti-CD22), were at least 50-fold less potent than (Rap)2-E1-(Rap)2 in MDA-MB-468 and BT-20 cells, both lacking the expression of the cognate antigen. Moreover, (Rap)2-E1-(Rap)2 was less effective (EC50 > 50 nM) in MDA-MB-231 (low Trop-2) or HCC1395 (no Trop-2), and did not show any toxicity to human peripheral blood mononuclear cells. In a mouse TNBC model, a significant survival benefit was achieved with (Rap)2-E1*-(Rap)2 when given the maximal tolerated dose. | The aim of the study was to compare the diameter response of retinal arterioles and retinal thickness in patients with different stages of diabetic maculopathy during an increase in the arterial blood pressure. Four groups each consisting of 19 individuals were studied. Group A consisted of normal individuals and groups B-D consisted of type 2 diabetic patients matched for diabetes duration, age, and gender, and characterized by: Group B no retinopathy, Group C mild retinopathy, Group D maculopathy not requiring laser treatment. The diameter changes of a large retinal arteriole were measured using the Retinal Vessel Analyzer (RVA, Imedos, Germany) before, during, and after an increase in the blood pressure induced by isometric exercise. Additionally, the retinal thickness was measured using optical coherence tomography scanning. The arterioles contracted during isometric exercise in normal persons (diameter response: -0.70+/-0.48%) and in patients with no retinopathy (-1.15+/-0.44%), but dilated in patients with mild retinopathy (0.41+/-0.49%) and diabetic maculopathy (0.54+/-0.44%), p=0.01. Retinal thickness was normal in Group A (260+/-5.0 microm), Group B (257+/-4.5 microm), and Group C (253+/-4.4 microm), but was significantly (p=0.006) increased in Group D (279+/-5.3 microm). |
Is lymphocyte proliferation in mice after a full laparotomy the same whether performed in a sealed carbon dioxide chamber or in room air? | Our laboratory has demonstrated that significantly more cell-mediated immunosuppression occurs after full laparotomy than after either anesthesia control or carbon dioxide (CO2) pneumoperitoneum. We further demonstrated that the postoperative immunosuppression is related to the length of the incision. Other investigators believe that the immunosuppression observed after laparotomy is caused by peritoneal exposure to small amounts of lipopolysaccharide found in circulating air. They believe that the better-preserved immune function associated with laparoscopic surgery results from the avoidance of air contamination of the peritoneal cavity. To investigate this hypothesis, we determined and compared postoperative lymphocyte proliferation rates after (a) laparotomy in room air, (b) laparotomy in a CO2 chamber, (c) CO2 insufflation in a murine model, and (d) anesthesia alone. Female C3H/He mice (n = 21) were divided randomly into four groups: (a) anesthesia control, (b) air laparotomy, (c) CO2 laparotomy, and (d) CO2 insufflation. The control mice underwent no procedure. The group 2 animals underwent a full midline incision (xiphoid to pubis) and exposure to room air for 20 min and then were clipped closed. The group 3 mice underwent a full midline incision in a sealed CO2 chamber for 20 min, and the group 4 mice insufflation with CO2 gas at 4 to 6 mm Hg for 20 min. Splenocytes were harvested from all the animals on day 2 after the interventions. Lymphocyte proliferation then was assessed using the nonradioactive colorimetric MTS/PMS system 72 h after concanavalin-A stimulation. There was no significant difference in lymphocyte proliferation between the air and CO2 laparotomy groups. Lymphocyte proliferation in the anesthesia control and CO2 insufflation groups was significantly higher than in both the air laparotomy (p<0.05) and CO2 laparotomy (p<0.05) groups (p values by Tukey-Kramer test). There was no significant difference between the anesthesia control and CO2 pneumoperitoneum groups. | Mutations at some retinitis pigmentosa (RP) loci are associated with variable penetrance and expressivity, exacerbating diagnostic challenges. The purpose of this study was to dissect the genetic underpinnings of nonsyndromic RP with variable age of onset in a large Mexican family. We ascertained members of a large, multigenerational pedigree using a complete ophthalmic examination. We performed whole exome sequencing on two affected first cousins, an obligate carrier, and a married-in spouse. Confirmatory sequencing of candidate variants was performed in the entire pedigree, as well as genotyping and mRNA studies to investigate expression changes in the causal locus. We identified a 14-base pair (bp) deletion in PRPF31, a gene implicated previously in autosomal dominant (ad) RP. The mutation segregated with the phenotype of all 10 affected females, but also was present in six asymptomatics (two females and four males). Studies in patient cells showed that the penetrance/expressivity of the PRPF31 deletion allele was concordant with the expression levels of wild-type message. However, neither the known PRPF31 modulators nor cis-eQTLs within 1 Mb of the locus could account for the variable expression of message or the clinical phenotype. |
Does lactoferrin protect against UV-B irradiation-induced corneal epithelial damage in rats? | Lactoferrin supplementation suppresses ultraviolet light B (UV-B)-induced oxidation of cultures of human corneal epithelial cells. To investigate the protective effect of lactoferrin containing eyedrops against UV-B-induced corneal damage in vivo, we examined lactoferrin efficacy in a rat UV-B keratitis model. Sprague-Dawley rats were irradiated with >10 kJ/m2 after anesthetization, and then corneal epithelial defect was observed at 24 h postirradiation. The pre- or postapplication of vehicle or lactoferrin-containing eyedrops was performed, and then corneal epithelial damage was scored based on fluorescein staining. Posttreatment with lactoferrin did not inhibit the extent of corneal damage and did not affect wound healing. However, pretreatment by topical application of lactoferrin suppressed development of a corneal epithelial defect induced by UV-B irradiation in rats. | Previous research has suggest that obesity is associated with increased risk for psychopathological disorders, however, little is known about which obese patients are most vulnerable to psychopathological disorders. We therefore investigated 126 treatment-seeking obese women to describe eating disorder pathology and mental health correlates, and to identify disordered eating behaviors that may place obese at increased risk for psychopathological disorders. The Structured Clinical Interview for DSM-IV (SCID) was used to identify Eating Disorders (ED). A battery of psychological tests, including the Anxiety Scale Questionnaire (ASQ,) Clinical Depression Questionnaire (CDQ), Eating Disorder Inventory-2 (EDI-2) Eating Attitudes Test-26 (EAT-26) scales and structured clinical interview were administered to all the patients. We analyzed the link between psychopathological disorders and eating attitudes by using both multiple regression analysis and non-parametric correlation. Disordered eating behaviors and emotional behavioral aspects related to Anorexia Nervosa, such as ineffectiveness, are strongly linked to the depression and anxiety in obese subjects. No correlation was found between psychopathological disorders and age or anthropometric measurements. |
Does a novel two-step genome editing strategy with CRISPR-Cas9 provide new insights into telomerase action and TERT gene expression? | To facilitate indefinite proliferation, stem cells and most cancer cells require the activity of telomerase, which counteracts the successive shortening of telomeres caused by incomplete DNA replication at the very end of each chromosome. Human telomerase activity is often determined by the expression level of telomerase reverse transcriptase (TERT), the catalytic subunit of the ribonucleoprotein complex. The low expression level of TERT and the lack of adequate antibodies have made it difficult to study telomerase-related processes in human cells. To overcome the low CRISPR-Cas9 editing efficiency at the TERT locus, we develop a two-step "pop-in/pop-out" strategy to enrich cells that underwent homologous recombination (HR). Using this technique, we fuse an N-terminal FLAG-SNAP-tag to TERT, which allows us to reliably detect TERT in western blots, immunopurify it for biochemical analysis, and determine its subcellular localization by fluorescence microscopy. TERT co-localizes detectably with only 5-7 % of the telomeres at a time in S-phase HeLa cells; no nucleolar localization is detected. Furthermore, we extend this approach to perform single base-pair modifications in the TERT promoter; reverting a recurrent cancer-associated TERT promoter mutation in a urothelial cancer cell line results in decreased telomerase activity, indicating the mutation is causal for telomerase reactivation. | This study was aimed to verify whether it is possible to detect at hospital admission, by means of INTERMED, pneumonology patients at risk of "complexity" and of specialized psychosocial intervention. With the Spanish version of INTERMED (for detection of risk for complexity of care) 144 patients were interviewed at admission by a standardized nurse. At discharge, patients were reassessed blindly with standardized Spanish versions of instruments including the Hospital Anxiety and Depression Scale (HADS). Somatic illness variables were independently documented, and severity was assessed by means of the Cumulative Illness Rating Scale. All variables were operationalized including complex (IM+; INTERMED>20) and non-complex patients (IM-), and probable need of psychosocial treatment/intervention. Statistical analysis included multivariate logistic regression. A complex course was documented in 9.6% of patients, and 28.8% had complex discharge. Significantly higher proportions of severe anxiety and/or depression were documented in IM+ cases (12.1%) when compared to IM- cases (0.9%), and the need of psychosocial treatment/intervention was also significantly more frequent among the former (24.2% versus 6.3% respectively). Furthermore, in the multivariate analysis and controlling for medical and sociodemographic confounders INTERMED was significantly associated with the variable need of psychosocial intervention. |
Does dPC4 gene status of the primary carcinoma correlate with patterns of failure in patients with pancreatic cancer? | Contrary to the extensive data accumulated regarding pancreatic carcinogenesis, the clinical and molecular features characteristic of advanced stage (stage III and IV) disease are unknown. A comprehensive study of pancreatic cancers from patients who have succumbed to their disease has the potential to greatly expand our understanding of the most lethal stage of this disease and identify novel areas for intervention. Rapid autopsies were performed on 76 patients with documented pancreatic cancer. The histologic features of end stage disease were determined and correlated to the stage at initial diagnosis, patterns of failure (locally destructive v metastatic disease) and the status of the KRAS2, TP53, and DPC4 genes. At autopsy, 30% of patients died with locally destructive pancreatic cancer, and 70% died with widespread metastatic disease. These divergent patterns of failure found at autopsy (locally destructive v metastatic) were unrelated to clinical stage at initial presentation, treatment history, or histopathologic features. However, Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy, a sensitive marker of DPC4 genetic status, was highly correlated with the presence of widespread metastasis but not with locally destructive tumors (P = .007). | Previous studies have observed that activation of cyclooxygenase-2 contributes to generation of superoxide anion after fluid percussion brain injury (FPI). This study was designed to characterize the effects of FPI on the vascular activity of two activators of a pertussis toxin-sensitive G protein, mastoparan and mastoparan-7, and the role of cyclooxygenase-2-dependent superoxide anion generation in such effects as a function of age. Lateral FPI was induced in anesthetized newborn (1-5-day-old) and juvenile (3-4-week-old) pigs equipped with a closed cranial window. Mastoparan (10(-8), 10(-6) M) elicited pial artery dilation that was blunted more in newborn versus juvenile pigs (9 +/- 1 and 16 +/- 1 vs. 3 +/- 1 and 5 +/- 1%, newborn; 9 +/- 1 and 15 +/- 1 vs. 6 +/- 1 and 9 +/- 1%, juveniles). Similar results were observed for mastoparan-7 but the inactive analog mastoparan-17 had no effect on pial artery diameter. Indomethacin (a cyclooxygenase-1 and cyclooxygenase-2 inhibitor), NS398 (a cyclooxygenase-2 inhibitor), and polyethylene glycol superoxide dismutase and catalase (free radical scavengers) partially restored impaired mastoparan dilation after FPI in the newborn in a roughly equivalent manner but not in the juvenile (3 +/- 1 and 5 +/- 1 vs. 8 +/- 1 and 13 +/- 1% newborn, 6 +/- 1 and 9 +/- 1 vs. 7 +/- 1 and 10 +/- 1% juvenile for NS398 pretreatment). |
Do exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis? | Stem cells derived from the dental pulp of human exfoliated deciduous teeth (SHEDs) have unique neurogenic properties that could be potentially exploited for therapeutic use. The importance of paracrine SHED signaling for neuro-regeneration has been recognized, but the exact mechanisms behind these effects are presently unknown. In the present study, we investigated the neuro-protective potential of exosomes and micro-vesicles derived from SHEDs on human dopaminergic neurons during oxidative stress-induced by 6-hydroxy-dopamine (6-OHDA). ReNcell VM human neural stem cells were differentiated into dopaminergic neurons and treated with 100 μmol/L of 6-OHDA alone or in combination with exosomes or micro-vesicles purified by ultracentrifugation from SHEDs cultivated in serum-free medium under two conditions: in standard two-dimensional culture flasks or on laminin-coated micro-carriers in a bioreactor. Real-time monitoring of apoptosis was performed with the use of time-lapse confocal microscopy and the CellEvent Caspase-3/7 green detection reagent. Exosomes but not micro-vesicles derived from SHEDs grown on the laminin-coated three-dimensional alginate micro-carriers suppressed 6-OHDA-induced apoptosis in dopaminergic neurons by approximately 80% throughout the culture period. Strikingly, no such effects were observed for the exosomes derived from SHEDs grown under standard culture conditions. | Chronic kidney disease (CKD) is a worldwide public health problem. It is very important to identify the factors that affect CKD. Previous studies have reported that serum bilirubin concentration was positively correlated with renal function in a cross-sectional study. The aim of this study was to investigate the relationship between serum bilirubin concentration and the progression of CKD. A cohort study was performed on a consecutive series of 2784 subjects without CKD, defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2), at baseline. We analyzed the relationship between serum total bilirubin concentration at baseline and new-onset CKD in the general population. We followed the subjects for a median period of 7.7 years. There were 1157 females and 1627 males, and 231 females and 370 males developed CKD during this period. Multiple Cox regression analyses revealed that serum total bilirubin concentration (hazard ratio (HR) per 1.0 μmol/L increase 0.97 (95% CI 0.95-0.99), P = 0.0084) in addition to age, gamma-glutamyl transpeptidase (GGT), uric acid (UA), creatinine and medication for hypertension in men and serum total bilirubin concentration (HR per 1.0 μmol/L increase 0.96 (95% CI 0.93-1.00), P = 0.0309) in addition to age, GGT, alanine aminotransferase, UA, creatinine and medication for dyslipidemia in women were independent predictors of new-onset CKD, after adjusting for confounders. |
Is diagnostic Ureteroscopy for Upper Tract Urothelial Carcinoma Independently Associated with Intravesical Recurrence after Radical Nephroureterectomy? | To determine the effect of diagnostic ureteroscopy on intravesical recurrence in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterec¬tomy (RNU). We conducted a retrospective analysis of 664 patients who were treated with RNU for UTUC from June 2000 to December 2011, excluding those who had concomitant/prior bladder tumors. Of the 664 patients, 81 underwent di¬agnostic ureteroscopy (URS). We analyzed the impact of diagnostic ureteroscopy on intravesical recurrence (IVR) using the Kaplan-Meier method. Univariate and multi¬variate analyses were used to determine the independent risk factors. The median follow-up time was 48 months (interquartile range (IQR): 31- 77 months). Patients who underwent ureteroscopy were more likely to have a small (p<0.01), early-staged (p=0.019), multifocality (p=0.035) and ureteral tumor (p<0.001). IVR occurred in 223 patients during follow-up within a median of 17 months (IQR: 7-33). Patients without preoperative ureteroscopy have a statistically significant better 2-year (79.3%±0.02 versus 71.4%±0.02, p<0.001) and 5-year intravesical recurrence-free survival rates (64.9%±0.05 versus 44.3%±0.06, p<0.001) than patients who un¬derwent ureteroscopy. In multivariate analysis, the diagnostic ureteroscopy (p=0.006), multiple tumors (p=0.001), tumor size <3cm (p=0.008), low-grade (p=0.022) and pN0 stage tumor (p=0.045) were independent predictors of IVR. | Although allergic sensitization can be generated against various allergens, it is unknown how such a diversity of antigens is able to promote TH2-mediated inflammation leading to atopy. Our previous studies demonstrated that allergen-specific IgG immune complexes (ICs) and house dust mite (HDM) extract both induced dendritic cells (DCs) to drive TH2-mediated inflammation, but the mechanism by which these diverse stimuli produce similar responses is unknown. We sought to identify the DC signaling pathways used by TH2 stimuli to promote TH2-mediated inflammation. C57BL/6, FcγRIII(-/-), FcRγ(-/-), and ST2(-/-) mice were sensitized and challenged with HDM, and inflammation was assessed based on results of flow cytometry and histology and cytokine production. Bone marrow-derived DCs from these strains were used in signaling and adoptive transfer experiments. Our findings indicate that 2 distinct TH2 stimuli, ICs and HDM, use the FcRγ-associated receptors FcγRIII and Dectin-2, respectively, to promote TH2-mediated lung inflammation. In this study we demonstrate that both ICs and HDM induce expression of IL-33, a critical mediator in asthma pathogenesis and the differentiation of TH2 cells, in DCs. Upregulation of IL-33 in DCs is dependent on FcRγ, Toll-like receptor 4, and phosphoinositide 3-kinase. Exogenous IL-33 is sufficient to restore the development of TH2 responses in FcRγ-deficient mice. Finally, adoptive transfer of allergen-pulsed FcRγ(+/-) bone-marrow derived DCs restores the development of TH2-type inflammation in FcRγ-deficient mice, demonstrating the necessity of this signaling pathway in DCs for allergen-induced inflammation. |
