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Is reduced PKCalpha expression in pulmonary arterioles of broiler chickens associated with early feed restriction?

The present study was conducted to investigate the effect of early feed restriction on protein kinase Calpha (PKCalpha) expression in pulmonary arterioles, which has been revealed to promote pulmonary vascular remodeling in pulmonary hypertensive broilers. A total of 270day-old mixed sex commercial broilers were randomly distributed to a normal temperature control group (NT), a low temperature control group (LT) and a low temperature plus feed restriction group (LR). The PHS incidence, the right/total ventricular weight ratio (RV/TV), the vessel wall area/vessel total area ratio (WA/TA), the mean media thickness in pulmonary arterioles (mMTPA) and the expression of PKCalpha in the pulmonary arterioles were measured weekly. Low temperature treatment significantly increased the PHS mortality. The RV/TV, WA/TA and mMTPA values of group LT were significantly elevated compared with those of group NT on d 35 and 42. The LT chickens had increased PKCalpha expression compared with their NT counterparts on d 28 and afterwards. Feed restriction reduced the PHS mortality, RV/TV, WA/TA and mMTPA in cold-exposed broilers. The LR chickens had much lower PKCalpha expression in pulmonary arterioles than the LT chickens.

Early time feed restriction inhibited pulmonary vascular remodeling in broilers, which might be partly attributed to reduced PKCalpha expression in pulmonary arterioles.

Does endothelial cell-specific liver kinase B1 deletion cause endothelial dysfunction and hypertension in mice in vivo?

Liver kinase B1 (LKB1), a tumor suppressor, is a central regulator of cell polarity and energy homeostasis. The role of LKB1 in endothelial function in vivo has not been explored. Endothelium-specific LKB1 knockout (LKB1(endo-/-)) mice were generated by cross-breeding LKB1(flox/flox) mice with VE-Cadherin-Cre mice. LKB1(endo-/-) mice exhibited hypertension, cardiac hypertrophy, and impaired endothelium-dependent relaxation. LKB1(endo-/-) endothelial cells exhibited reduced endothelial nitric oxide synthase activity and AMP kinase (a downstream enzyme of LKB1) phosphorylation at Thr172 compared with wild-type (WT) cells. In addition, the levels of caveolin-1 were higher in the endothelial cells of LKB1(endo-/-) mice, and knockdown of caveolin-1 by siRNA normalized endothelial nitric oxide synthase activity. Human antigen R bound with the adenylate-uridylate-rich elements of caveolin-1 mRNA 3' untranslated region, resulting in the increased stability of caveolin-1, and genetic knockdown of human antigen R decreased the expression of caveolin-1 in LKB1-deficient endothelial cells. Finally, adenoviral overexpression of constitutively active AMP kinase, but not green fluorescent protein, decreased caveolin-1, lowered blood pressure, and improved endothelial function in LKB1(endo-/-) mice in vivo.

Our findings indicate that endothelial LKB1 regulates endothelial nitric oxide synthase activity, endothelial function, and blood pressure by modulating AMP kinase-mediated caveolin-1 expression.

Does prolonged combined androgen blockade have survival benefits over short-term combined androgen blockade therapy?

To explore whether less than 120 days of an antiandrogen plus a luteinizing hormone-releasing hormone agonist resulted in a different survival outcome than 120 days or more of combined treatment in patients with Stage D2 prostate cancer. Survival data were available from a previously published controlled trial that had evaluated the efficacy and tolerability of two antiandrogens, bicalutamide and flutamide, each combined with a monthly depot preparation of leuprolide or goserelin, in 813 patients with Stage D2 prostate cancer. Cox's proportional hazards regression model assessed the relative effects of the length of combined androgen blockade (CAB) therapy on survival. This analysis was repeated in the subset of patients who lived at least 2 years beyond the date of randomization. Data were obtained at a median follow-up of 160 weeks. A survival benefit was demonstrated for patients receiving prolonged CAB therapy, with a hazard ratio of 0.275 (95% confidence interval 0.213 to 0.355, P = 0.0001) in favor of patients who received 120 days or more of CAB therapy (median survival 1035 days versus 302 days for less than 120 days of therapy). This result was confirmed in the patients who lived at least 2 years, in whom the median survival time was increased by 35%. The hazard ratio for 120 days or more of CAB therapy versus less than 120 days was 0.415 (95% confidence interval 0.246 to 0.702, P = 0.001).