Does chronic oral gabapentin reduce elements of central sensitization in human experimental hyperalgesia? | In chronic pain, increased activity from intact or damaged peripheral nerve endings results in an enhanced response in central pain transmission systems, a mechanism known as central sensitization. Central sensitization can also be invoked in human experimental models. Therefore, these models may be useful to characterize novel analgesics in humans. The anticonvulsant gabapentin has demonstrated efficacy in patients with neuropathic pain, but its mode of action remains unclear. This study examined the effects of gabapentin on signs of central sensitization (brush and pinprick hyperalgesia) in a human model of capsaicin-evoked pain, using a gabapentin dosing regimen similar to that used in the clinic. The aims were to determine whether gabapentin, dosed in a manner similar to that used in the clinic, affected the various components of central sensitization and to assess the utility of this model for characterizing novel analgesics. Intradermal capsaicin (100 microg/20 microl) was administered in the volar forearm of 41 male human volunteers to induce pain and clinical signs of central sensitization. Gabapentin (titrated to 2,400 mg daily) or placebo was given orally for 15 days in a randomized, double-blind, parallel-group design. The capsaicin test was conducted at baseline and after gabapentin or placebo. Endpoints were the size of areas of brush-evoked allodynia (with cotton gauze) and pinprick hyperalgesia (with von Frey filament), and the intensity of ongoing brush- and pinprick-evoked pain. Gabapentin significantly reduced the area of brush allodynia compared with placebo (P </= 0.05) and insignificantly attenuated the area of pinprick hyperalgesia. Gabapentin had no significant effect on spontaneous and evoked pain intensity. | To observe the relationship between skewed X-chromosomal inactivation (SXCI) and development of lung cancer in females. DNA was isolated from peripheral blood cells from patients with primary lung cancer (n = 148) and control subjects (n =289). Exon 1 of androgen receptor ( AR) gene was amplified, with its products from different alleles resolved on denaturing polyacrylamide gels and visualized by silver staining. The corrected ratio (CR) between products from different AR alleles before and after Hpa II pretreatment was calculated. All statistical tests were two-sided. With CR> or = 10 adopted as the criterion, SXCI was found more frequently in the younger patients ( C50 years; 7. 9%) than in the controls of the same age group (1. 2% ; P = 0. 046). The SXCI frequency, however, were not significantly different between the old patients ( > 50 years; 4. 5% ) and the controls of the same age group (5. 4% ; P =0. 488). Whether taking CR> or =3 or CR> or =10 as the criteria, the average ages of the patients with SXCI were more than 10 years younger than those without SXCI (P < 0. 05). |
Does mood influence the Concordance of Subjective and Objective Measures of Sleep Duration in Older Adults? | Sleep plays a central role in maintaining health and cognition. In most epidemiologic studies, sleep is evaluated by self-report questionnaires but several reports suggest that these evaluations might be less accurate than objective measures such as polysomnography or actigraphy. Determinants of the discrepancy between objective and subjective measures remain to be investigated. The aim of this pilot-study was to examine the role of mood states in determining the discrepancy observed between objective and subjective measures of sleep duration in older adults. Objective sleep quantity and quality were recorded by actigraphy in a sample of 45 elderly subjects over at least three consecutive nights. Subjective sleep duration and supplementary data, such as mood status and memory, were evaluated using ecological momentary assessment (EMA). A significant discrepancy was observed between EMA and actigraphic measures of sleep duration (p < 0.001). The magnitude of this difference was explained by the patient's mood status (p = 0.020). No association was found between the magnitude of this discrepancy and age, sex, sleep quality or memory performance. | Cells are not mixed bags of signaling molecules. As a consequence, signals must travel from their origin to distal locations. Much is understood about the purely diffusive propagation of signals through space. Many signals, however, propagate via signaling cascades. Here, we show that, depending on their kinetics, cascades speed up or slow down the propagation of signals through space, relative to pure diffusion. We modeled simple cascades operating under different limits of Michaelis-Menten kinetics using deterministic reaction-diffusion equations. Cascades operating far from enzyme saturation speed up signal propagation; the second mobile species moves more quickly than the first through space, on average. The enhanced speed is due to more efficient serial activation of a downstream signaling module (by the signaling molecule immediately upstream in the cascade) at points distal from the signaling origin, compared to locations closer to the source. Conversely, cascades operating under saturated kinetics, which exhibit zero-order ultrasensitivity, can slow down signals, ultimately localizing them to regions around the origin. |
Does anti-miR-197 inhibit migration in HCC cells by targeting KAI 1/CD82? | To investigate the metastatic effects and mechanisms of miR-197 in hepatocellular carcinoma (HCC). The levels of miR-197 increased in HCC cells and tissues compared with a normal hepatic cell line (LO2) and adjacent nontumorous liver tissues, respectively. miR-197 expression negatively correlated with CD82 mRNA expression in these cell lines and tissues. Dual luciferase reporter assay and Western blot confirmed a direct interaction between miR-197 and CD82 3'UTR sequences. After miR-197 was silenced in HCC cells, CD82 expression increased. In the presence of human hepatocyte growth factor (HGF), cells silenced for anti-miR-197 exhibited elongated cellular tails and diminished lamellipodia due to reductions in both ROCK activity and the levels of Rac 1 protein. Downregulation of miR-197 along with the upregulation of CD82 in HCC cells resulted in the inhibition of HCC migration and invasion in vitro and in vivo. | Nasal polyposis (NP) is a chronic inflammatory disease often found coexisting with asthma. As this disorder tends to cluster in families, a genetic predisposition has been suggested. Interleukin-1 (IL-1) has been proposed to play a role in the pathogenesis of NP. We analysed the single G-to-T base exchange polymorphism in exon 5 at +4845 of the gene encoding IL-1alpha (IL1A) and the C-to-T base exchange polymorphism at -511 of the gene encoding IL-1beta (IL1B) in a population-based sample of adult asthma patients (n = 245). The data were assessed for correlation with data on history of NP and other phenotype-related characteristics. The prevalence of NP in our study group was 14.3%. The distribution of the IL1A genotype differed significantly between asthmatics with and without NP (P = 0.005). The risk of NP was markedly increased in allele G homozygous subjects (OR = 2.73; 95%CI = 1.40-5.32). In the case of IL1B we found no significant associations. Asthmatics with NP had more symptoms than others, but lung function and blood eosinophil counts were similar. |
Does inhibition of glucose absorption by phlorizin affect intestinal functions in rats? | To investigate the mechanism of regulation of intestinal disaccharidase activity and glucose absorption, the effect of dietary intake of phlorizin, a potent and specific inhibitor of intestinal glucose transport, on intestinal disaccharidase activity and Na(+)-dependent glucose transporter was examined in rats. Jejunal disaccharidase activity and the number of Na(+)-dependent glucose transporters were determined in rats maintained on a low-starch diet, a high-starch diet, or low-starch diets containing various amounts of phlorizin (0.1%-0.9% wt/wt). Jejunal disaccharidase activity increased in a dose- and time-dependent manner. Stimulation of jejunal disaccharidase activity only occurred when phlorizin was added to starch-containing diets, not when it was added to a carbohydrate-free diet. Addition of the same amount of phloretin and glucose (constituents of phlorizin), to the diet failed to increase disaccharidase activity. The maximum binding of phlorizin to brush border membrane vesicles was increased in the rats fed phlorizin, whereas the dissociation constant remained unchanged, suggesting an increase of glucose transporter expression. | : Trauma center physicians need to know the patient's prognosis to make appropriate clinical decisions when they take over the care of a transferred patient. We sought to compare the survival of injured patients after transfer to a trauma center with survival from a comparable time after injury among patients who had been admitted to the trauma center directly from the scene of injury. : Study included 2,867 patients 18 years to 84 years of age with at least one Abbreviated Injury Scale score >/=3 injury transferred to a trauma center and 7,570 patients admitted directly to a trauma center. The outcome was death within one year after injury. Cox proportional hazards model for death was used accounting for time since injury, adjusted for age group, gender, injury severity, injury mechanism, and comorbidities. : Overall, there was almost no increase in the adjusted risk of death for transfer patients in the year after injury [hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.27]. The adjusted risk of death was higher in transfer patients than nontransfer patients between 50 days and 365 days after injury (HR 1.28, 95% CI 0.79, 2.07), but not within the first 50 days (HR 0.95, 95% CI 0.76, 1.18). However these modest differences in survival within each period were not statistically significant. |
Does silencing of ETS1 reverse adriamycin resistance in MCF-7/ADR cells via downregulation of MDR1? | Clinical resistance to chemotherapeutic agents is one of the major hindrances in the treatment of human cancers. Erythroblastosis virus E26 oncogene homolog 1 (ETS1) is involved in the drug resistance of various cancer cells, and is overexpressed in drug-resistant human breast cancer cell lines. In this study, we investigated the effects of ETS1 on adriamycin resistance in MCF-7/ADR cells. siRNAs against ETS1 or negative control siRNAs was transfected to MCF-7/ADR breast cancer cells. Reverse transcription-PCR and Western blotting were used to determine the mRNA and protein expression of ETS1 and MDR1. The cytotoxicity of adriamycin was assessed using the MTT assay. Drug efflux was investigated by flow cytometry using the Rhodamine 123 intracellular accumulation assay. ETS1 mRNA and protein was significantly overexpressed in MCF-7/ADR cells, compared to MCF-7 cells. ETS1 siRNA successfully silenced ETS1 mRNA and protein expression. Silencing of ETS1 also significantly reduced the mRNA and protein expression levels of MDR1 (multidrug resistance 1; also known as ABCB1, P-glycoprotein/P-gp), which is a major ATP-binding cassette (ABC) transporter linked to multi-drug resistance in cancer cells. Silencing of ETS1 significantly increased the sensitivity of MCF-7/ADR cells to adriamycin, compared to cells transfected with negative control siRNA. In addition, intracellular accumulation of Rhodamine 123 significantly increased in MCF-7/ADR cells transfected with ETS1 siRNA, indicating that silencing of ETS1 may reduce drug efflux. | The aim of the present study was to evaluate the influence of sleep duration on cardiovascular risk factors in obese children. Cross-sectional analysis of 90 obese children ages 7 to 16 years. Anthropometric and clinical evaluation with specification of dietary and lifestyle habits was carried out during an office visit. Sleep duration was evaluated by the BEARS (B = bedtime issues, E = excessive daytime sleepiness, A = night awakening, R = regularity and duration of sleep, S = snoring) questionnaire on children's sleep characteristics. Sleep time adequacy by age was assessed according to the criteria of the National Sleep Foundation. Biochemical blood variables indicative of metabolic risk (glucose, lipid profile, and insulin) were obtained. Emergent new factors of metabolic risk, including high-sensitive C-reactive protein, γ-glutamyltranspeptidase, homocysteine, retinol-binding protein 4 (RBP4), thyroid-stimulating hormone (TSH), inflammatory markers, and the adipokines leptin, adiponectin, and ghrelin were also evaluated. The relations between the duration of sleep and these variables were analyzed by general lineal model analysis. Significant variables were introduced in logistic regression analysis to determine the odds ratio (OR) and 95% confidence interval (CI) of cardiometabolic factors with respect to sleep. Children who slept for short duration were significantly more at risk of severe central obesity. In the regression model, the mean arterial pressure (odds ratio [OR] 1.10, 95% confidence interval [CI] 1.02-1.17, P = 0.008), homocysteine (OR 1.41, 95% CI 1.08-1.84, P = 0.013), RBP4 (OR 1.78, 95% CI 1.15-2.78, P = 0.010), and TSH (OR 2.01, 95% CI 1.21-3.34, P = 0.007) remain as significant independent predictors related to short sleep duration. We did not find any association between sleep duration and inflammatory markers or adipokines. |
Does prenatal cigarette smoke exposure attenuate recovery from hypoxemic challenge in preterm infants? | The effects of prenatal cigarette smoke (CS) exposure and hypoxemia on cardiorespiratory control have been investigated in full-term infants. However, few data are available in preterm infants, who form a particularly vulnerable population, with developmentally immature cardiorespiratory control. To investigate the effects of prenatal CS exposure on the duration and recovery of breathing pauses and oxygen saturation levels under baseline and hypoxemic conditions in preterm infants. The study was performed on 22 (12 born to smoking and 10 to nonsmoking mothers) spontaneously breathing preterm infants between 28 and 36 weeks' gestation. Cardiorespiratory variables were recorded under baseline normoxemic and hypoxemic conditions. Breathing pauses, pause indices, time to recovery, percent pause recovery, oxygen saturation (Sp(O2)), periods of wakefulness, and cardiorespiratory rates were compared between the two groups. Spontaneous recovery of breathing pauses (P = 0.03) and Sp(O(2)) levels (P = 0.017) were attenuated in CS-exposed infants as compared with the control group during the hypoxemic and posthypoxemic periods, respectively. The episodes of wakefulness during the hypoxemic challenge were similar between the two groups. Furthermore, CS-exposed infants showed a greater increase in heart rate (P < 0.001) during the hypoxemic challenge when compared with control infants. | To explore whether pretreatment features of synovial tissue in patients with gonarthritis could predict the clinical effect of radiation synovectomy with yttrium-90 (90Y) and glucocorticoids or with intra-articular glucocorticoids alone. A synovial biopsy was carried out blindly 2 weeks before treatment in 66 patients with persistent gonarthritis, who were randomised to treatment either with 90Y and triamcinolone or with placebo and triamcinolone. Immunohistochemistry was used to detect T cells, macrophages, B cells, plasma cells, fibroblast-like synoviocytes, adhesion molecules and pro-inflammatory cytokines. Stained sections were evaluated by digital image analysis. Individual patient improvement was expressed using a composite change index (CCI; range 0-12). Successful treatment was defined as CCI > or = 6 after 6 months. Patients with rheumatoid arthritis, psoriatic arthritis, undifferentiated arthritis and other causes of gonarthritis were included. The overall response rate was 47%. Clinical efficacy in both therapeutic groups was similar and not dependent on diagnosis. No significant differences were noted between baseline microscopic features of synovial tissue inflammation in patients with rheumatoid arthritis and in those with non-rheumatoid arthritis (ie, all diagnoses other than rheumatoid arthritis). The number of macrophages in the synovial sublining was significantly higher in responders than in non-responders (p = 0.002), independent of treatment group and diagnosis. The clinical effect was positively correlated with pretreatment total macrophage numbers (r = 0.28; p = 0.03), sublining macrophage numbers (r = 0.34; p = 0.005) and vascular cell adhesion molecule 1 expression (r = 0.25; p = 0.04). |
Does resting energy expenditure in insulin resistance fall with decompensation of insulin secretion in obese children? | Low resting energy expenditure (REE) and respiratory quotient (RQ) have been shown in adults to predispose to obesity and diabetes mellitus. To correlate REE and RQ in 73 obese children and young adults (body mass index [BMI] 37 +/- 10 kg/m2) with measures of insulin secretion and resistance (IR) indices, percent carbohydrate and fat oxidation, and prolactin and leptin levels. During a 3-day admission, REE and RQ were determined by indirect calorimetry. Blood chemistries and oral glucose tolerance test (OGTT) were obtained, and intravenous glucose tolerance test (IVGTT) modified by tolbutamide was conducted after an overnight fast, permitting calculation of acute insulin response (AIR), insulin resistance (SiIVGTT), and disposition index (DI). Patients fell into two groups according to their SiIVGTT: those with normal insulin sensitivity (NIS) and those with insulin resistance (IR). IR patients were subdivided on the basis of DI (cut-off value 0.13 min(-1)) into compensated (CIR) or decompensated (DIR) groups. CIR patients had higher RQ, REE corrected by BMI, AIR, and carbohydrate oxidation and lower fat oxidation than NIS and DIR patients. REE correlated positively with BMI, leptin, and AIR, and negatively with SiIVGTT. | Metastasis remains the main cause of death in both bladder (BCa) and prostate (PCa) cancers. The results of chemotherapy did not show any significant improvement of the survival the past years. Cancer research has led to the identification of signaling pathways involved and molecular targets that could change the natural history. The epithelial-mesenchymal transition (EMT), critical during embryonic development, becomes potentially destructive in many epithelial tumors progression where it is inappropriately activated. The cell-cell and cell-extracellular matrix interactions are altered to release cancer cells, which are able to migrate toward metastatic sites. Hallmarks of EMT include the down-regulation of E-cadherin expression, which is the main component of the adherens junctions. The protein TWIST is a transcriptional repressor of E-cadherin, tumor progression, and metastasis, and could be used as a molecular target to restore the chemosensitivity in BCa and PCa. We selected the last 5-year basic research literature on EMT and TWIST but also clinical studies on BCa and PCa in which TWIST is overexpressed and could be considered as an efficient prognostic marker and molecular target. TWIST is considered as a potential oncogene promoting the proliferation and inhibiting the apoptosis. TWIST promotes the synthesis of the pro-angiogenic factor, vascular endothelial growth factor (VEGF) involved in tumor progression and metastasis. Apoptosis and angiogenesis are two essential cancer progression steps in many epithelial tumors, including BCa and PCa. |
Does a common variant in the adiponutrin gene influence liver enzyme values? | Two recent genome-wide association studies identified the liver expressed transmembrane protein adiponutrin to be associated with liver related phenotypes such as non-alcoholic fatty liver disease and liver function enzymes. These associations were not uniformly reported for various ethnicities. The aim of this study was to investigate a common non-synonymous variant within adiponutrin (rs738409, exon 3) with parameters of liver function in three independent West Eurasian study populations including a total of 4290 participants. The study was performed in (1) the population based Bruneck Study (n=783), (2) the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk Study from Austria based on a healthy working population (n=1705), and the Utah Obesity Case-Control Study including a group of 1019 severely obese individuals (average body mass index 46.0 kg/m(2)) and 783 controls from the same geographical region of Utah. Liver enzymes measured were alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT). A strong recessive association of this polymorphism was found with age and gender adjusted ALT and AST concentrations: being homozygous for the minor allele resulted in a highly significant increase of ALT concentration of 3.53 U/l (p=1.86 x 10(-9)) and of AST concentration of 2.07 U/l (p=9.58 x 10(-6)), respectively. The associations were consistently found in all three study populations. | To determine the incidence of parametrial involvement in a select group of patients with early cervical cancer. We retrospectively reviewed the records of patients with cervical cancer and a maximum tumor diameter of 2 cm, infiltration depth<10 mm and negative pelvic lymph nodes who underwent a radical hysterectomy in two university hospitals. In addition, the literature was reviewed. 103 patients were identified in our databases that met the abovementioned criteria. In two of these patients (1.94%), parametrial involvement was found. Both patients had LVSI. Literature review revealed 696 patients described in three studies that satisfied the selection criteria. Three (0.43%) of these patients had parametrial involvement. In patients with early stage cervical carcinoma, tumor size<2 cm, infiltration depth<10 mm, negative pelvic lymph nodes and absent LVSI the risk of parametrial involvement is 0.63%. |
Does mitotane have an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans? | Side effects of mitotane (o,p'-DDD) have suggested estrogenic effects. The objective of the study was to explore o,p'-DDD potential estrogenic effect on SHBG and corticosteroid-binding globulin (CBG). Human hepatoma cell lines (HepG2), lacking estrogen receptor (ER)-alpha, and Hep89, stably transfected by ERalpha, were used. The study was conducted at an academic research laboratory and medical center. The study included 10 male patients with recurrent adrenal carcinoma, receiving mitotane (4-6.5 g daily) for more than 6 months. The main outcome measures were SHBG/CBG mRNA levels measured by real-time PCR, culture medium SHBG/CBG concentrations measured by specific immunoassays, and transient transfection experiments with human SHBG proximal promoter reporter constructs. Increased serum SHBG and CBG concentrations, which exceeded normal male limits, were observed in most mitotane-treated patients. In the HepG2 cell line, 17beta-estradiol (E2) or o,p'-DDD treatment had no effect on mRNA or SHBG/CBG concentrations. In contrast, in the Hep89 cell line, E2 increased concentrations of SHBG (r = 0.44, P < 0.0001) and CBG (r = 0.585, P < 0.0001) secreted into culture media in a dose-dependent manner. o,p'-DDD significantly increased SHBG (150% vs. control, P < 0.05) and CBG (184% vs. control, P < 0.05) production by Hep89 cells, at a concentration of 2 x 10(-5) m. Transient transfection experiments in Hep89 cells showed that E2 or o,p'-DDD treatment did not increase the transcriptional activity of the minimal proximal promoter of human SHBG gene. | The aim of this study was to determine the reasons for which erupted third molars (3M) are extracted in a sample of Mexican patients. A retrospective cross-sectional study was performed on a sample of 83 patients attending exodontia (minor oral surgery) clinics of a public university in Mexico (Autonomous University of Hidalgo State). The outcome variable was the reason for extractions using Kay and Blinkhorn's classification. The independent variables were age, gender, arch and tooth number according to the World Health Organization (WHO). For statistical analysis, we used the Chi-squared test in Stata 9.0. Eighty-three patients underwent 150 3M extractions. Mean age was 38.67 ± 13.96 years, and 71.1% were female. The four reasons for 3M extraction were prosthetic (44.0%), followed by orthodontic (24.7%), dental caries (20.0%) and periodontal disease (11.3%). Differences were observed in the reasons for 3M extractions across age groups (p < 0.05). No significant differences existed between men and women (p > 0.05), or the WHO tooth number (p > 0.05). |
Is early laparoscopic cholecystectomy the preferred management of acute cholecystitis? | Early laparoscopic cholecystectomy (LC) results in a shorter length of stay and acceptable conversion and complication rates when compared with antibiotic therapy plus interval LC or percutaneous cholecystostomy in patients admitted to a surgical service because of acute cholecystitis. However, actual practice does not conform to current evidence. Retrospective cohort study. Urban teaching hospital. Data were abstracted from the medical records of all patients with acute cholecystitis admitted to the surgical service via the emergency department during 36 months (October 1, 2002, to September 30, 2005). Patients were divided into 5 groups on the basis of treatment received. Length of stay, duration of symptoms, major complications, and conversion rates were analyzed. Of 173 patients with acute cholecystitis, 71 (41%) underwent early LC. Of 102 patients treated with antibiotic therapy alone (59%), 57 were discharged; antibiotic therapy was unsuccessful in 45 patients. Of the patients in whom antibiotic therapy was unsuccessful, 26 underwent late LC and 19 underwent percutaneous cholecystostomy. Interval LC was eventually performed in 55 patients who did not undergo surgery during the index admission. Length of stay was significantly shorter in the early LC group compared with the interval LC group (P < .001). Conversion rates were not statistically different for the 3 LC groups (early LC, 5.6%; late LC, 11.5%; and interval LC, 9.1%). The only biliary complication occurred in the interval LC group. | A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis. To explore this possibility, we performed an association study in affected versus unaffected females, considering three tiers of single nucleotide polymorphisms (SNPs) as follows: 1) regions of chromosome X that escape X-inactivation, 2) all of chromosome X, and 3) genome-wide. No evidence of a SNP meeting the criteria for a single FPE locus was observed, despite the analysis being well powered to detect this effect. |
Do song characteristics track bill morphology along a gradient of urbanization in house finches ( Haemorhous mexicanus )? | Urbanization can considerably impact animal ecology, evolution, and behavior. Among the new conditions that animals experience in cities is anthropogenic noise, which can limit the sound space available for animals to communicate using acoustic signals. Some urban bird species increase their song frequencies so that they can be heard above low-frequency background city noise. However, the ability to make such song modifications may be constrained by several morphological factors, including bill gape, size, and shape, thereby limiting the degree to which certain species can vocally adapt to urban settings. We examined the relationship between song characteristics and bill morphology in a species (the house finch, Haemorhous mexicanus) where both vocal performance and bill size are known to differ between city and rural animals. We found that bills were longer and narrower in more disturbed, urban areas. We observed an increase in minimum song frequency of urban birds, and we also found that the upper frequency limit of songs decreased in direct relation to bill morphology. | In vitamin K antagonist (VKA)-treated patients with severe hemorrhage, guidelines recommend prompt VKA reversal with prothrombin complex concentrate (PCC) and vitamin K. The aim of this observational cohort study was to evaluate the impact of guideline concordant administration of PCC and vitamin K on seven-day mortality. Data from consecutive patients treated with PCC were prospectively collected in 44 emergency departments. Type of hemorrhage, coagulation parameters, type of treatment and seven-day mortality mortality were recorded. Guideline-concordant administration of PCC and vitamin K (GC-PCC-K) were defined by at least 20 IU/kg factor IX equivalent PCC and at least 5 mg of vitamin K performed within a predefined time frame of eight hours after admission. Multivariate analysis was used to assess the effect of appropriate reversal on seven-day mortality in all patients and in those with intracranial hemorrhage (ICH). Data from 822 VKA-treated patients with severe hemorrhage were collected over 14 months. Bleeding was gastrointestinal (32%), intracranial (32%), muscular (13%), and "other" (23%). In the whole cohort, seven-day mortality was 13% and 33% in patients with ICH. GC-PCC-K was performed in 38% of all patients and 44% of ICH patients. Multivariate analysis showed a two-fold decrease in seven-day mortality in patients with GC-PCC-K (odds ratio (OR) = 2.15 (1.20 to 3.88); P = 0.011); this mortality reduction was also observed when only ICH was considered (OR = 3.23 (1.53 to 6.79); P = 0.002). |
Does probucol suppress macrophage infiltration and MMP expression in atherosclerotic plaques of WHHL rabbits? | Probucol is a lipid-lowering drug that is often prescribed for the treatment of familial hypercholesterolemia. However, it is not known whether probucol can change the lesion quality of atherosclerosis. We examined this possibility using WHHL rabbits, a model of human familial hypercholesterolemia. Three-month-old male WHHL rabbits were treated with either probucol(85 mg/kg/day) or atorvastatin(6 mg/kg/day) for 16 weeks, and their plasma lipid levels and atherosclerotic lesions were compared with those of a control group. We found that probucol treatment reduced the plasma cholesterol levels, but less remarkably than atorvastatin treatment. In spite of this, probucol treatment led to a prominent reduction of aortic en face lesions by 39%(P＜0.01), whereas atorvastatin reduced these by 16%(P＞0.05), compared with those in the control. Histological examinations revealed that the aortic lesions of probucol-treated rabbits were characterized by reduced macrophages and increased smooth muscle cells compared with those from both the control and atorvastatin groups. Furthermore, probucol treatment reduced the coronary artery stenosis and increased the plaque stability. | Despite the strong correlation of T-cell CD38 expression with HIV disease progression, evidence linking CD38 expression and dysfunction at the single cell level is scant. Since CD38⁺ memory CD4⁺ T cells, especially those from HIV-infected persons, fail to induce CD154 (CD40L) while responding to a superantigen with interferon (IFN)-γ or interleukin (IL)-2, we aimed to determine if recall responses to cytomegalovirus (CMV) were similarly affected in the CD38⁺ memory CD4⁺ T-cell subpopulation. Peripheral blood mononuclear cells from HIV+ patients and healthy controls were incubated 14 h with CMV antigens, the superantigen Staphylococcus aureus enterotoxin B or medium, and labeled for identification of central memory (T(CM)) and effector memory (T(EM)) CD4⁺ T cells, and for the intracellular detection of induced CD154, IFN-γ and/or IL-2 by flow cytometry. Compared with CD38⁻ cells, CD38⁺ T(CM) cells from patients had less CD40L induction after CMV stimulation, and increased IFN-γ response. Patients' CD38⁺ T(EM) cells showed a lower IL-2 response, and tended to have a greater IFN-γ response, in which CD154 induction frequently failed. CMV-specific responses of patients' CD38⁺ T(CM) and T(EM) cells were dominated by IFN-γ, and almost all IL-2⁺ cells co-expressed IFN-γ. IL-2 responses to the polyclonal activator S. aureus enterotoxin B were also significantly less frequent among CD38⁺ T(CM) and T(EM) cells than in CD38⁻ cells. |
Does iCAM-2 regulate vascular permeability and N-cadherin localization through ezrin-radixin-moesin ( ERM ) proteins and Rac-1 signalling? | Endothelial junctions control functions such as permeability, angiogenesis and contact inhibition. VE-Cadherin (VECad) is essential for the maintenance of intercellular contacts. In confluent endothelial monolayers, N-Cadherin (NCad) is mostly expressed on the apical and basal membrane, but in the absence of VECad it localizes at junctions. Both cadherins are required for vascular development. The intercellular adhesion molecule (ICAM)-2, also localized at endothelial junctions, is involved in leukocyte recruitment and angiogenesis. In human umbilical vein endothelial cells (HUVEC), both VECad and NCad were found at nascent cell contacts of sub-confluent monolayers, but only VECad localized at the mature junctions of confluent monolayers. Inhibition of ICAM-2 expression by siRNA caused the appearance of small gaps at the junctions and a decrease in NCad junctional staining in sub-confluent monolayers. Endothelioma lines derived from WT or ICAM-2-deficient mice (IC2neg) lacked VECad and failed to form junctions, with loss of contact inhibition. Re-expression of full-length ICAM-2 (IC2 FL) in IC2neg cells restored contact inhibition through recruitment of NCad at the junctions. Mutant ICAM-2 lacking the binding site for ERM proteins (IC2 ΔERM) or the cytoplasmic tail (IC2 ΔTAIL) failed to restore junctions. ICAM-2-dependent Rac-1 activation was also decreased in these mutant cell lines. Barrier function, measured in vitro via transendothelial electrical resistance, was decreased in IC2neg cells, both in resting conditions and after thrombin stimulation. This was dependent on ICAM-2 signalling to the small GTPase Rac-1, since transendothelial electrical resistance of IC2neg cells was restored by constitutively active Rac-1. In vivo, thrombin-induced extravasation of FITC-labeled albumin measured by intravital fluorescence microscopy in the mouse cremaster muscle showed that permeability was increased in ICAM-2-deficient mice compared to controls. | The purpose of the present study was to investigate the effect of supplementation with chicken breast extract (CBEX), which was a rich source of carnosine and anserine, on acid-base balance and performance during intense intermittent exercise. Eight male subjects performed intense intermittent exercise that consisted of 10 x 5-s maximal cycle ergometer sprints with a 25-s recovery period between each sprint. The subjects ingested 190 g of the test soup containing either CBEX or a placebo 30 min before the commencement of exercise. Arterial blood samples were collected at rest and during exercise to estimate the carnosine and anserine concentrations, pH, and bicarbonate concentration ([HCO3-]). Concentrations of anserine and its related amino acid significantly increased 30 min after CBEX supplementation, as compared with their values at rest. However, carnosine did not increase significantly. Following CBEX supplementation, the pH was significantly higher (P < 0.05) at the end of exercise, and [HCO3-] was also significantly higher (P < 0.05) during the latter half of exercise and after exercise. There were no significant differences in the total power and mean power of each set between the CBEX and placebo supplemented groups. |
Is elevated CC chemokine level in bronchoalveolar lavage fluid predictive of a poor outcome of idiopathic pulmonary fibrosis? | CC chemokines play important roles in the pathogenesis of interstitial lung diseases. Elevated CC chemokine levels have been observed in bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis (IPF). We aimed to examine whether the levels of four CC chemokines, i.e. monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1 alpha (MIP-1 alpha/CCL3), thymus- and activation-regulated chemokine (TARC/CCL17), and macrophage-derived chemokine (MDC/CCL22), in BAL fluid are predictive of the prognosis of IPF patients. We compared the chemokine levels of patients alive 5 years after diagnosis and those who had died. Lung function data, CT scores, and serum markers were also compared. Among 39 patients (29 males, median age, 60 years), 19 patients (48%) died within 5 years after the diagnosis. Whereas percent vital capacity was not different, percent lung diffusion capacity for carbon monoxide was significantly higher in the surviving patients than in the nonsurviving patients (p < 0.01). Median CCL2 levels of surviving and nonsurviving patients were 154.3 (interquartile range, IQR: 67.3-381.8) and 427.2 (IQR: 329.2-1184.1) pg/ml, respectively (p < 0.02). CCL3 levels in BAL fluid did not differ between the surviving and nonsurviving patients. CCL17 was detected in BAL fluid of 7 patients, 6 of whom died within 5 years. CCL22 was detectable in BAL fluid of 10 patients, only 1 of whom survived. Serum levels of KL-6 and lactate dehydrogenase did not differ between the surviving and nonsurviving patients. | Fracture risk in type 1 diabetes (T1D) is supposed to be underestimated by bone mineral density (BMD). Individuals with T1D had more prevalent fractures in a cross-sectional study. Serum levels of pentosidine, an advanced glycation end product, and poor glycaemic control were associated with prevalent fractures independent of BMD. Type 1 diabetes (T1D) is associated with increased fracture risk. Bone mineral density (BMD) underestimates the risk of fractures in some individuals. The accumulation of advanced glycation end products (AGEs) impairs bone matrix and reduces bone strength. In a cross-sectional study, 128 men and premenopausal women with T1D were evaluated. We compared traditional risk factors for fractures, BMD, parameters of bone metabolism and AGEs in individuals with and without prevalent fractures. An independent association of serum AGE levels with prevalent fractures was investigated. Individuals with prevalent fractures exhibited a longer duration of T1D, higher HbA1c and more diabetic-related complications. BMD at the femoral neck (z-score -0.76 ± 0.94 vs. -0.23 ± 1.02; p = 0.031) and total hip (z-score -0.54 ± 0.93 vs. 0.11 ± 1.11; p = 0.017) was lower in those with prevalent fractures. Individuals with fractures had higher pentosidine levels (164.1 ± 53.6 vs. 133.2 ± 40.4; p = 0.002). The levels of N-ε-(carboxymethyl)-lysine (CML) and endogenous secretory receptor for AGEs (esRAGE) did not significantly differ. Multivariate logistic regression analysis adjusted for age, BMI, family history of fractures, smoking, vitamin D deficiency, BMD at lumbar spine, femoral neck and total hip identified pentosidine levels and HbA1c as independent factors associated with prevalent fractures (odds ratio 1.02, 95% CI 1.00-1.03/pmol/ml increase of pentosidine; p = 0.008 and odds ratio 1.93, 95% CI 1.16-3.20 per percentage increase of HbA1c; p = 0.011). |
Is implementation of a surgical intensive care unit service associated with improved outcomes for trauma patients? | Our trauma service recently transitioned from a pulmonary intensive care unit (ICU) service to a surgical ICU (SICU) service. We hypothesized that a newly formed SICU service could provide comparable outcomes to the existing pulmonary ICU service. A specific aim of this study was to compare outcomes of trauma patients admitted to the ICU before and after implementation of a SICU service. We performed a retrospective study of trauma patients admitted to the ICU of our urban, American College of Surgeons- verified, Level 1 trauma center during a 4-year period (2009-2012). Patients managed by the pulmonary ICU service (2009-2010) were compared with patients managed by a SICU service (2011-2012). The primary outcome was mortality, while secondary outcomes included complications (pulmonary, infectious, cardiac, and thromboembolic), hospital and ICU length of stay, ventilator days, and need for reintubation. There were 2,253 trauma patients admitted to the ICU during the study period, 1,124 and 1,129 managed by the pulmonary ICU and SICU services, respectively. When comparing outcomes for SICU and pulmonary ICU patients, there was no difference in mortality (11% vs. 13%, p = 0.41), but patients managed by the SICU service had fewer pulmonary complications (3% vs. 6%, p < 0.001), fewer days on the ventilator (3 vs. 4, p = 0.002), and less often required reintubation after extubation (4% vs. 9%, p < 0.001). | To describe the findings of enhanced depth imaging (EDI) optical coherence tomography (OCT) of the lamina cribrosa (LC) in glaucoma and pachychoroid spectrum diseases associated with peripapillary retinoschisis. Retrospective, observational case series. A total of 16 patients from 1 institution. Detailed medical case histories, optic disc and retinal imaging with EDI using the Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany), and clinical course were reviewed for patients with peripapillary retinoschisis without a known predisposing condition. Clinical features and findings of the EDI OCT. Among the 16 eyes with peripapillary retinoschisis that had abnormal findings on EDI of the LC, 8 had glaucoma and 8 had pachychoroid spectrum diseases, including chronic central serous chorioretinopathy (CSC) (6 eyes), small pigment epithelium detachment (1 eye), and polypoidal choroidal vasculopathy (PCV) (1 eye). The abnormal LC findings were central or peripheral focal LC defects in eyes with glaucoma and LC disinsertions or peripheral focal LC defects in eyes with pachychoroid spectrum diseases. Central LC defects were related to inner layer retinoschisis, whereas LC disinsertions and peripheral LC defects were related to outer layer retinoschisis. The peripapillary retinoschisis did not show a topographic association with the underlying chronic CSC- or PCV-associated lesions. In 6 treated eyes with pachychoroid, peripapillary retinoschisis resolved along with subretinal fluid after anti-vascular endothelial growth factor injection in 4 eyes, whereas retinoschisis persisted after the resolution of subretinal fluid in 2 eyes. |