The results of the present exploratory analysis suggest that prolonged (120 days or more) antiandrogen treatment as part of CAB therapy may result in a better survival outcome.

Does stereotype threat contribute to social difficulties in people with schizophrenia?

The experience of stereotype threat (where the prospect of conforming to a stereotype, or of being treated in terms of it, becomes self-threatening) affects members of social groups about whom devaluing stereotypes exist. Although a widely endorsed stereotype of schizophrenia concerns social skill impairment, it is unclear whether the experience of stereotype threat impacts social functioning in this group. The purpose of the present study was to test whether people with schizophrenia would perform more poorly in a social setting in which they felt stereotyped as mentally ill. Thirty individuals with schizophrenia engaged in conversations with two confederates, one of whom they were told knew nothing about them (control conversation), and the other of whom they were told had been informed of their diagnosis (stereotype threat conversation). In reality, neither confederate had been informed of participants' mental health status. Although participants with schizophrenia did not perceive any differences in their own social behaviour across the two conditions, their social skill was rated by the confederates as poorer in the stereotype threat conversation on three out of the six measures used.

These results suggest that social skill difficulties in people with schizophrenia may be exacerbated by their awareness that others know of their diagnosis. These findings have implications for disclosure of mental health status.

Does activation of protease-activated receptor 2 induce VEGF independently of HIF-1?

Human adipose stem cells (hASCs) can promote angiogenesis through secretion of proangiogenic factors such as vascular endothelial growth factor (VEGF). In other cell types, it has been shown that induction of VEGF is mediated by both protease activated receptor 2 (PAR2) and hypoxia inducible factor 1(HIF-1). The present study hypothesized that PAR2 stimulation through activation of kinase signaling cascades lead to induction of HIF-1 and secretion of VEGF. Immunohistochemistry revealed the expression of PAR2 receptors on the surface of hASCs. Blocking the PAR2 receptors with a specific antibody prior to trypsin treatment showed these receptors are involved in trypsin-evoked increase in VEGF secretion from hASCs. Blocking with specific kinase inhibitors suggested that that activation of MEK/ERK and PI3-kinase/Akt pathways are involved in trypsin-eveoked induction of VEGF. The effect of the trypsin treatment on the transcription of VEGF peaked at 6 hours after the treatment and was comparable to the activation observed after keeping hASCs for 24 hours at 1% oxygen. In contrast to hypoxia, trypsin alone failed to induce HIF-1 measured with ELISA, while the combination of trypsin and hypoxia had an additive effect on both VEGF transcription and secretion, results which were confirmed by Western blot.

In hASCs trypsin and hypoxia induce VEGF expression through separate pathways.

Is improvement in the health-related quality-of-life symptoms of hyperparathyroidism durable on long-term follow-up?

Subjective symptoms such as decreased energy, chronic fatigue, and depression are associated with hyperparathyroidism. Studies have shown that these symptoms are improved during short-term follow-up after parathyroidectomy. This study evaluates the durability of this subjective improvement in quality-of-life symptoms in a large population of patients with follow-up greater than 1 year after operation. Between 2002 and 2005, 258 patients underwent parathyroidectomy, 100 (81 females and 19 males) of whom were available for this study. The patients were evaluated with a survey based on the Health Outcomes Institute Health Status Questionnaire. Some answers were quantified on a 1 to 6 scale, while others consisted of "yes" or "no" responses. Patients completed a questionnaire prior to parathyroidectomy and postoperatively at 1 month, 3 to 6 months, and 1 to 2 years or greater intervals. Statistical analysis was used to detect changes attributable to parathyroidectomy. A P value <.05 was considered statistically significant. At 1-month follow-up, patients' perceptions of their overall health, energy level, and mood significantly improved. At 6-month follow-up, significant improvements in muscle strength, health, endurance, and relief of anxiety were documented. At the interval of 1 to 2 years, overall health, energy level, endurance, and relief of anxiety were improved. There was no significant decrement in the quality of life in these patients after parathyroidectomy.

Parathyroidectomy for hyperparathyroidism is associated with significant lasting improvement in subjective symptoms. The potential durable improvement in these quality-of-life symptoms is a valid indication for parathyroidectomy.

Does upregulation of miR-497 induce hepatic insulin resistance in E3 rats with HFD-MetS by targeting insulin receptor?