Do occupational therapy service use among people aging with multiple sclerosis? | We examined the use of occupational therapy services in a sample of people aging with multiple sclerosis (MS). A total of 1,282 people with MS, ages 45 to 90, participated in telephone interviews to identify unmet health-related service needs. Occupational therapy was 1 of 22 services examined. Proportional odds models were used to examine factors associated with how recently services were used. Four hundred eighty-four participants (38.2%) had used occupational therapy services at some point since their diagnosis; 211 had used these services in the year before the interview. Recent users identified occupational therapy services as important to health and well-being. Satisfaction with services was high. Greater activity limitations and living in an urban or suburban area were associated with more recent use of occupational therapy services. | Endothelial cell migration is required for physiological angiogenesis, but also contributes to various pathological conditions, including tumour vascularization. The mRNA expression of PP1cβ, the beta isoform of the catalytic PP1 subunit, was shown to be upregulated in chronic hypoxia. Since hypoxia is a major regulator of angiogenesis, the potential role of PP1cβ in angiogenesis was investigated. We examined PP1cβ protein level in pediatric heart following chronic hypoxia and found PP1cβ upregulation in cyanotic compared with acyanotic myocardium. By treating HUVEC cells with hypoxia mimicking agent, PP1cβ protein level increased with maximum at 8 hours. The effect of PP1cβ pharmacological inhibition, knockdown and overexpression, on endothelial cell migration and morphogenesis, was examined using in vitro wound healing scratch assay and endothelial tube formation assay. The PP1cβ knockdown effects on F-actin reorganization (phalloidin staining), focal adhesion formation (vinculin) and focal adhesion kinases (FAK) activation, were evaluated by immunocytochemical staining and immunoblotting with specific antibodies. PP1cβ knockdown significantly reduces endothelial cell migration, but does not have any significant effect on endothelial tube formation. Endothelial cell migration in the knockdown group is restored to the control level upon consecutive transfection with PP1cβ cDNA. PP1cβ overexpression does not significantly affect endothelial cell migration. Furthermore, PP1cβ knockdown induces profound cytoskeletal reorganization, loss of focal adhesion sites and impairment of focal adhesion kinases (FAK) activation. |
Does twice cutting method reduce tibial cutting error in unicompartmental knee arthroplasty? | Bone cutting error can be one of the causes of malalignment in unicompartmental knee arthroplasty (UKA). The amount of cutting error in total knee arthroplasty has been reported. However, none have investigated cutting error in UKA. The purpose of this study was to reveal the amount of cutting error in UKA when open cutting guide was used and clarify whether cutting the tibia horizontally twice using the same cutting guide reduced the cutting errors in UKA. We measured the alignment of the tibial cutting guides, the first-cut cutting surfaces and the second cut cutting surfaces using the navigation system in 50 UKAs. Cutting error was defined as the angular difference between the cutting guide and cutting surface. The mean absolute first-cut cutting error was 1.9° (1.1° varus) in the coronal plane and 1.1° (0.6° anterior slope) in the sagittal plane, whereas the mean absolute second-cut cutting error was 1.1° (0.6° varus) in the coronal plane and 1.1° (0.4° anterior slope) in the sagittal plane. Cutting the tibia horizontally twice reduced the cutting errors in the coronal plane significantly (P<0.05). | People diagnosed with cancer often self-administer complementary and alternative medicines (CAMs) to supplement their conventional treatments, improve health, or prevent recurrence. Flor-Essence and Essiac Herbal Tonics are commercially available complex mixtures of herbal extracts sold as dietary supplements and used by cancer patients based on anecdotal evidence that they can treat or prevent disease. In this study, we evaluated Flor-Essence and Essiac for their effects on the growth of human tumor cells in culture. The effect of Flor-Essence and Essiac((R)) herbal tonics on cell proliferation was tested in MCF-7, MDA-MB-436, MDA-MB-231, and T47D cancer cells isolated from human breast tumors. Estrogen receptor (ER) dependent activation of a luciferase reporter construct was tested in MCF-7 cells. Specific binding to the ER was tested using an ICI 182,780 competition assay. Flor-Essence and Essiac herbal tonics at 1%, 2%, 4% and 8% stimulated cell proliferation relative to untreated controls in both estrogen receptor positive (MCF-7 and T47D) and estrogen receptor negative (MDA-MB-231 and MDA-MB-436) cell lines. Exposure to the tonics also produced a dose-dependent increase in ER dependent luciferase activity in MCF-7 cells. A 10(-7) M concentration of ICI 182,780 inhibited the induction of ER dependent luciferase activity by Flor-Essence and Essiac, but did not affect cell proliferation. |
Is repeat hepatic resection for recurrent colorectal liver metastases associated with favourable long-term survival? | The management of patients with recurrent colorectal liver metastases (RCLM) remains controversial. This study aimed to determine whether repeat liver resection for RCLM could be performed with acceptable morbidity, mortality and long-term survival. Of 1121 consecutive liver resections performed and prospectively analysed between 1987 and 2005, 852 'curative' resections were performed on patients with colorectal liver metastases. Single liver resection was performed in 718 patients, and 71 repeat hepatic resections for RCLM were performed in 66 patients. There were no postoperative deaths following repeat hepatic resection compared with a postoperative mortality rate of 1.4 per cent after single hepatic resection. Postoperative morbidity was comparable following single and repeat hepatectomy (26.1 versus 18 per cent; P = 0.172), although median blood loss was greater during repeat resection (450 versus 350 ml; P = 0.006). Actuarial 1-, 3- and 5-year survival rates were 94, 68 and 44 per cent after repeat hepatic resection for RCLM, compared with 89.3, 51.7 and 29.5 per cent respectively following single hepatectomy. | Cervical compressive myelopathy (CCM) is caused by chronic spinal cord compression due to spondylosis, a degenerative disc disease, and ossification of the ligaments. Tip-toe walking Yoshimura (twy) mice are reported to be an ideal animal model for CCM-related neuronal dysfunction, because they develop spontaneous spinal cord compression without any artificial manipulation. Previous histological studies showed that neurons are lost due to apoptosis in CCM, but the mechanism underlying this neurodegeneration was not fully elucidated. The purpose of this study was to investigate the pathophysiology of CCM by evaluating the global gene expression of the compressed spinal cord and comparing the transcriptome analysis with the physical and histological findings in twy mice. Twenty-week-old twy mice were divided into two groups according to the magnetic resonance imaging (MRI) findings: a severe compression (S) group and a mild compression (M) group. The transcriptome was analyzed by microarray and RT-PCR. The cellular pathophysiology was examined by immunohistological analysis and immuno-electron microscopy. Motor function was assessed by Rotarod treadmill latency and stride-length tests. Severe cervical calcification caused spinal canal stenosis and low functional capacity in twy mice. The microarray analysis revealed 215 genes that showed significantly different expression levels between the S and the M groups. Pathway analysis revealed that genes expressed at higher levels in the S group were enriched for terms related to the regulation of inflammation in the compressed spinal cord. M1 macrophage-dominant inflammation was present in the S group, and cysteine-rich protein 61 (Cyr61), an inducer of M1 macrophages, was markedly upregulated in these spinal cords. Furthermore, C1q, which initiates the classical complement cascade, was more upregulated in the S group than in the M group. The confocal and electron microscopy observations indicated that classically activated microglia/macrophages had migrated to the compressed spinal cord and eliminated synaptic terminals. |
Does pregestational maternal obesity impair endocrine pancreas in male F1 and F2 progeny? | The aim of this study was to evaluate the effects of maternal obesity on pancreas structure and carbohydrate metabolism in early adult life, focusing on the F1 and F2 generations after F0 maternal pregestational, gestation, and lactation high-fat diet (HF). C57 BL/6 female mice (F0) were fed standard chow (SC) or an HF diet for 8 wk before mating and during the gestation and lactation periods to provide the F1 generation (F1-SC and F1-HF). At 3 mo old, F1 females were mated to produce the F2 generation (F2-SC and F2-HF). The male offspring from all groups were evaluated at 3 mo old. F0-HF and F1-HF dams were overweight before gestation and had a higher body mass gain and energy intake during gestation, although only F0-HF dams presented pregestational hyperglycemia. The F1-HF offspring had higher body mass, energy intake, fasting glucose levels, and were glucose intolerant compared with F1-SC offspring. These parameters were not significantly altered in F2-HF offspring. Both F1-HF and F2-HF offspring showed hyperinsulinemia, hyperleptinemia, decreased adiponectin levels, increased pancreatic mass, and islet volume density with elevated α- and β-cell mass, hypertrophied islet characterized by an altered distribution of α- and β-cells and weak pancreatic-duodenal homeobox (Pdx)1 immunoreactivity. | Prospective cohort. Elbow stiffness is the most common adverse event after isolated radial head fractures. To assess the effect of coaching on elbow motion during the same office visit in patients with such fractures. We enrolled 49 adult patients with minimally displaced radial head fractures, within 14 days of injury. After diagnosis, we measured demographics, catastrophic thinking, health anxiety, symptoms of depression, upper extremity-specific symptoms and disability, pain, and elbow and wrist motion. The patient was taught to apply an effective stretch in spite of the pain to limit stiffness, and elbow motion was measured again. With the exception of radial deviation and pronation, motion measures improved slightly but significantly on average immediately after coaching. Elbow flexion improved from 79% (110° ± 22°) of the uninjured side to 88% (122° ± 18°) after coaching (P < .001); elbow extension improved from 71% (29° ± 14°) to 78% (22° ± 15°) (P = .0012). |
Do higher HPV16 and HPV18 Penile Viral Loads Are Associated With Decreased Human Papillomavirus Clearance in Uncircumcised Kenyan Men? | Whether higher penile human papillomavirus (HPV) viral load is associated with a lower rate of HPV clearance remains unknown. We examined the association between penile HPV16 and HPV18 viral load and subsequent HPV clearance in uncircumcised Kenyan men. Participants were human immunodeficiency virus (HIV)-seronegative, sexually active, 18- to 24-year-old men randomized to the control arm of a male circumcision trial in Kisumu, Kenya. Men provided exfoliated penile cells from two anatomical sites (glans/coronal sulcus and shaft) every 6 months for 2 years. GP5+/6+ polymerase chain reaction was used to identify 44 HPV-DNA types. Human papillomavirus viral load testing was conducted using a LightCyler real-time polymerase chain reaction assay; viral load was classified as high (>250 copies/scrape) or low (≤250 copies/scrape), for nonquantifiable values. The Kaplan-Meier method and Cox regression modeling were used to examine the association between HPV viral load and HPV clearance. A total of 1097 men, with 291 HPV16 and 131 HPV18 cumulative infections over 24 months were analyzed. Human papillomavirus clearance at 6 months after first HPV detection was lower for high versus low viral load HPV16 infections in the glans (adjusted hazard ratio [aHR], 0.65; 95% confidence interval [CI], 0.46-0.92)] and shaft (aHR, 0.44; 95% CI, 0.16-0.90), and HPV18 infections in the glans (aHR, 0.05; 95% CI, 0.01-0.17). | To determine the association between early neonatal diffusion tensor imaging (DTI) and the development of unilateral spastic cerebral palsy (USCP) in preterm infants with periventricular hemorrhagic infarction (PVHI). Preterm infants with PVHI were assessed with early (≤4 wk after birth) and term-equivalent age MRI-DTI. Involvement of corticospinal tracts was assessed by visual assessment of the posterior limb of the internal capsule (PLIC) on DTI (classified asymmetrical, equivocal, or symmetrical) and by an atlas-based approach calculating fractional anisotropy asymmetry index in the PLIC. Motor outcome was assessed at ≥15 mo corrected age. Seven out of 23 infants with PVHI developed USCP. Their PLIC was visually scored as asymmetrical in 6 and equivocal in 1 on the early DTI. Thirteen out of 16 infants with a symmetrical motor development had a symmetrical PLIC on early DTI, the remaining 3 were equivocal. All infants with USCP had a fractional anisotropy asymmetry index of >0.05 (optimal cut-off value) on early DTI. In infants with a symmetrical motor development (n = 16), 14 had an asymmetry index ≤0.05 while 2 had an index >0.05. |
Does neo/adjuvant chemotherapy improve outcome in resected primary synovial sarcoma : a study of the French Sarcoma Group? | There are only scarce data about the benefit of adjunctive chemotherapy in patients with localized synovial sarcoma (SS). Data from 237 SS patients recorded in the database of the French Sarcoma Group were retrospectively analyzed. The respective impact of radiotherapy, neo-adjuvant chemotherapy and adjuvant chemotherapy on overall survival (OS), local recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) were assessed after adjustment to prognostic factors. The median follow-up was 58 months (range 1-321). Adjuvant, neo-adjuvant chemotherapy and postoperative radiotherapy were administered in 112, 45 and 181 cases, respectively. In all, 59% of patients treated with chemotherapy received an ifosfamide-containing regimen. The 5-year OS, LRFS and DRFS rates were 64.0%, 70% and 57%, respectively. On multivariate analysis, age >35 years old, grade 3 and not-R0 margins were highly significant independent predictors of worse OS. After adjustment to prognostic factors, radiotherapy significantly improved LRFS but not DRFS or OS. Neither neo-adjuvant nor adjuvant chemotherapy had significant impact on OS, LRFS or DRFS. | Dehydroepiandrosterone (DHEA) was shown to improve the immune function and survival in experimental sepsis. This study examined the effect of DHEA on intestinal leukocyte recruitment during experimental sepsis, considering factors of gender (male, female and ovariectomized female animals) and combined treatment using orthovanadate (OV) in two models of sepsis. Male rats underwent colon ascendens stent peritonitis (CASP) or endotoxemia. DHEA was administered after induction of experimental sepsis. Changes in leukocyte adherence and capillary perfusion (measured as intestinal functional capillary density - FCD) were assessed using intravital microscopy. While DHEA increased baseline leukocyte adherence in control animals, DHEA reduced leukocyte adherence and increased FCD in male animals with CASP. These effects were also observed in DHEA-treated ovariectomized female rats with CASP. Similarly, the administration of DHEA reduced the number of adherent leukocytes to intestinal venules by 30% in the endotoxemia model. The combined treatment of DHEA and OV significantly reduced adherence of leukocytes to intestinal venules and improved FCD. |
Does ankle brace effectively reduce recurrence of ankle sprains in female soccer players? | The purpose of this study was to examine the effectiveness of ankle bracing and taping in preventing recurrencess of ankle sprains, specifically in female athletes. Varsity soccer players' medical records over a five-year period were retrospectively reviewed at a Division III women's college. Data were extracted regarding any history of ankle sprain(s), type of intervention used as prophylaxis after the ankle sprain, number of exposures, and any incidence of recurrence. All collegiate varsity soccer players who had suffered a previous sprain to either one or both ankles (38 players) were identified as subjects. Each previously injured ankle (n = 56) was considered as a case for the analysis. Ankles that had a previous sprain received one of four interventions: 1) a canvas, laced ankle brace (n = 19), 2) taping (n = 12), 3) a combination of taping and ankle bracing (n = 8), or 4) no treatment (n = 17). The four intervention groups had a total of 1717 practice exposures and 650 competitive game exposures; exposures did not differ among the 4 groups. Ankle sprain recurrence frequency was 0%, 25%, 25%, and 35% for the braced, taped, combination, and untreated groups, respectively. The recurrence incidence for the braced group was significantly lower than that of the other three groups. The ankle sprain recurrence frequency did not differ among the taped, combination, and no treatment groups. | Lung transplant recipients with documented gastroesophageal reflux disease (GERD) are at increased risk for graft dysfunction. Here, we present the first large-animal model of gastric aspiration after allogeneic lung transplantation and some preliminary data demonstrating the effect of chronic aspiration on the direct and indirect pathways of allorecognition. Left orthotopic lung transplants (n=3) were performed in miniature swine across a major histocompatibility complex class I disparity, followed by 12 days of high-dose cyclosporine A. At the time of transplantation, a transtracheal catheter was placed at the carina, above the bronchial anastomosis. A gastrostomy tube was placed for daily aspiration of gastric contents. Subsequently, graft lungs were instilled with gastric aspirate daily (3 mL/hrX8 hr/day) for 50 days. Recipients were followed up with daily complete blood count, scheduled chest radiographs, and biopsies. In vitro studies, including cell-mediated lympholysis, mixed lymphocyte reactions, and peptide proliferation assays, were performed. Results from these three recipients were compared with those of historical controls (n=6) who were treated identically, except for the tracheal cannulation and simulated gastric aspiration. Two of the experimental animals were euthanized with nonviable lungs soon after the postoperative day 50 biopsy. In both cases the native lung was normal. The third animal survived over 180 days without the evidence of chronic rejection. After immunosuppressive treatment, all animals demonstrated donor-specific hyporesponsiveness by assays of direct alloresponse (cell-mediated lympholysis, mixed lymphocyte reaction). A significant response to synthetic donor-derived class I peptide, however, was seen in all animals. A more pronounced and diffuse response was seen in the animals rejecting their grafts. The historical controls showed medium-term graft survival with evidence of chronic rejection in the majority of animals, as previously reported. |