The study aims to find regulatory microRNA(s) responsible for down-regulated insulin receptor (InsR) in the liver of HFD-MetS E3 rats with insulin resistance. Firstly, hepatic insulin resistance in HFD-MetS E3 rats was evaluated by RT-qPCR, western blotting, immunohistochemistry and PAS staining. Secondly, the candidate miRNAs targeting rat InsR were predicted through online softwares and detected in the liver of HFD-MetS E3 rats with insulin resistance. Then, the expression of InsR, phosphorylated IRS-1 (pIRS-1) at Tyr632, phosphorylated AKTs (pAKTs) at Ser473 and Thr308, phosphorylated GSK-3β (p GSK-3β) at Ser9, phosphorylated GS (pGS) at Ser641 and the glycogen content were detected in CBRH-7919 cells treated with 100 nM insulin for different time periods by western blotting or PAS staining respectively, after transient transfection with miR-497 mimics or inhibitors for 24 h. Lastly, the relation between miR-497 and InsR was further determined using dual luciferase reporter assay. Elevated miR-497 was negatively related with down-regulated InsR in the liver of HFD-MetS E3 rats with insulin resistance. Comparing with the mNC group, glycogen content and the expression of InsR, pIRS-1 (Tyr632), pAKTs (Ser473 and Thr308) and pGSK-3β (Ser9) decreased significantly in CBRH-7919 cells, while pGS (Ser641) increased significantly, after transient transfection with miR-497 mimics for 24 h and treatment with 100 nM insulin for corresponding time periods, counter to those results in CBRH-7919 cells after similar procedures with miR-497 inhibitors and insulin. In addition, dual luciferase reporter assay further confirmed that miR-497 can bind to the 3'UTR of rat InsR.

Insulin receptor is the target gene of miR-497, and elevated miR-497 might induce hepatic insulin resistance in HFD-MetS E3 Rats through inhibiting the expression of insulin receptor and confining the activation of IRS-1/PI3K/Akt/GSK-3β/GS pathway to insulin.

Does relationship of the time of storage and transfusion reactions to platelet concentrate from buffy coats?

Transfusion reactions to platelet concentrates prepared from buffy coats (BC-PCs) were reviewed to determine the effect of some variables of BC-PC preparation and storage: time of BC storage before BC-PC preparation (1-2 days); time of BC-PC storage before transfusion (1-5 days); no white cell reduction versus laboratory and bedside BC-PC white cell reduction. A multiple linear logistic regression model was used by which the relative effect of one variable is expressed as the relative risk of transfusion reaction against a baseline level (1-day storage, no white cell reduction). During the 14 months of study, a total of 2707 BC-PC transfusions were given to 192 patients; 37 reactions (1.4%) were reported in 25 patients (13%). The transfusion reactions were febrile, nonhemolytic in 23 cases; allergic in 5; febrile and allergic in 2; and other in 7. The relative risk of transfusion reaction to BC-PCs prepared from BCs stored for 2 days was 1.98 times that to BC-PCs prepared from BCs stored for 1 day (p = 0.07). The relative risk of transfusion reaction of 5-day-old BC-PCs was 10.7 times that of 1-day-old BC-PCs (p = 0.001). The relative risk of transfusion reactions of BC-PCs white cell-reduced in the laboratory and at the bedside were 0.65 (p = 0.3) and 1.87 (p = 0.1) times, respectively, that of non-white cell-reduced BC-PCs.

Time of storage seems to be an important variable associated with BC-PC transfusion reaction.

Should cell-free fetal DNA be included in first trimester screening (FTS) for common trisomy?

The primary aim was to determine the performance of the first trimester screening (FTS) test in a general obstetrics population. Cost-benefit analysis of a hypothetic model based on implementation of the FTS test by cell-free fetal (cff) DNA was calculated. A total of 6697 women were screened using FTS test. A two-step strategy based upon nuchal translucency, serum screening and ultrasound assessment of nasal bone (NB) was applied. Three groups were identified (high-risk:>1:250; intermediate-risk: 1:251-1:999 and low-risk group:<1:1000). Women at intermediate-risk (1:251-1:999) underwent NB assessment and recalculation of individual risk. All women at high-risk were offered fetal karyotyping. A total of 321 women (4.8%) resulted at high-risk while 480 women (7.1%) with intermediate-risk underwent assessment of the NB, which was absent in 15 fetuses. Overall, 54 aneuploidies were detected for a 96.4% sensitivity, a 96.1% specificity, a 99.9% negative predictive value and a false positive rate of 4.8%. Audit was conducted on a yearly basis and lost to follow up was 0.47% (32 cases).