Is lymphocyte inhibition compromised in mesenchymal stem cells from psoriatic skin? | Psoriasis is a chronic inflammatory skin disorder associated with a host of immune abnormalities. Mesenchymal stem cells (MSCs) have immunosuppressive properties and, in earlier studies, we found that the bone marrow MSCs of patients with psoriasis exhibit abnormal cytokine secretion. Since MSCs can be isolated from skin, we hypothesized that the biological characteristics of MSCs in psoriatic skin lesions might reflect the pathogenesis of psoriasis. To investigate the effects of MSCs from psoriatic skin lesions on T-cell proliferation. MSCs obtained from psoriatic skin lesions and healthy human skin were examined by flow cytometry and cell differentiation assays. MSCs were co-cultured with normal peripheral blood T cells to assess changes in T-cell proliferation. Concentrations of interleukin (IL)-6, IL-11, hepatocyte growth factor (HGF), and transforming growth factor (TGF)-β1 in the MSC culture supernatants were measured by enzyme-linked immunosorbent assays. Surface markers and differentiation capacity were similar in MSCs from both sources. MSCs in psoriatic skin lesions were weaker inhibitors of T-cell proliferation (p<0.05) and exhibited increased secretion of IL-11 and reduced secretion of IL-6 and HGF (p<0.05). Secretion of TGF-β1 was unchanged (p > 0.05). | Patients with single ventricle physiology are at increased anesthetic risk when undergoing noncardiac surgery. To review the outcomes of anesthetics for patients with single ventricle physiology undergoing noncardiac surgery. This study is a retrospective chart review of all patients who underwent a palliative procedure for single ventricle physiology between January 1, 2007 and January 31, 2014. Anesthetic and surgical records were reviewed for noncardiac operations that required sedation or general anesthesia. Any noncardiac operation occurring prior to completion of a bidirectional Glenn procedure was included. Diagnostic procedures, including cardiac catheterization, insertion of permanent pacemaker, and procedures performed in the ICU, were excluded. During the review period, 417 patients with single ventricle physiology had initial palliation. Of these, 70 patients (16.7%) underwent 102 anesthetics for 121 noncardiac procedures. The noncardiac procedures included line insertion (n = 23); minor surgical procedures such as percutaneous endoscopic gastrostomy or airway surgery (n = 38); or major surgical procedures including intra-abdominal and thoracic operations (n = 41). These interventions occurred on median day 60 of life (1-233 days). The procedures occurred most commonly in the operating room (n = 79, 77.5%). Patients' median weight was 3.4 kg (2.4-15 kg) at time of noncardiac intervention. In 102 anesthetics, 26 patients had an endotracheal tube or tracheostomy in situ, 57 patients underwent endotracheal intubation, and 19 patients had a natural or mask airway. An intravenous induction was performed in 77 anesthetics, an inhalational induction in 17, and a combination technique in 8. The median total anesthetic time was 126 min (14-594 min). In 22 anesthetics (21.6%), patients were on inotropic support upon arrival; an additional 24 patients required inotropic support (23.5%), of which dopamine was the most common medication. There were 10 intraoperative adverse events (9.8%) including: arrhythmias requiring treatment (n = 4), conversion from sedation to a general anesthetic (n = 2), difficult airway (n = 1), inadvertent extubation with desaturation and bradycardia (n = 1), hypotension and desaturation (n = 1), and cardiac arrest (n = 1). Postoperative events (<48 h) included ST segment changes requiring cardiac catheterization (n = 1), and cardiorespiratory arrest (n = 1). Age, size, gender, type of cardiac palliation, patient location, procedure location, and type of procedure were not associated with adverse outcome. After 62 anesthetics (60.8%), patients went postoperatively to the cardiac ICU. There were no deaths at 48 h. |
Does endothelin antiserum decrease volume-stimulated and basal plasma concentration of atrial natriuretic peptide? | Endothelin-1 (ET-1) is the most powerful factor known to release atrial natriuretic peptide (ANP) in vivo and in cultured cardiac myocytes or preparations of atrium. We tested the role of endogenous ET-1 in the regulation of ANP release by passive immunization in anesthetized rats. Intravenous injection of antiserum against ET-1 was shown to decrease basal and volume-stimulated plasma concentrations of ANP, whereas control serum was without effect. Antiserum generated in rabbits cross-reacted 100% with endothelin-2 and -3. In pentobarbital-anesthetized Wistar rats treated with ET-1 antiserum, plasma ANP concentration measured by radioimmunoassay was reduced by 37% from starting level after 10 minutes and by 30% after 60 minutes. Control rat serum had no effect on plasma ANP. Rapid intravenous infusion of 8 mL of 0.9% NaCl caused a sixfold increase of plasma ANP concentration in control rats but only twofold in rats pretreated with ET-1 antiserum (P < .01). This effect of ET-1 antiserum was dose dependent. ET-1 antiserum changed neither blood pressure nor heart rate significantly in anesthetized rats. Pretreatment with ET-1 antiserum did not affect the initial hypotensive response to intravenous ET-1 0.5 nmol/kg but significantly attenuated the subsequent hypertensive response to endothelin. | Mitochondrial DNA (mtDNA) copy number correlates with tumor pathology in some cancers. To investigate mtDNA copy number in head and neck cancer (HNC). mtDNA copy number was determined and compared between HNC patients and malignancy-free controls. The mtDNA copy number was significantly higher in HNC patients, increased with cancer progression and correlated negatively with patient survival. |
Does tests of the Attachment and Clinical Issues Questionnaire as It apply to Alcohol Dependence? | Although many major theories tie the addictions to specific pathways and neurochemical systems evolutionarily implicated in food and social behavioral systems, there is a paucity of instruments from the psychological level that can measure these important attachment, social, and emotional counterparts. Two studies were designed to examine whether the Attachment and Clinical Issues Questionnaire (ACIQ) could help fill this limitation in psychological measurement. In study 1, the ACIQ was given to patients in a substance abuse unit and control participants funneled to match from a larger population. To address the issue of their hypothesized tendency to blame everything on past experiences, study 2 tested whether the above results would be replicated with high school students predicted to develop alcohol dependence. In study 1, on the patient population, significant differences were found on the attachment and clinical scales in predicted directions. In study 2, on the high school students, the central predictions were again confirmed with this different and larger population, but with interesting developmental differences. | Retinal neovascularization (RNV) is a primary cause of blindness and involves the dysfunction of retinal capillaries. Recent studies have emphasized the beneficial effects of inhibitors of HMG-CoA reductase (statins) in preventing vascular dysfunction. In the present study, the authors characterized the therapeutic effects of statins on RNV. Statin treatment (10 mg/kg/d fluvastatin) was tested in a mouse model of oxygen-induced retinopathy. Morphometric analysis was conducted to determine the extent of capillary growth. Pimonidazole hydrochloride was used to assess retinal ischemia. Western blot and immunohistochemical analyses were used to assess protein expression levels and immunolocalization. Lipid peroxidation and superoxide radical formation were determined to assess oxidative changes. Fluvastatin treatment significantly reduced the area of the capillary-free zone (P < 0.01), decreased the formation of neovascular tufts (P < 0.01), and ameliorated retinal ischemia. These morphologic and functional changes were associated with statin effects in preventing the upregulation of VEGF, HIF-1 alpha, phosphorylated STAT3, and vascular expression of the inflammatory mediator ICAM-1 (P < 0.01). Superoxide production and lipid peroxidation in the ischemic retina were also reduced by statin treatment (P < 0.01). |
Does proton MR spectroscopy improve discrimination between tumor and pseudotumoral lesion in solid brain masses? | Differentiating between tumors and pseudotumoral lesions by conventional MR imaging may be a challenging question. This study aims to evaluate the potential usefulness and the added value that single-voxel proton MR spectroscopy could provide on this discrimination. A total of 84 solid brain lesions were retrospectively included in the study (68 glial tumors and 16 pseudotumoral lesions). Single-voxel spectra at TE 30 ms (short TE) and 136 ms (long TE) were available in all cases. Two groups were defined: "training-set" (56 cases) and "test-set" (28 cases). Tumors and pseudotumors were compared in the training-set with the Mann-Whitney U test. Ratios between resonances were defined as classifiers for new cases, and thresholds were selected with receiver operating characteristic (ROC) curves. The added value of spectroscopy was evaluated by 5 neuroradiologists and assessed with the Wilcoxon signed-rank test. Differences between tumors and pseudotumors were found in myo-inositol (mIns); P < .01) at short TE, and N-acetylaspartate (NAA; P < .001), glutamine (Glx; P < .01), and choline (CHO; P < .05) at long TE. Classifiers suggested tumor when mIns/NAA ratio was more than 0.9 at short TE and also when CHO/NAA ratio was more than 1.9 at long TE. Classifier accuracy was tested in the test-set with the following results: short TE, 82% (23/28); long TE, 79% (22/28). The neuroradiologists' confidence rating of the test-cases on a 5-point scale (0-4) improved between 5% (from 2.86-3) and 27% (from 2.25-2.86) with spectroscopy (mean, 17%; P < .01). | Traditional Chinese medicine herbs (TCMHs) are used in medicines as well as in daily dietary supplements in Asia. In this study, we employed pNF-kappaB-Luc or pIFN-gamma-Luc and BALB/c mice peritoneal macrophages or splenocytes to investigate both the immune and inflammatory effects of six selected plant species. Specifically, we used ethyl acetate fractions of Astragalus membranaceus (Fisch.) Bunge var. mongholicus (Bunge) Hsiao (Fabaceae) (AM), Andrographis paniculata (Burm. f.) Nees (Acanthaceae) (AP), Angelica sinensis (Oliv.) Diels (Apiaceae) (AS), Eucommia ulmodes Oliv. (Eucommiaceae) leaves (EU leaves), Isatis indigotica Fort. (Brassicaceae) (II) and Morus alba L. (Moraceae) (MA). We found that ethyl acetate fractions of AP, AS and MA significantly decreased NF-kappaB luciferase activity and also the secretion of NO and PGE(2) in LPS/IFN-gamma stimulated mouse peritoneal macrophages (p<0.05). In contrast, they did not affect IFN-gamma luciferase activity or IFN-gamma production in concanavalin A (Con A)-activated mouse splenocytes. Our results indicated that the anti-inflammatory properties of these plant extracts might be resulted from the inhibition of pro-inflammatory mediators (e.g., NO and PGE(2)), at least in part via suppression of a signaling pathway such as NF-kappaB. |
Is non-dipping pattern in untreated hypertensive patients related to increased pulse wave velocity independent of raised nocturnal blood pressure? | Non-dipper pattern, characterized by diminished nocturnal decline in blood pressure (BP), is associated with an increase in cardiovascular events. Carotid-femoral pulse wave velocity (CF-PWV) has been accepted as the gold standard measurement of arterial stiffness. CF-PWV is a well-recognized predictor of an adverse cardiovascular outcome with higher predictive value than classical cardiovascular risk factors. In this study, we investigated the association between PWV as the surrogate of arterial stiffness and non-dipper pattern in untreated hypertensive patients. The present study was cross-sectional and observational. Hypertensive patients were diagnosed according to ambulatory BP measurements (mean BP ≥ 130/80 mmHg). Eighty-four hypertensive patients, consulted for initial evaluation of hypertension, were enrolled. CF-PWV as the indicator of arterial stiffness was measured by a validated tonometry system (SphygmoCor). Patients with the history of any cardiovascular disease were excluded from the study. Fifty-six patients had non-dipper pattern and 28 patients had dipper pattern in the study. Baseline characteristics were not significantly different between the two groups, except the CF-PWV (non-dipper vs dipper; 8.91 ± 2.53 vs 7.66 ± 1.08 m/s, p = 0.002), female gender (55% vs 32%, p = 0.045) and nocturnal BP measurements (for mean BP; 106 ± 11 vs 92 ± 8 mmHg, p < 0.001). Multiple logistic regression analysis including age, gender, BP and PWV measurements, revealed female gender (odds ratio, OR = 5.112, 95% confidence interval, CI 1.282-20.4, p = 0.021), nocturnal mean BP (OR = 1.243, 95% CI 1.107-1.396, p < 0.001) and CF-PWV (OR = 1.992, 95% CI 1.240-3.198, p = 0.004) as the independent predictors of non-dipper hypertensive pattern. | Our prior studies show that intravenous (IV) total parenteral nutrition (TPN) produces atrophy of the small intestine-related gut-associated lymphoid tissue and significant decreases in intestinal IgA levels, the major system of mucosal immunity. Others have noted increased small intestinal permeability, bacterial adherence and translocation, and decreased IgA levels in TPN-fed animals. Bombesin, a neuropeptide, may play a regulatory role in mucosal immunity. It is not clear whether bombesin attenuates the TPN-associated gut-associated lymphoid tissue atrophy. To examine the effect of bombesin on gut-associated lymphoid tissue integrity and function during IV TPN feeding. Randomized animal study. A university laboratory. Male ICR mice weighing 25 to 30 g were randomized to chow plus IV saline solution (n = 12), IV TPN (n = 12), or IV TPN plus bombesin (15 micrograms/kg, administered intramuscularly three times a day) (n = 12). Animals were killed after 5 days of receiving the experimental diet. Total small intestinal IgA level was quantified by enzyme-linked immunosorbent assay. Lymphocytes were isolated from Peyer's patches, intraepithelial spaces, and lamina propria and were stained with specific antibodies for B and T cells and for T-cell expression of CD4 and CD8 by flow cytometric analysis. Data were analyzed by analysis of variance. Bombesin prevented the IV TPN decreases in (1) total cell yield and B-cell yield from the Peyer's patches, intraepithelial spaces, and lamina propria; (2) T-cell yield in the intraepithelial spaces and lamina propria; and (3) small intestinal IgA levels. Bombesin also reversed IV TPN decreases in CD4+ and CD8+ T cells in the intraepithelial spaces and Peyer's patches and prevented the decrease in the CD4/CD8 ratio in the lamina propria. |
Does intratumoural heterogeneity of intestinal expression reflect environmental induction and progression-related loss of induction in undifferentiated-type gastric carcinomas? | Gene expression in tumours is regulated by environmental as well as genetic/epigenetic factors. This study assessed the environmental factors in intestinal expression of gastric cancers. We immunohistochemically examined intratumoural heterogeneity in the expression of Cdx2, MUC2, MUC5AC and MUC6 in 39 intramucosal and 49 extramucosally invasive undifferentiated-type gastric carcinomas (UGCs), consisting of signet ring cell carcinomas showing a layered structure (LS) in the mucosa and dedifferentiated tubular adenocarcinomas without LS and with minor tubular components (TC). The LS retains mucosal vertical polarity with superficial MUC5AC expression. Loss of this polarity was independent of intestinal expression and associated with extramucosal invasion. In LS(+) UGCs, intestinal expression was enhanced as the size of mucosal spread increased and was significantly reduced with deeper extramucosal invasion, whereas, in LS(-)/TC(+) UGCs, intestinal expression was frequent and predominant in the mucosa and was insignificantly reduced with deeper extramucosal invasion. | To investigate the mechanism of platelet function caused by Lysophosphatidic acid (LPA), by observing the change of the L-arginine/nitric oxide synthase/nitric oxide (L-Arg/NOS/NO) pathway of platelet in rats. LPA (10(-6), 10(-5) and 5x10(-5) mol/L) was administrated in rats and incubated for 30 and 60 minutes. The nitrite production was measured by Greiss assay; NOS activities and L-arginine transportation were detected by isotope tracer method and intracellular [Ca(2+)]i changes by fluorescent probe. LPA increased NO release by 35% and 56%, after incubating for 30 and 60 minutes, respectively. LPA (10(-6), 10(-5)aand 5x10(-5) mol/L) enhanced the NO productions of platelets in a concentration-dependent manner (P<0.01). EC(50) was 17.8 micromol/L, and 95% CI was 13.3-24.2 micromol/L, involved in the physiological concentration of LPA in plasma (P<0.01). Simultaneously, different doses of LPA increased NOS activities and L-arginine uptake in a dose-dependent manner (P<0.01). In this study, LPA (50 micromol/L) increased the intracellular free calcium ion concentration ([Ca(2+)]i, P<0.01), after incubating for 30 and 60 minutes. Pre-treated with NOS inhibitor-L-NAME for 20 minutes, LPA obviously enhanced the effects by 20% and 32% respectively (P<0.01). On the contrary, pre-treated with L-arginine (200 micromol/L) for the same times obviously reduced the effects by 14% and 18% respectively (P<0.01). |
Does mechanical stress eliminate the effects of plasma from patients with preeclampsia on endothelial cells? | Our purpose was to determine whether mechanical deformation alters in vitro effects of plasma from patients with preeclampsia on endothelial cell function to produce a paradigm similar to the in vivo disease state. The effects of 2% plasma from 12 patients with preeclampsia and 12 normal pregnant women on prostacyclin, nitric oxide, and endothelin production by cultured endothelial cells were measured in the presence or absence of cyclic stretch and laminar shear stress. In the absence of mechanical stress plasma from patients with preeclampsia resulted in greater prostacyclin and nitric oxide production (but no change in endothelin production) compared with plasma from normal pregnant women. Cyclic stretch did not affect prostacyclin or endothelin production but produced similar increases in nitric oxide production in cells exposed to plasma from the two groups. Shear stress markedly increased prostacyclin and nitric oxide production (but did not alter endothelin production). In the presence of shear stress there were no differences in production rates of nitric oxide or prostacyclin between cells exposed to plasma from the two groups. | To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC). The expression of SIRT6 in 60 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry. The expression of SIRT6 in 101 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by Western blotting analysis and qPCR. The biologic consequences of overexpression and knockdown of SIRT6 in HCC cell lines were studied in vitro and in vivo SIRT6 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with tumor grade (P = 0.02), tumor size (P = 0.02), vascular invasion (P = 0.004), and shorter survival (P = 0.024). Depletion of SIRT6 from multiple liver cancer cell lines inhibited their growth and induced apoptosis in vitro At the molecular level, we observed that the activation of the BCL2-associated X protein (Bax) signaling pathway, a major pathway that determines cancer cell apoptosis, is regulated by SIRT6 via its deacetylase activity. SIRT6 was recruited to the promoter of Bax, where it deacetylated histone 3 lysine 9 and suppressed its promoter activity. Binding of transcription factors (p53 and E2F-1) to Bax promoter was also generally increased in SIRT6-depleted cells. In mouse xenografts, SIRT6 suppression inhibited tumor growth and induced apoptosis. Finally, there is a negative correlation between SIRT6 and Bax mRNA expressions in human HCC samples. |