Public health system would not be able to cover the cost of including cff DNA in women undergoing first trimester screening on universal basis. However, assuming a possible scenario based on implementation of FTS by cff DNA in women at high-risk would result in a 6-fold reduction in the number of invasive procedures while avoiding two false negative results (trisomy 21) that were diagnosed in women with intermediate-risk using current screening strategy by combined test.

Should children with non-Hodgkin lymphoma be treated with different protocols according to histopathologic subtype?

The New York protocol, primarily developed to treat children with high-risk acute lymphoblastic leukemia (ALL), is characterized by early intensive chemotherapy followed by less intensive pulse chemotherapy during maintenance. This study was performed to evaluate the efficacy of this protocol in children with non-Hodgkin lymphoma (NHL), irrespective of histopathologic subtype. From January 1996 to December 2011, 146 newly diagnosed children and adolescents with NHL were treated with the modified New York protocol. Treatment duration was determined according to the stage. The 5-year failure-free survival (FFS), event-free survival (EFS), and overall survival (OS) rates were 86.7 ± 2.9%, 79.1 ± 3.5%, and 84.7 ± 3.1%, respectively. The 5-year FFS for patients with mature B-cell lymphoma, T-cell and NK-cell lymphoma (T/NK-cell lymphoma), and lymphoblastic lymphoma were 95.4 ± 2.6%, 76.1 ± 7.0%, and 82.1 ± 6.6%, respectively. In multivariate analysis, T/NK-cell lymphoma and non-complete response (non-CR) at the end of induction chemotherapy were associated with a significant increase in treatment failure rate (relative risk [RR], 4.5, P = 0.03, and RR, 5.0, P = 0.002).

The protocol appears to be efficacious in the treatment of children and adolescents with NHL, irrespective of histopathologic subtype. Achievement of CR after intensive induction chemotherapy was an important prognostic factor. Early response to treatment may be used to stratify risk groups and modify therapy in children with NHL.

Does mHC class II expression on myeloid cells inversely correlate with disease progression in early rheumatoid arthritis?

To investigate whether MHC class II expression on myeloid cells of patients with treatment-naive early rheumatoid arthritis (RA) correlates with disease progression. Monocytes were isolated by negative selection from the peripheral blood of 15 patients with early RA (disease duration < or =12 months), differentiated to macrophages and analysed for MHC class II expression by flowcytometry. The phenotypical data were correlated with clinical disease progression for up to 45 months. Before treatment was initiated, in vitro differentiated macrophages of 10/15 early RA patients expressed MHC class II comparable with macrophages from healthy controls. In sharp contrast, macrophages of the remaining five patients expressed significantly fewer MHC class II molecules. In contrast to patients with normal levels of myeloid cell MHC class II expression, who developed a smouldering, non-progressive disease, patients with decreased expression of MHC class II on macrophages early in their disease developed a continuously active disease as demonstrated by persistently increased disease activity scores (chi(2) = 4.54, P < 0.02) and progressive bone destructions (chi(2) = 5.66, P < 0.02) despite aggressive therapy.

The level of myeloid cell MHC class II expression in recent onset RA allows a reliable distinction between patients who develop active and destructive RA and patients with a smouldering, slowly progressive disease.

Are synaptogenesis and outer segment formation perturbed in the neural retina of Crx mutant mice?

In Leber's congenital amaurosis (LCA), affected individuals are blind, or nearly so, from birth. This early onset suggests abnormal development of the neural retina. Mutations in genes that affect the development and/or function of photoreceptor cells have been found to be responsible in some families. These examples include mutations in the photoreceptor transcription factor, Crx. A Crx mutant strain of mice was created to serve as a model for LCA and to provide more insight into Crx's function. In this study, an ultrastructural analysis of the developing retina in Crx mutant mice was performed. Outer segment morphogenesis was found to be blocked at the elongation stage, leading to a failure in production of the phototransduction apparatus. Further, Crx-/- photoreceptors demonstrated severely abnormal synaptic endings in the outer plexiform layer.