Does lichen endophyte derived pyridoxatin inactivate Candida growth by interfering with ergosterol biosynthesis? | This study is to characterize the antifungal effects of pyridoxatin (PYR), a small natural product isolated from an endolichenic fungus. The susceptibility tests in vitro and in vivo by using Caenorhabditis elegans as an infectious model were performed to evaluate the antifungal efficacy of PYR against Candida species. The cytotoxicity of PYR against normal human cells was tested using MTT assay. The transcriptional levels of genes related to sterol synthesis and cell cycle regulation were measured using real-time quantitative PCR (qPCR). The contents ergosterol, squalene, lanosterol were detected by liquid chromatography/tandem mass spectrometry (LC/MS). PYR was effective against four tested Candida species with its minimal inhibitory concentrations (MICs) ranging from 1-4μg/ml. No obvious cytotoxicity was observed for PYR against normal human cells. PYR inhibited the growth of Candida albicans, preventing the biofilm formation. And the antifungal action was independent on efflux pumps. The in vivo test showed PYR greatly prolonged the survival of infected C. elegans. qPCR results revealed that most of the genes related to sterol biosynthesis were considerably down-regulated in PYR-treated cells. Determination of the sterol content found that PYR inhibited the ergosterol synthesis dose dependently and caused the accumulation of squalene and lanosterol. Moreover, analysis of the structure-activity relationship revealed the heterocyclic hydroxamic acid in PYR was the key group for the antifungal action. | Hypertension of the recipient is strongly associated with chronic allograft nephropathy. It is unclear, however, whether hypertension is the cause or the consequence of chronic allograft nephropathy. The present study was performed in the Fisher to Lewis rat kidney transplant model. Transplanted rats (N = eight in each group) received either no treatment or were made hypertensive by administration of deoxycorticosteron acetate (DOCA) and salt. Proteinuria and systolic blood pressure was measured monthly, grafts were harvested at 3 and 6 months for semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and for immunohistology. Systolic blood pressure was markedly elevated in rats receiving DOCA/salt. Allografts of hypertensive animals contained significantly more cells expressing the proliferating cell nuclear antigen compared to isografts and to allografts from normotensive animals (P < 0.05). Histologic staining and mRNA expression of major histocompatibility complex (MHC) II was markedly increased in allografts of hypertensive animals compared to all other groups (P < 0.05). Expression of mRNA for platelet-derived growth factor-B (PDGF-B), transforming growth factor-beta (TGF-beta) and collagen was higher in allografts than in isografts and was highest in hypertensive animals. |
Do [ Phamacoeconomic analysis of antibiotics use in the Clinical Center of Vojvodina ]? | The investigation was performed in three phases and included all patients hospitalized at eight selected clinics known to be the biggest antibiotic spenders in the Clinical center of Vojvodina. The first phase comprised retrospective evaluation of the total antibiotic use in therapy of all bacterial infections during a three-month period in 2006/2007. A total cost of all spent antibiotics was calculated, and a daily dose per 100 clinical day care was defined for each of investigated clinics. In the second phase, the structure of bacterial causes and their resistance to standard antimicrobial therapy was established for all isolated strains from each clinic. According to the the results of bacterial resistance surveilance, guidelines for initial adequate antimicrobial therapy were made (regarding localization and type of bacteria) considering resistance maps for isolated bacterial strains. The guidelines took into consideration all essential ellements: pharamcotherapeutic/pharmacoeconomic principles, bacterial resistance, patterns of antimicrobial prescriptions and lowest therapy costs. | Arteriogenesis represents the maturation of preformed vascular connections in response to flow changes and shear stress. These collateral vessels can restore up to 60% of the native blood flow. Shear stress and vascular injury can induce the release of nucleotides from vascular smooth muscle cells and platelets that can serve as signaling ligands, suggesting they may be involved in mediating arteriogenesis. The P2Y2 nucleotide receptor (P2Y2R) has also been shown to mediate smooth muscle migration and arterial remodeling. Thus, we hypothesize that P2Y2R mediates arteriogenesis in response to ischemia. Hind limb ischemia was induced by femoral artery ligation (FAL) in C57Bl/6NJ or P2Y2R negative mice (P2Y2(-/-)). Hind limb perfusion was measured with laser Doppler perfusion imaging and compared with the sham-operated contralateral limb immediately and at 3, 7, 14, 21, and 28 days after ligation. Collateral vessel size was measured by Microfil casting. Muscle specimens were harvested and analyzed with immunohistochemistry for Ki67, vascular cell adhesion molecule, macrophages, and muscle viability by hematoxylin and essoin stain. Hind limb ischemia induced by FAL in C57Bl/6NJ mice resulted in significant ischemia as measured by laser Doppler perfusion imaging. There was rapid recovery to nearly normal levels of perfusion by 2 weeks. FAL in P2Y2(-/-) mice resulted in severe ischemia with greater tissue loss. Recovery of perfusion was impaired, achieving only 40% compared with wild-type mice by 28 days. Collateral vessels in the P2Y2(-/-) mice were underdeveloped, with reduced vascular cell proliferation and smaller vessel size. The collaterals were ∼65% the size of wild-type collateral vessels (P = .011). Angiogenesis at 28 days in the ischemic muscle, however, was greater in the P2Y2(-/-) mice (P < .001), possibly related to persistent ischemia leading and angiogenic drive. Early macrophage recruitment was reduced by nearly 70% in P2Y2(-/-) despite significantly more myocyte necrosis. However, inflammation was greater at 28 days in the P2Y2(-/-) mice. |
Is decrease in daytime sleeping associated with improvement in cognition after hospital discharge in older adults? | To examine the relationship between changes in objectively assessed sleep and global cognitive functioning from inpatient postacute rehabilitation to 6-month follow-up. Secondary analysis of two prospective, longitudinal studies. Inpatient rehabilitation units at a Veterans Affairs Medical Center. Older adults (mean age 73.8 ± 9.4) undergoing inpatient rehabilitation (n = 192). All participants completed 7 nights and days of ambulatory sleep monitoring using wrist actigraphy (yielding an estimate of nighttime wakefulness and daytime sleep) and the Mini-Mental State Examination (MMSE) during a postacute inpatient rehabilitation stay and 6 months after discharge. The 5-item Geriatric Depression Scale, Geriatric Pain Measure, and Cumulative Illness Rating Scale for Geriatrics were completed during inpatient rehabilitation. Growth curve modeling (controlling for baseline age, education, sex, body mass index, depression, pain, and comorbidity burden) revealed that individuals whose amount of daytime sleep decreased from inpatient postacute rehabilitation to 6-month follow-up also experienced improvements in MMSE score (β = -0.01, t(80 = -3.22, P = .002)). Change in nighttime wakefulness was not a significant predictor of change in MMSE score. | Notch signaling plays an acknowledged role in bile-duct development, but its involvement in cholangiocyte-fate determination remains incompletely understood. We investigated the effects of early Notch2 deletion in Notch2(fl/fl)/Alfp-Cre(tg/-) ("Notch2-cKO") and Notch2(fl/fl)/Alfp-Cre(-/-) ("control") mice. Fetal and neonatal Notch2-cKO livers were devoid of cytokeratin19 (CK19)-, Dolichos-biflorus agglutinin (DBA)-, and SOX9-positive ductal structures, demonstrating absence of prenatal cholangiocyte differentiation. Despite extensive cholestatic hepatocyte necrosis and growth retardation, mortality was only ~15%. Unexpectedly, a slow process of secondary cholangiocyte differentiation and bile-duct formation was initiated around weaning that histologically resembled the ductular reaction. Newly formed ducts varied from rare and non-connected, to multiple, disorganized tubular structures that connected to the extrahepatic bile ducts. Jaundice had disappeared in ~30% of Notch2-cKO mice by 6 months. The absence of NOTCH2 protein in postnatally differentiating cholangiocyte nuclei of Notch2-cKO mice showed that these cells had not originated from non-recombined precursor cells. Notch2 and Hnf6 mRNA levels were permanently decreased in Notch2-cKO livers. Perinatally, Foxa1, Foxa2, Hhex, Hnf1β, Cebpα and Sox9 mRNA levels were all significantly lower in Notch2-cKO than control mice, but all except Foxa2 returned to normal or increased levels after weaning, coincident with the observed secondary bile-duct formation. Interestingly, Hhex and Sox9 mRNA levels remained elevated in icteric 6 months old Notch2-cKOs, but decreased to control levels in non-icteric Notch2-cKOs, implying a key role in secondary bile-duct formation. |
Do integrative Mouse and Human Studies Implicate ANGPT1 and ZBTB7C as Susceptibility Genes to Ischemic Injury? | The extent of ischemic injury in response to cerebral ischemia is known to be affected by native vasculature. However, the nonvascular and dynamic vascular responses and their genetic basis are not well understood. We performed a genome-wide association study in 235 mice from 33 inbred strains using the middle cerebral artery occlusion model. Population structure and genetic relatedness were accounted for using the efficient mixed-model association method. Human orthologs to the genes associated with the significant and suggestive single-nucleotide polymorphisms from the mouse strain survey were examined in patients with M1 occlusions admitted with signs and symptoms of acute ischemic stroke. We identified 4 genome-wide significant and suggestive single-nucleotide polymorphisms to be associated with infarct volume in mice (rs3694965, P=2.17×10(-7); rs31924033, P=5.61×10(-6); rs32249495, P=2.08×10(-7); and rs3677406, P=9.56×10(-6)). rs32249495, which corresponds to angiopoietin-1 (ANGPT1), was also significant in the recessive model in humans, whereas rs1944577, which corresponds to ZBTB7C, was nominally significant in both the additive and dominant genetic models in humans. ZBTB7C was shown to be upregulated in endothelial cells using both in vitro and in vivo models of ischemia. | Advances in digital imaging methods have resulted in use of telecytology in the immediate assessment of fine-needle aspiration (FNA) specimens. We retrospectively compared the nondiagnostic rate for endoscopic ultrasound-guided (EUS) FNA of pancreatic lesions in two groups: one with on-site evaluation for adequacy via telecytopathology and the other without on-site adequacy evaluation. All patients undergoing EUS-FNA of pancreatic lesions over a 2-year period were included. Direct smears were immediately wet-fixed or air-dried, and any residual material was rinsed in saline for cell block or cytospin preparation. Patients were divided into two groups: Group 1 had on-site telecytopathology evaluation for adequacy by a cytopathologist, and Group 2 had no on-site adequacy evaluation. The cytologic diagnoses were reviewed, and the nondiagnostic rates for each group were calculated. The age, sex, and characteristics of pancreatic lesions (solid versus cystic) between the two groups were compared. In total, 217 patients were included. Telecytopathology on-site evaluation was provided for 95 (43.8%) cases. There was no difference between the groups in terms of age and sex. Pancreatic lesions were predominantly solid in the group that underwent telecytopathology on-site evaluation (p<0.005). The nondiagnostic rates for solid lesions in Group 1 and Group 2 were 3.7% and 25.6%, respectively (p<0.0001). Although the nondiagnostic rate for cystic lesion was higher in Group 2, it did not reach a level of statistical significance (16.5% versus 7.1%; p=0.249). After adjusting for the effects of sex and lesion characteristics (solid versus cystic lesion) with multivariate logistic regression, the odds of having a nondiagnostic specimen in Group 2 was 6.9 times greater than in Group 1, and the result was statistically significant (p=0.0013). |
Does [ Capsular saliva acid of Streptococcus suis 2 influence virulence and host inflammatory responses ]? | We clarified the pathogenic influence of the absence of Streptococcus suis type 2 capsular saliva acid on BLAB/c mice. The virulence of the experimental strains were compared; the distribution of strains in vivo was determined by quantitative plating. Histopathological analysis was used to qualitatively compare the different pathogenicity of wild strain and knockout strains. ELISA was used to test the levels of cytokine in whole blood cells for the stimulation of strains. The virulence of mutant strains was significantly reduced, and when the genes were restored, toxicity levels were recovered to that of the wild type strain. The distribution in blood and in the brain between wild strain and knock out strains has significant difference, and Streptococcus suis type 2 strains can cause different degrees of brain damage. During the in vitro test, the mutant strains can stimulate the whole blood cells to secrete higher levels of MCP-1 and IL-6. | We sought to determine the predictors of treatment response in simple endometrial hyperplasia without atypia. We prospectively treated 67 women with simple endometrial hyperplasia without atypia who were administered cyclic oral medroxyprogesterone acetate 10 mg/day for 12 days of luteal phase for 3 months and underwent control endometrial sampling after treatment. All subjects were evaluated in terms of age, gravidity, parity, body mass index (BMI), menstrual cycle, endometrial thickness, uterine fibroids, ovarian cysts, serum CA 125 levels, systemic disorders and cigarette smoking. All parameters were used to predict treatment success. Persistent hyperplasia was observed in 11 subjects. Endometrial thickness was significantly correlated with treatment failure (r=0.293, p=0.015). In ROC analysis, endometrial thickness was found to be predictive for persistent hyperplasia (area under curve: 0.724, P=0.019). Optimal cut off value was calculated to be 16.5 mm with 64% sensitivity, 72% specificity and 91% negative predictive value. The number of persistent hyperplasia in women with and without endometrial thickness greater than 16.5 mm was significantly different (7/23 vs. 4/45, p=0.029). Odds ratio of endometrial thickness higher than 16.5 mm for treatment failure was 4.4 (95% CI, 1.2-17.4, p=0.03). |
Does granulocyte colony-stimulating factor prevent loss of spermatogenesis after sterilizing busulfan chemotherapy? | To determine whether granulocyte colony-stimulating factor (G-CSF) could prevent loss of spermatogenesis induced by busulfan chemotherapy via protection of undifferentiated spermatogonia, which might serve as an adjuvant approach to preserving male fertility among cancer patients. Laboratory animal study. University. Laboratory mice. Five-week-old mice were treated with a sterilizing busulfan dose and with 7 days of G-CSF or vehicle treatment and evaluated 10 weeks later (experiment 1) or 24 hours after treatment (experiment 2). Experiment 1: testis weights, epididymal sperm counts, testis histology. Experiment 2: PLZF immunofluorescent costaining with apoptotic markers. Molecular analysis of G-CSF receptor expression in undifferentiated spermatogonia. Ten weeks after treatment, busulfan-treated mice that also received treatment with G-CSF exhibited significantly better recovery of spermatogenesis and epididymal sperm counts than animals receiving busulfan alone. G-CSF led to increased numbers of PLZF+ spermatogonia 24 hours after treatment that was not accompanied by changes in apoptosis. To address the cellular target of G-CSF, mRNA for the G-CSF receptor, Csf3r, was found in adult mouse testes and cultured THY1+ (undifferentiated) spermatogonia, and cell-surface localized CSF3R was observed on 3% of cultured THY1+ spermatogonia. | Impulsivity is a "tendency to act prematurely without foresight." Clinical experience suggests that such impulsive behavior can impact on the fall risk in Parkinson's disease (PD), but this has never been tested. We investigated whether trait impulsivity is related to fall risk in a large cohort of PD patients. We also investigated whether trait impulsivity affects the fall risk differently for patients with more or less postural instability and gait disability (PIGD). 388 patients with PD (H&Y ≤ 3) completed the Barratt Impulsiveness Scale (BIS-11, higher scores indicating greater impulsivity) to assess trait impulsivity, including three subscales: motor impulsivity (e.g. "I do things without thinking"), attentional impulsivity (e.g. "I concentrate easily") and non-planning (e.g. "I plan tasks carefully"). Falls were registered prospectively for 6 months. Patients classified as non-fallers (0 falls, n = 237) were compared to recurrent PD fallers (>1 fall, n = 78). Total impulsivity scores were higher for recurrent fallers (59.5) compared to non-fallers (56.8; p = .012). This effect was predominantly driven by higher scores on the subscale for attentional impulsivity (p = .003). The difference in attentional impulsivity was independent of gender, disease severity, dopaminergic medication, and cognitive function. Motor and non-planning impulsivity did not differ between recurrent fallers and non-fallers. There was no evidence that impulsivity modulated the association between PIGD and fall risk. |
Do cAP37-derived antimicrobial peptides have in vitro antiviral activity against adenovirus and herpes simplex virus type 1? | The antiviral activity of an established antibacterial CAP37 domain and its extracellular mechanism of action were investigated. CAP37-derived peptides modified to assess the importance of disulfide bonds were evaluated in cytotoxicity and antiviral assays (direct time kill, dose dependency, and TOTO-1) for adenovirus (Ad) and herpes simplex virus type 1 (HSV-1). Variable virus, adenovirus serotype-dependent, and dose-dependent inhibition were demonstrated without cytotoxicity. For peptide A (CAP37(20-44)), TOTO-1 dye uptake was demonstrated for Ad5 and HSV-1. | To determine the effect of pre-existing maternal obesity and gestational diabetes mellitus (GDM) on the circulating levels of insulin growth factor-binding protein (IGFBPs) in cord and maternal plasma. IGFBP-1-7 levels were measured on maternal and cord plasma from women with normal glucose tolerance (NGT) (30 non-obese and 36 obese) and GDM (44 non-obese and 26 obese) at the time of term elective cesarean section. Maternal plasma IGFBP-1, IGFBP-6 and IGFBP-rP1 concentrations were significantly lower in NGT obese compared with NGT non-obese women and in non-obese GDM women compared with non-obese NGT women. In cord plasma, IGFBP-1-3 and IGFBP-rP1 concentrations were significantly lower in NGT obese compared with NGT non-obese women and in non-obese GDM women compared with non-obese NGT women. Significant positive correlations were observed between maternal and cord plasma IGFBP-1 and IGFBP-rP1 levels and maternal insulin resistance. In cord plasma, significant positive correlations were observed between IGFBP-1-3 and IGFBP-rP1 levels and fetal insulin resistance. Fetal birthweight was inversely correlated with maternal plasma IGFBP-1 levels and cord plasma IGFBP-1 and IGFBP-2 levels. When corrected for maternal body mass index, the only significant relationship that still existed was between cord plasma IGFBP-1 concentrations and fetal birthweight. |