This is the first report of a synaptogenesis defect in an animal model for LCA. These data confirm the essential role this gene plays in multiple aspects of photoreceptor development and extend our understanding of the basic pathology of LCA.

Does acute or subchronic clozapine treatment ameliorate prepulse inhibition ( PPI ) deficits in CPB-K mice with low levels of hippocampal NMDA receptor density?

The hypo-glutamatergic hypothesis of schizophrenia is based on clinical similarities between schizophrenia and phencyclidine (PCP)-induced psychosis in mentally healthy humans. Sensorimotor gating, as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR), is impaired in schizophrenic patients. In animals, noncompetitive N-methyl-D: -aspartate (NMDA) antagonists such as PCP disrupt PPI in a way that resembles the defect seen in schizophrenia. In a previous study with inbred mouse strains, low PPI levels have been demonstrated in CPB-K mice possessing low levels of hippocampal NMDA receptor densities. The present study was performed to test whether the low magnitude of PPI in CPB-K mice can be reversed by the atypical antipsychotic drug clozapine (CLZ). Before any treatment, CPB-K mice displayed a significant (p < 0.001) lower level in PPI and a significant (p < 0.001) higher ASR when compared to BALB/cJ mice known to have high hippocampal NMDA receptor densities. Acute and subchronic effects of a 2-week treatment with CLZ at daily doses of 5 and 10 mg/kg intraperitoneally, respectively, did not reveal any significant alteration of PPI levels in CPB-K mice. Nevertheless, the examination of motor behavior during nonstimulus trials provided a positive control for the drug's effectiveness.

In summary, (1) this study confirmed our working hypothesis: Lower levels of hippocampal glutamatergic receptor densities correspond to lower sensorimotor gating in CPB-K mice, and (2) acute or subchronic treatment with CLZ did not elevate low PPI levels in CPB-K mice. Thus, further experiments will concentrate on other antipsychotic drugs to prove the predictive validity of this animal model.

Does subarachnoid morphine reduce stimulation-induced but not basal expression of preproenkephalin in rat spinal cord?

To evaluate directly the possibility that the potent exogenous opioid analgesic morphine may alter neuronal expression of opioid peptide genes, we assessed the effect of subarachnoid morphine on basal and noxious stimulation-induced expression of preproenkephalin in spinal cord neurons. Twenty male Sprague-Dawley rats were prepared 48 h in advance with lumbar subarachnoid catheters. In the first phase, basal expression was evaluated in rats that received morphine 10 micrograms or saline intrathecally (n = 5 per group). Subsequently, the experiment was repeated (n = 5 per group), except that 10 min after morphine or saline administration rats received a hindpaw footpad injection of 50 microliters 5% formalin. Rats were killed during pentobarbital anesthesia 2 h later, and messenger RNA transcribed from preproenkephalin was measured in lumbar spinal cord with quantitative in situ hybridization with a complementary sulfur 35-labeled oligonucleotide probe and emulsion autoradiography. In control (nonstimulated) rats, 20% of the neurons in laminae I-II and 10% of those in laminae III-IV expressed preproenkephalin. Injection of formalin increased the fraction of positive neurons by 34% (P < 0.05) and 20% (P < 0.05) in laminae I-II and V-VI, respectively, but had no effect on expression in laminae III-IV. Subarachnoid morphine did not alter basal expression of preproenkephalin but markedly attenuated the noxious stimulation-induced increase in laminae I-II (P < 0.01) and V-VI (P < 0.05) by preventing the stimulation-evoked recruitment of preproenkephalin-expressing neurons that otherwise would have occurred.

Subarachnoid morphine does not acutely alter basal expression of preproenkephalin in spinal cord neurons but inhibits the increase in preproenkephalin expression that would otherwise occur after noxious stimulation.

Do patient-reported outcomes offer a more sensitive method for comparing the outcomes of consultants than mortality?

Patient-reported outcome measures (PROM) might be better for comparing consultant surgeons' outcomes than mortality. To describe variation in outcomes between consultants, compare the number of outlying consultants according to different measures, explore the effect that the hospital in which a consultant works has on their outcomes and determine the scope for improving outcomes by reducing variation between consultants. Consultants performing hip replacement (n=948), knee replacement (1130) and hernia repair (974) in National Health Service hospitals in England in 2009-2012; disease-specific and generic PROMs and complications; fixed-effects and multilevel models to assess consultant outcomes, were all compared. Influence of patient factors and hospital factors was assessed. Fixed-effects models showed that most consultants are 'as or better than expected'. However, unlike with mortality, some consultants are more than three SDs 'worse than expected' according to disease-specific PROMs (2.4% for hip and 1.2% for knee replacement), generic PROMs (1.2% and 1.0%) and incidence of complications (1.8% and 0.8%). The proportion of consultants worse than expected is less with random-effects models. Controlling for hospital factors reduced the proportion further. After controlling for known patient characteristics, consultants and hospitals contribute little towards variation in patient outcomes.