Is reactive hyperemia associated with adverse clinical outcomes in heart failure? | Impaired endothelial function, as assessed by brachial artery flow-mediated dilation (FMD), is an established risk factor for cardiovascular events. FMD is impaired in heart failure (HF) patients, but less is known about hyperemic brachial artery flow. We investigated the relationship between FMD and hyperemic flow with adverse clinical outcomes in HF patients. Brachial artery FMD and hyperemic flow were assessed in 156 patients (70.5 % Male; 45.5% Caucasian; mean age (± SD) = 56.2 (±12.4) years) with HF and reduced left ventricular ejection fraction (LVEF). Cox proportional hazard models were used to assess the potential explanatory association of FMD and hyperemic flow with the composite outcome of death or cardiovascular hospitalization over a median 5-year follow-up period. Both FMD and hyperemic flow were negatively correlated with age, but unrelated to sex, race, body mass index, LVEF or N-terminal pro-B-Type natriuretic peptide (NT-ProBNP). Reduced hyperemic flow, but not FMD, was associated with an increased risk of death or cardiac hospitalization after controlling for traditional risk factors. | The p53 tumor suppressor gene has been well studied in epithelial ovarian cancers. However, little is known of the expression of this gene in ovarian germ cell tumors. The authors attempted to investigate whether p53 alterations occurred in this group of tumors. Twenty-two patients with malignant ovarian germ cell tumors were included in this study. Immunohistochemical staining for p53 was performed on paraffin embedded tissue of each case. Single-strand conformation polymorphism analysis of exons 4-9 of the p53 gene was performed on 9 of the 22 tumors where genomic DNAs were obtained from the frozen tissue samples. Three tumors that revealed focal p53 positivity by immunostaining were studied further with direct DNA sequencing. Overexpression of p53 was not observed in all of the 22 ovarian germ cell tumors; only 3 were found to have nuclear staining in a small fraction of the malignant cells (< 5% in 1 immature teratoma, 5-10% in 2 yolk-sac tumors). Among the nine frozen tumors subjected to single-strand conformation polymorphism analysis, none revealed p53 mutation in exons 4-9. There was no p53 mutation detected by DNA sequencing of the three tumors with focal immunoreactivity. |
Does tSG101 Silencing suppress Hepatocellular Carcinoma Cell Growth by Inducing Cell Cycle Arrest and Autophagic Cell Death? | The tumor susceptibility gene 101 (TSG101) was originally identified as a tumor-suppressor gene that mediates many molecular and biological processes, such as ubiquitination, endosomal trafficking, cell survival, and virus budding, but its role in hepatocellular carcinoma (HCC) is currently unknown. We assessed the expression of TSG101 in HCC and paracancerous tissues using qPCR. Then, we used the TSG101-specific siRNA mix to disrupt the expression of TSG101 to investigate the subsequent effect on human hepatoma-7 (Huh7) cells. Western blot was used to detect the protein expression of TSG101 and other molecules. Cell growth assay was performed using CCK8. Transwell assay was used to investigate the migration and invasion ability of Huh7 cells after transfection with of TSG101 siRNA. Flow cytometry was used to estimate the effect of TSG101 knockdown on cell cycle and apoptosis. Confocal laser scanning microscopy was used to observe the actin filaments change and the formation of autophagy. TSG101 was over-expressed in HCC tissues. TSG101 silence was able to suppress Huh7 cell proliferation, migration, and invasion. Furthermore, silencing of TSG101 could induce cell cycle arrest at G1 phase and inhibit the expression of cyclin A and cyclin D, while up-regulating the expression of CDK2. The mechanism might be induction of autophagic cell death and inactivation of Akt and ERK1/2. | Depressed mood has been prospectively associated with hypertension. Altered ANS function, as reflected in poor CV recovery, may be one mechanism that underlies this relationship. The purpose of this study was to investigate the relationship between depressed mood and cardiovascular recovery following a standard mental stress task in healthy young women. Depressed mood was assessed in 63 young women. Cardiovascular data were collected during a 5-min baseline period, 5-min public speaking stress task, and 15-min recovery period. Depressed mood accounted for 9.6% of the variation in HR reactivity (F(1,58) = 6.513, p = 0.013) and 4.5% of DBP recovery (F(1,58) = 4.538, p = 0.037). |
Is pIVKA-II the best prognostic predictor in patients with hepatocellular carcinoma after radiofrequency ablation therapy? | This study was undertaken to assess the prognostic predictor in patients with hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). This study retrospectively evaluated clinical outcomes in a cohort of 179 Child-Pugh stage A cirrhotic patients who received curative RFA for naive HCC within Milan criteria. The median follow-up period was 40.5 months. The cumulative survival rate was significantly lower in patients with prothrombin induced by vitamin K absence or antagonist II (PIVKA-II) > or =100 mAU/ml compared with PIVKA-II <100 mAU/ml (58.0 vs. 84.0% at 5 years; p < 0.001). The cumulative recurrence-free survival rates were significantly lower in patients with PIVKA-II > or =100 mAU/ml compared with PIVKA-II <100 mAU/ml (12.1 vs. 16.9% at 5 years; p < 0.032). The cumulative rate of maintaining period within Milan criteria was significantly lower in patients with PIVKA-II > or =100 mAU/ml compared with PIVKA-II <100 mAU/ml (34.1 vs. 55.6% at 5 years; p < 0.001). Cox regression analysis showed that low serum albumin (<3.5 g/dl; p = 0.002, RR 3.75, CI 1.64-8.56), a high level of PIVKA-II (> or =100 mAU/ml; p = 0.04, RR 3.15, CI 1.45-6.87), and multiple nodules (p = 0.021, RR 2.61, CI 1.15-5.91) were independently significant mortality risk factors. | Neutrophils infiltrate systemic vasculature of women with preeclampsia, so we tested the hypothesis that factors in plasma of preeclamptic women activate endothelial cells to produce IL-8 resulting in transendothelial migration of neutrophils. Neutrophil migration was studied using the Transwell system. An endothelial cell line was grown to confluence on the inserts and treated with 10% plasma from normal nonpregnant (NNP), normal pregnant (NP) and preeclamptic (PE) women or with an oxidizing solution containing linoleic acid (OxLA). Compared to medium control, NNP plasma or NP plasma, PE plasma significantly stimulated IL-8 and neutrophil migration which was inhibited by vitamins E and C or IL-8 neutralizing antibody. Compared to medium control or LA, OxLA stimulated IL-8 and neutrophil migration which was inhibited by vitamins E and C or IL-8 antibody. |
Is clinical Assessment of Fluid Balance Incomplete for Colorectal Surgical Patients? | Fluid balance for the surgical patient has been proven very important for the postoperative outcome and development of complications. The aim of this study was to evaluate, for the first time in modern times, the accordance between nurse-based fluid charting (cumulated fluid balance) and body weight change for general surgical patients. This was a descriptive study with prospectively collected data from two clinical randomized multicenter trials. A total of 113 patients from American Society of Anesthesiology group I-III undergoing elective colorectal surgery were included. Cumulated fluid balance and body weight change were charted preoperatively and daily at the same time during a postoperative period of 6 days. Differences were calculated by subtracting cumulated fluid balance from body weight change (1 g = 1 mL), and agreement was assessed by making Bland-Altman plots as well as Pearson correlations. From day 1 to 4, the mean difference between cumulated fluid balance and body weight change was below 0.4 kg/L. On day 5 and 6, the discrepancies increased with mean differences of, respectively, 1.2 kg/L (p < 0.002*) and 2 kg/L (p < 0.0001*). Bland-Altman plots showed increasingly poor agreement for all postoperative days with wide limits of agreement, ranging from more than 6 kg/L to almost 10 kg/L. Pearson correlations were moderate to strong at all times ranging from 0.437 (day 1) to 0.758 (day 4). | Whole-genome physical maps facilitate genome sequencing, sequence assembly, mapping of candidate genes, and the design of targeted genetic markers. An automated protocol was used to construct a Vitis vinifera 'Cabernet Sauvignon' physical map. The quality of the result was addressed with regard to the effect of high heterozygosity on the accuracy of contig assembly. Its usefulness for the genome-wide mapping of genes for disease resistance, which is an important trait for grapevine, was then assessed. The physical map included 29,727 BAC clones assembled into 1,770 contigs, spanning 715,684 kbp, and corresponding to 1.5-fold the genome size. Map inflation was due to high heterozygosity, which caused either the separation of allelic BACs in two different contigs, or local mis-assembly in contigs containing BACs from the two haplotypes. Genetic markers anchored 395 contigs or 255,476 kbp to chromosomes. The fully automated assembly and anchorage procedures were validated by BAC-by-BAC blast of the end sequences against the grape genome sequence, unveiling 7.3% of chimerical contigs. The distribution across the physical map of candidate genes for non-host and host resistance, and for defence signalling pathways was then studied. NBS-LRR and RLK genes for host resistance were found in 424 contigs, 133 of them (32%) were assigned to chromosomes, on which they are mostly organised in clusters. Non-host and defence signalling genes were found in 99 contigs dispersed without a discernable pattern across the genome. |
Do distinct genomic and epigenomic features demarcate hypomethylated blocks in colon cancer? | Large mega base-pair genomic regions show robust alterations in DNA methylation levels in multiple cancers. A vast majority of these regions are hypomethylated in cancers. These regions are generally enriched for CpG islands, Lamin Associated Domains and Large organized chromatin lysine modification domains, and are associated with stochastic variability in gene expression. Given the size and consistency of hypomethylated blocks (HMB) across cancer types, we hypothesized that the immediate causes of methylation instability are likely to be encoded in the genomic region near HMB boundaries, in terms of specific genomic or epigenomic signatures. However, a detailed characterization of the HMB boundaries has not been reported. Here, we focused on ~13 k HMBs, encompassing approximately half of the genome, identified in colon cancer. We modeled the genomic features of HMB boundaries by Random Forest to identify their salient features, in terms of transcription factor (TF) binding motifs. Additionally we analyzed various epigenomic marks, and chromatin structural features of HMB boundaries relative to the non-HMB genomic regions. We found that the classical promoter epigenomic mark--H3K4me3, is highly enriched at HMB boundaries, as are CTCF bound sites. HMB boundaries harbor distinct combinations of TF motifs. Our Random Forest model based on TF motifs can accurately distinguish boundaries not only from regions inside and outside HMBs, but surprisingly, from active promoters as well. Interestingly, the distinguishing TFs and their interacting proteins are involved in chromatin modification. Finally, HMB boundaries significantly coincide with the boundaries of Topologically Associating Domains of the chromatin. | To investigate in a unilaterally nephrectomized porcine model whether gadolinium contrast media (Gd-CM) are less nephrotoxic than iodine media (I-CM) in x-ray arteriography of a kidney made temporarily ischemic by arterial balloon occlusion. In a noncrossover design, 3 mL of each test solution were injected in eight pigs (mean weight 19 kg) at a rate of 20 mL/min into the right renal artery at the start of a 10-minute period of ischemia. In group 1 (40 pigs) we injected 0.5 M gadopentetate, 0.5 M gadodiamide, 0.5 M iohexol (190 mg I/mL), 0.18 M iohexol (70 mg I/mL; with an x-ray attenuation equal to that of 0.5 M Gd-CM at 80 kV), and saline. In group 2 (24 pigs), we tested 0.18 M iohexol with ischemia and saline with and without ischemia. Gd- and iodine contrast media functioned as markers of glomerular filtration rate (GFR). When saline was tested, a low dose of iohexol (3 mL per pig; 300 mg I/mL) was injected as GFR marker intravenously in group 1 and into the renal artery in group 2. The plasma half-life elimination times of the CM 1-3 hours after injection were used to compare the effects of the different test solutions on GFR. Longer half-life means lower GFR. Group 1: median plasma half-life elimination time of the GFR marker was 3 340 minutes after injection of 0.5 M gadopentetate, 256 after 0.5 M gadodiamide, 179 after 0.5 M iohexol, 143 after 0.18 M iohexol, and 133 minutes after saline. All differences except that between 0.18 M iohexol and saline were statistically significant (P < .01). Group 2: median plasma half-life was 174 minutes after 0.18 M iohexol with ischemia, 196 minutes after saline with ischemia, and 195 minutes after saline without ischemia. There were no significant differences between the test solutions in group 2 (P > .05). |
Are ex-smokers happier than current smokers among Chinese adults in Hong Kong? | To investigate the cross-sectional association between smoking and happiness in Chinese adults in Hong Kong. Telephone surveys were conducted between 2009 and 2012, with 4553 randomly sampled Chinese adults (male 54%, mean age 58.3 years) in Hong Kong. Happiness was measured using the four-item Subjective Happiness Scale (SHS) and single-item Global Happiness Item (GHI). Smoking status was categorized as current smokers (7.7%%), ex-smokers (6.5%, 93% quit for >6 months) and never smokers (85.8%). Linear and ordinal logistic regressions were used to calculate adjusted β-coefficients for SHS and proportional adjusted odds ratios (aOR) for GHI in relation to smoking. Compared with current smokers, ex-smokers enjoyed greater happiness according to both SHS (adjusted β = 0.16, P < 0.05) and GHI (aOR = 1.52, P < 0.05) measurements, but current and never smokers were similar. Among current smokers, the number of cigarettes smoked was not associated with happiness, but the lack of any attempt to quit was associated significantly with greater happiness (adjusted β = 0.31 for SHS, aOR = 1.82 for GHI) compared with smokers who had tried to quit but not succeeded. Smokers not intending to quit in the next 6 months had higher odds of happiness (GHI) than those wanting to quit within 6 months (aOR = 1.86, P < 0.05). | Ischemia, such as that caused by a tourniquet, stimulates thromboxane (Tx) A(2) synthesis. TxA(2) might sensitize the operated limb to various complications, such as compartment syndrome and thromboembolic events. We studied the effect of pretreatment with a single dose of acetylsalicylic acid (ASA) (25, 100, and 500 mg) given 3 hours before surgery on the formation of TxB(2), a stable metabolite of TxA(2), after tourniquet deflation in 32 knee or ankle surgery patients. Tourniquet time varied between 60 +/- 8 to 71 +/- 7 (SE) minutes. In control patients without ASA pretreatment, the platelet-produced femoral vein serum TxB(2) concentration over 30 minutes in vitro coagulation increased remarkably (from 40.0 +/- 20 ng/mL to 73.5 +/- 39 ng/mL) immediately after tourniquet deflation. Plasma concentrations increased similarly, approximately threefold. Pretreatment with 100 or 500 mg ASA prevented the increase in TxB(2) concentrations. Radial artery concentrations of TxB(2) were similar to venous concentrations in the different treatment groups. |
Is viral infection uncommon in adult patients with severe hospital-acquired pneumonia? | Viral pathogens have not generally been regarded as important causes of severe hospital-acquired pneumonia (HAP), except in patients with hematologic malignancy or transplant recipients. We investigated the role and distribution of viruses in adult with severe HAP who required intensive care. From March 2010 to February 2012, adult patients with severe HAP required admission to the intensive care unit (ICU), 28-bed medical ICU in a tertiary care hospital, were prospectively enrolled. Respiratory viruses were detected using multiplex reverse-transcription polymerase chain reaction and/or shell vial culture. A total of 262 patients were enrolled and 107 patients (40.8%) underwent bronchoscopic BAL for etiologic diagnosis. One hundred and fifty-six patients (59.5%) had bacterial infections and 59 patients (22.5%) had viral infections. Viruses were detected in BAL fluid specimens of 37 patients (62.7%, 37/59). The most commonly identified viruses were respiratory syncytial virus and parainfluenza virus (both 27.1%, 16/59), followed by rhinovirus (25.4%, 15/59), and influenza virus (16.9%, 10/59). Twenty-one patients (8.0%, 21/262) had bacterial-viral coinfections and Staphylococcus aureus was the most commonly coexisting bacteria (n = 10). Viral infection in non-immunocompromised patients was not uncommon (11.1%, 16/143), although it was not as frequent as that in immunocompromised patients (36.4%, 43/119). Non-immunocompromised patients were significantly older than immunocompromised patients and had significantly higher rates of underlying chronic obstructive pulmonary disease, tuberculous destroyed lung and chronic kidney disease. The 28 day mortalities of patients with bacterial infections, viral infections and bacterial-viral coinfections were not significantly different (29.5%, 35.6% and 19.0%, respectively; p = 0.321). | To examine whether trichostatin A (TSA), a histone deacetylase inhibitor (HDACI), can induce up-regulation of peroxisome proliferator-activating receptor gamma (PPAR gamma) and to see whether LG100268, a retinoid X receptor (RXR) ligand, can inhibit proliferation of endometriotic cells alone or in synergy with ciglitazone, a PPAR gamma agonist. One endometrial stromal cell line and two endometriotic cell lines used as a model system: Western blot analysis to determine whether TSA can up-regulate PPAR gamma expression, and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) proliferation assay to see whether ciglitazone and LG100268 have any antiproliferative effects individually or jointly. Academic. None. Culture of immortalized endometrial and endometriotic cell lines with TSA, or ciglitazone or LG100268. PPAR gamma protein expression levels in cells treated with or without TSA, and number of viable cells treated with or without ciglitazone, LG100268, or both. The TSA treatment resulted in up-regulation of PPAR gamma expression in all cell lines in a dose-dependent fashion. Both ciglitazone and LG100268 inhibited proliferation in a dose-dependent manner, and the antiproliferative effects appeared to be synergistic. In addition, endometriotic cells were more sensitive than endometrial stromal cells to LG100268 treatment. |
Does a Common Polymorphism in a Williams Syndrome Gene predict Amygdala Reactivity and Extraversion in Healthy Adults? | Williams syndrome (WS), a genetic disorder resulting from hemizygous microdeletion of chromosome 7q11.23, has emerged as a model for identifying the genetic architecture of socioemotional behavior. Common polymorphisms in GTF2I, which is found within the WS microdeletion, have been associated with reduced social anxiety in the general population. Identifying neural phenotypes affected by these polymorphisms would help advance our understanding not only of this specific genetic association but also of the broader neurogenetic mechanisms of variability in socioemotional behavior. Through an ongoing parent protocol, the Duke Neurogenetics Study, we measured threat-related amygdala reactivity to fearful and angry facial expressions using functional magnetic resonance imaging, assessed trait personality using the Revised NEO Personality Inventory, and imputed GTF2I rs13227433 from saliva-derived DNA using custom Illumina arrays. Participants included 808 non-Hispanic Caucasian, African American, and Asian university students. The GTF2I rs13227433 AA genotype, previously associated with lower social anxiety, predicted decreased threat-related amygdala reactivity. An indirect effect of GTF2I genotype on the warmth facet of extraversion was mediated by decreased threat-related amygdala reactivity in women but not men. | The aim of this study was to evaluate patterns of the initial recurrence after pancreatectomy for pancreatic cancer and risk factors in each pattern. This study included 209 pancreatic cancer patients who underwent pancreatectomy and of whom the detailed information on the first recurrent lesions detected by imaging during postoperative followup were available. Relapse patterns were classified into 4 groups: liver, peritoneal, local and extra-abdominal recurrences. We evaluated their associations with prognosis and various clinicopathological factors to identify relevant risk factors. Cumulative numbers of patients with liver, peritoneal, local, and extra-abdominal recurrences were 81, 70, 98 and 22, respectively, for the first recurrences. Hepatic relapse was associated with significantly shorter overall survival than other sites (p<0.001) and was an independent prognostic factor in multivariate analysis (p<0.001). Pathological portal vein invasion was the only independent risk factor for hepatic relapse (p=0.045). There was no significant correlation between the depth of invasion and prevalence of hepatic relapse. |
Is impaired vascular function in physically active premenopausal women with functional hypothalamic amenorrhea associated with low shear stress and increased vascular tone? | Exercise-trained hypoestrogenic premenopausal women with functional hypothalamic amenorrhea (ExFHA) exhibit impaired endothelial function. The vascular effects of an acute bout of exercise, a potent nitric oxide stimulus, in these women are unknown. Three groups were studied: recreationally active ExFHA women (n = 12; 24.2 ± 1.2 years of age; mean ± SEM), and recreationally active (ExOv; n = 14; 23.5 ± 1.2 years of age) and sedentary (SedOv; n = 15; 23.1 ± 0.5 years of age) ovulatory eumenorrheic women. Calf blood flow (CBF) and brachial artery flow-mediated dilation (FMD) were evaluated using plethysmographic and ultrasound techniques, respectively, both before and 1 hour after 45 minutes of moderate-intensity exercise. Endothelium-independent dilation was assessed at baseline using glyceryl trinitrate. Calf vascular resistance (CVR) and brachial peak shear rate, as determined by the area under the curve (SRAUCpk), were also calculated. FMD and glyceryl trinitrate responses were lower (P < .05) in ExFHA (2.8% ± 0.4% and 11.6% ± 0.7%, respectively) than ExOv (8.8% ± 0.7% and 16.7% ± 1.3%) and SedOv (8.0% ± 0.5% and 17.1% ± 1.8%). SRAUCpk was also lower (P < .05) in ExFHA. Normalization of FMD for SRAUCpk (FMD/SRAUCpk) did not alter (P > .05) the findings. CBF was lower (P < .05) and CVR higher (P < .05) in ExFHA. After exercise, FMD and SRAUCpk were augmented (P < .05), but remained lower (P < .05), in ExFHA. FMD/SRAUCpk no longer differed (P > .05) between the groups. CBF in ExFHA was increased (P < .05) and CVR decreased (P < .05) to levels observed in ovulatory women. | The aim of this study was to examine the growth arrest and DNA damage-inducible (Gadd45a) expression and its role in tumor progression, invasion and metastasis in oral squamous cell carcinoma (OSCC). Growth arrest and DNA damage-inducible 45a distribution was detected by immunohistochemistry in tumor sections of 106 patients with primary OSCC and sections of adjacent pericancerous tissues from 60 patients among the 106. The association between the Gadd45a expression and clinical prognosis of OSCC were performed by statistical analysis. Gadd45a gene knockdown was performed in Tca8113 cells by small interfering ribonucleic acid treatment and its effects on cell cycle, and migration were detected by Flow Cytometric (Becton Dickinson, USA) and transwell chamber assay respectively. |
Do eptifibatide and abciximab inhibit insulin-induced focal adhesion formation and proliferative responses in human aortic smooth muscle cells? | The use of abciximab (c7E3 Fab) or eptifibatide improves clinical outcomes in diabetics undergoing percutaneous coronary intervention. These beta3 integrin inhibitors antagonize fibrinogen binding to alphaIIbbeta3 integrins on platelets and ligand binding to alphavbeta3 integrins on vascular cells. alphavbeta3 integrins influence responses to insulin in various cell types but effects in human aortic smooth muscle cells (HASMC) are unknown. | Cell death induced by intracellular glutathione depletion has been reported to be dependent on the presence of trace amounts of extracellular copper ions. Since little is known about the relationship between glutathione depletion and copper homeostasis, we have in the present study further investigated the role of low amounts of copper ions in glutathione depletion. Glutathione turnover was investigated in HeLa and hepatoma cell cultures with normal and low cysteine content in the presence of copper ions (1 and 10micromol/L) and two other glutathione-stimulating agents (lipoic acid and mercury ions). Copper ions (10micromol/L) caused relatively small increases in total amount of glutathione (the sum of the intracellular and the extracellular amount of glutathione) in HeLa and hepatoma cell cultures with normal cysteine levels (420nmol/mL) compared to control cell cultures, whereas lipoic acid and mercury ions strongly increased total glutathione in both types of cell cultures. Lower amount of total glutathione was observed in cell cultures with a lower cysteine levels (84nmol/mL), which is similar to that in human plasma. A strongly decreased total amount of glutathione in the presence of copper ions was observed in hepatoma cell cultures with lower cysteine levels, whereas the other agents showed effects similar to those described for cell cultures with normal cysteine levels. |
Do why women accept randomisation for place of birth : feasibility of a RCT in The Netherlands? | The purpose of this study was to investigate why low-risk nulliparae were not willing to participate in a randomised controlled trial (RCT) of place of birth. Prospective study. The Netherlands. All low-risk nulliparous women starting their pregnancy under midwife. A questionnaire for 107 nulliparae who were willing to participate in a cohort study on place of birth, but at an earlier stage in their pregnancy declined to participate in a RCT of place of birth. This questionnaire included 12 items on a 4-point Likert scale but was not subjected to formal validation. Reasons why nulliparae did not accept randomisation of place of birth. The most important reason why women refused participation in the trial was that they had already chosen their place of birth before they were asked to participate at 12 weeks of pregnancy. From their answers, it became clear that pregnant women strongly value their autonomy of choice. The decision not to participate in the trial was not influenced by the information given by the midwife and the additional written information. | Despite advances in the understanding of diabetic retinopathy, the nature and time course of molecular changes in the retina with diabetes are incompletely described. This study characterized the functional and molecular phenotype of the retina with increasing durations of diabetes. Using the streptozotocin-induced rat model of diabetes, levels of retinal permeability, caspase activity, and gene expression were examined after 1 and 3 months of diabetes. Gene expression changes were identified by whole genome microarray and confirmed by qPCR in the same set of animals as used in the microarray analyses and subsequently validated in independent sets of animals. Increased levels of vascular permeability and caspase-3 activity were observed at 3 months of diabetes, but not 1 month. Significantly more and larger magnitude gene expression changes were observed after 3 months than after 1 month of diabetes. Quantitative PCR validation of selected genes related to inflammation, microvasculature and neuronal function confirmed gene expression changes in multiple independent sets of animals. |
Does ankle joint mobilization decrease hypersensitivity by activation of peripheral opioid receptors in a mouse model of postoperative pain? | Investigate whether ankle joint mobilization (AJM) decreases hypersensitivity in the mouse plantar incision (PI) model of postoperative pain as well as to analyze the possible mechanisms involved in this effect. Experiment 1: PI male Swiss mice (25-35 g, N = eight animals per group) were subjected to five sessions of AJM, each lasting either 9 or 3 minutes. AJM movement was applied at a grade III as defined by Maitland. Paw withdrawal frequency to mechanical stimuli was assessed before realization of PI and before and after daily AJM sessions. Mechanical hypersensitivity was also assessed following systemic (intraperitoneal [i.p.]) and local (intraplantar) injection of naloxone (a nonselective opioid receptor antagonist; 1 mg/kg, i.p.; 5 µg/paw, respectively, experiment 2); and systemic injection of fucoidin (100 µg/mouse, i.p., an inhibitor of leukocyte rolling, experiment 3) in different groups of mice. Nine but not 3 minutes of AJM reduced mechanical hypersensitivity caused by PI, an effect that was prevented by systemic and local administrations of naloxone but not by fucoidin. | Women who develop pre-eclampsia in pregnancy are at increased risk of cardiovascular disease. The offspring from pregnancies complicated by pre-eclampsia have higher blood pressures during childhood, but little is known about their long-term health. We hypothesized that pre-eclampsia would lead to an increased risk of cardiovascular disease in the offspring. We traced 6410 babies born in Helsinki, Finland, from 1934 to 1944. We used the mothers' blood pressure levels and the presence of proteinuria during pregnancy to define pre-eclampsia and gestational hypertension without proteinuria according to modern criteria. Two hundred eighty-four of the pregnancies were complicated by pre-eclampsia (120 with nonsevere and 164 with severe disease) and 1592 by gestational hypertension. The crude hazard ratio for all forms of stroke among people whose mothers had pre-eclampsia was 1.9 (1.2 to 3.0; P=0.01); among people whose mothers had gestational hypertension, it was 1.4 (1.0 to 1.8; P=0.03). There was no evidence that these pregnancy disorders were associated with coronary heart disease in the offspring. Pre-eclampsia, in particular severe disease, was associated with a reduced mean head circumference at birth, whereas gestational hypertension was associated with an increased head circumference in relation to body length. |
Is the diagnostic randomized clinical trial the best solution for management issues in critical limb ischemia? | The value of a new diagnostic test is usually established by analyzing its accuracy in relation to a reference standard. Here we describe a potentially better model of diagnostic research, namely, a diagnostic randomized clinical trial (D-RCT), and discuss its pros and cons using management of critical limb ischemia as an example. Patients clinically suspected of critical limb ischemia are randomized either for the conventional management strategy (treating physician determines the diagnostic and therapeutic strategy on clinical judgment and ankle pressure) or new strategy (transcutaneous oxygen and toe pressure determine the diagnostic and therapeutic strategy). The effect of the diagnostic work-up on the diagnostic and therapeutic process and clinical outcome will be evaluated. A D-RCT is suited when a true reference standard is lacking. It is the best available research method to control for confounding and bias, and it also incorporates the total effect (interpretation and side effects) on clinical outcome. The D-RCT has some disadvantages, however, as to the power and size of the trial and the influence of treatment on the outcome parameter. | ErbB family receptor tyrosine kinases (ErbBs) play a role in cell adhesion and migration and are frequently overexpressed in esophageal squamous cell carcinomas (ESCCs) or esophageal adenocarcinomas (EACs). Targeting ErbBs by tyrosine kinase inhibitors (TKIs) may therefore limit esophageal cancer cell migration. Here, we studied the impact of TKIs on ErbB dimerization, cell signaling pathways, and cell migration in three esophageal cell lines: OE21 (ESCC), OE33 (EAC), and Het-1A (non-neoplastic esophageal epithelium). In OE21 cells, the TKIs erlotinib, gefitinib, and lapatinib slightly affected epidermal growth factor receptor EGFR/EGFR, but not EGFR/HER2 dimerization as detected by in situ proximity ligation assay (in situ PLA). Still, TKIs inhibited ERK1/2, Akt, STAT3, and RhoA activity in OE21 cells, as assessed by Western blot, antibody arrays, and Rho GTPase effector pull-down assays. This was accompanied by reduced OE21 cell migration, induction of focal adhesions, and actin cytoskeleton reorganization, as shown by Oris™ migration assay and focal adhesion kinase (FAK)/phalloidin staining. In contrast, in OE33 cells, only lapatinib decreased STAT5, Src family kinase (SFK), and FAK activity as well as β-catenin expression. This impeded cell migration and induced morphological changes in OE33 cells. No alterations were seen for the non-neoplastic Het-1A cells. Thus, we identified the ErbB signaling network as regulator of esophageal cancer cell's actin cytoskeleton, focal adhesions, and cell migration. ErbB targeted TKIs therefore also limit ESCC and EAC cell motility and migration. |
Does hyperoxia inhibit nitric oxide treatment effects in alveolar epithelial cells via effects on L-type amino acid transporter-1? | The aims of this study were to determine hyperoxia effects on S-nitrosothiol (SNO) accumulation and L-type amino acid transporter 1 (LAT1) expression/function in alveolar epithelium and to determine whether hyperoxia impairs exogenous nitric oxide (NO) treatment effects in alveolar epithelium through effects on LAT1 expression and/or function. SNO accumulation in vitro and in vivo after NO treatment was dependent on the LAT1 system transport. Hyperoxia (60% or 90%) impaired NO effects on SNO accumulation and soluble guanylyl cyclase activation in proportion to the magnitude of hyperoxia and the duration of exposure, up to 12 h, in type I-like (R3/1) and type II-like (L2) rat and human (A549) alveolar epithelial cells. LAT function, determined by sodium-independent (3)H-leucine uptake, was impaired in a parallel manner. Hyperoxia impaired LAT1 expression in alveolar epithelial cells, determined by immunoblots and immunofluorescence, and in newborn rats exposed to 60% O2 for 4 days, determined by immunohistochemistry. Despite significant preclinical evidence, inhaled NO has shown disappointing limitations in clinical applications. Our studies suggest an important explanation: oxidative stress, a common feature of diseases in which therapeutic NO would be considered, impairs LAT1 expression and function, blocking a major route for inhaled NO (iNO) action, that is, the uptake of S-nitrosocysteine via LAT1. | Comprehensiveness is lauded as 1 of the 5 core virtues of primary care, but its relationship with outcomes is unclear. We measured associations between variations in comprehensiveness of practice among family physicians and healthcare utilization and costs for their Medicare beneficiaries. We merged data from 2011 Medicare Part A and B claims files for a complex random sample of family physicians engaged in direct patient care, including 100% of their claimed care of Medicare beneficiaries, with data reported by the same physicians during their participation in Maintenance of Certification for Family Physicians (MC-FP) between the years 2007 and 2011. We created a measure of comprehensiveness from mandatory self-reported survey items as part of MC-FP examination registration. We compared this measure to another derived from Medicare's Berenson-Eggers Type of Service (BETOS) codes. We then examined the association between the 2 measures of comprehensiveness and hospitalizations, Part B payments, and combined Part A and B payments. Our full family physician sample consists of 3,652 physicians providing the plurality of care to 555,165 Medicare beneficiaries. Of these, 1,133 recertified between 2007 and 2011 and cared for 185,044 beneficiaries. There was a modest correlation (0.30) between the BETOS and self-reported comprehensiveness measures. After adjusting for beneficiary and physician characteristics, increasing comprehensiveness was associated with lower total Medicare Part A and B costs and Part B costs alone, but not with hospitalizations; the association with spending was stronger for the BETOS measure than for the self-reported measure; higher BETOS scores significantly reduced the likelihood of a hospitalization. |
Does cLOSING MACULAR hole WITH `` MACULAR PLUG '' WITHOUT GAS TAMPONADE AND POSTOPERATIVE POSTURING? | To investigate the surgical results of macular hole surgery without gas tamponade or postoperative posturing in patients with Stage 3 and Stage 4 macular holes with ≥500 μm mean base diameter. Retrospective interventional case series. Twenty-six patients with Stage 3 and Stage 4 macular holes. Twenty-six eyes of 26 patients with Stage 3 and Stage 4 macular holes and a mean base diameter of 892.8 ± 349 μm underwent pars plana 23-gauge vitrectomy with broad internal limiting membrane peel (ILM peel), inverted ILM flap repositioning (ILMR), and use of autologous gluconated blood clumps as a macular plug to close the macular hole. No fluid-air exchange, endotamponade, or postoperative posturing was used. The subjects were followed up for 12 months. The anatomical outcome of the procedure was evaluated by fundus examination and optical coherence tomography. Spectral domain optical coherence tomography was used to study the restoration of the outer retinal layer integrity in the postoperative period. The preoperative and postoperative best-corrected visual acuities in logMAR units were compared to evaluate functional outcome. Macular hole closure and best-corrected visual acuity before and after surgery. Twenty-six patients with mean age 62.8 ± 7.3 years, preoperative median best-corrected visual acuity 6/60 (1.0 logMAR units), and a mean base diameter of 892.8 ± 349 μm underwent surgery to close macular holes without gas tamponade or postoperative posturing. Twenty patients (76.9%) were phakic. Twenty eyes (76.92%) had Stage 3 macular holes and 6 eyes (23.10%) had Stage 4 macular holes. After a single surgery, hole closure was achieved in 100% of eyes. The median best-corrected visual acuity improved from 6/60 (1.0 logMAR units) to 6/18 (0.50 logMAR units) (P < 0.001). Three patients needed cataract surgery at 12-month follow-up. No major intraoperative or postoperative complications were observed. | Epigenetic code modifications by histone deacetylase inhibitors (HDACi) have been proposed as potential new therapies for lymphoid malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma for which standard first line treatment is the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) combined with the monoclonal anti-CD20 antibody rituximab (R-CHOP). The HDACi valproate, which has for long been utilized in anti-convulsive therapy, has been shown to sensitize to chemotherapy in vitro. Valproate upregulates expression of CD20 in lymphoma cell lines; therefore, 48 hour pre-treatment with valproate before first line R-CHOP in DLBCL stages II-IV is evaluated in the phase I clinical trial VALFRID; Valproate as First line therapy in combination with Rituximab and CHOP in Diffuse large B-cell lymphoma. Pretreatment with valproate at oral doses comparable to anti-convulsive therapy, resulted in upregulation of CD20 mRNA and CD20 protein on the cell surface as measured by qPCR and FACS analysis in lymphoma biopsies from three evaluated patients from the VALFRID study. Valproate-treatment corresponded to increased acetylation of Histone3Lysine9 (H3K9ac) in peripheral blood mononuclear cells (PBMCs), which were employed as surrogate tissue for valproate-related epigenetic modifications. |
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