PROMs offer a more appropriate and sensitive method for comparing consultants' outcomes. The influence of hospitals must be considered to ensure comparisons are meaningful. Improvements will be achieved by shifting the distribution of consultants rather than by reducing variation between them.

Is elevation of preoperative serum C-reactive protein level related to poor prognosis in esophageal squamous cell carcinoma?

An increased serum C-reactive protein (CRP) level was found in patients with various malignant tumors and was associated with poor prognosis. The aim of this study was to analyze the clinicopathological significance and the prognostic value of preoperative CRP levels in patients with esophageal squamous cell carcinomas. The preoperative CRP level was measured by enzyme-linked immunosorbent assay (ELISA) in 150 patients with primary esophageal squamous cell carcinomas. All patients underwent radical surgery without any preoperative therapy. The patients were divided into two groups using a cut-off value of 1.0 mg/dl. The pathological classifications of the tumor were examined according to the TNM/UICC classification. The associations between the clinicopathological factors and CRP level were determined. The prognostic value of CRP was determined using Cox's proportional hazards model. Thirty-five patients (23%) showed high CRP levels (more than 1.0 mg/dl). Statistically significant differences in CRP levels were observed depending on tumor depth (P = 0.022) and TNM/UICC stage (P = 0.001). A high CRP level was associated with poor survival (P = 0.005) and was confirmed by multivariate analysis.

A high CRP level is associated with tumor progression and poor survival in patients with esophageal squamous cell carcinoma.

Is nitric oxide produced by cytokine-activated pulmonary artery smooth muscle cells cytotoxic to cocultured endothelium?

We recently demonstrated that rat pulmonary artery smooth muscle (RPASM) generates maximal nitric oxide (NO) when exposed to inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. Our hypothesis is that NO produced by cytokine-stimulated RPASM has local cytotoxic effects on endothelium. Accordingly, we designed a pulmonary smooth muscle and endothelial coculture experiment in which the effects of NO on endothelium can be distinguished from the direct effects of cytokines. RPASM cells were incubated with a mixture of TNF-alpha (500 units/ml) and IFN-gamma (100 units/ml) for 24 hours. This cytokine mixture was then removed and the NO-producing smooth muscle cells were incubated in a coculture transwell system with rat pulmonary artery endothelial (RPAE) cells. Subsequent NO production (as measured by nitrite concentration in cell supernatants), and the number of viable attached endothelial cells were then measured at 48 hours. RPASM continued to produce large amounts of NO, in the absence of further cytokine stimulation, after a 24-hour exposure to TNF-alpha and IFN-gamma. This RPASM-generated NO decreased the number of viable attached endothelial cells after 24 hour RPASM-RPAE coculture by 57%. The competitive stereospecific inhibitor of inducible NO synthase (iNOS), NG-monomethyl-L-arginine (NMA), returned the inducible NO production to basal levels and reversed the cytotoxic effects on endothelial cells. The number of viable attached endothelial cells returned to control levels.

The NO produced by cytokine-activated RPASM has local cytotoxic effects on RPAE in coculture. Such NO produced in the vasculature may be a factor in the origin of acute lung injury under conditions of trauma and sepsis.

Does immobilization after radiofrequency-induced shrinkage influence the biomechanical properties of collagenous tissue?

Despite widespread use of radiofrequency-induced shrinkage of collagenous tissue, there have been no animal studies on the effects of postoperative immobilization on the biomechanical behavior of shrunken tissue. To examine the role of postoperative immobilization after radiofrequency-induced shrinkage, with special emphasis on the biomechanical properties of shrunken collagenous tissue. Controlled laboratory study. One patellar tendon of 66 New Zealand White rabbits was shrunk. Six rabbits were sacrificed immediately after surgery. Twenty rabbits were not immobilized, twenty were immobilized for 3 weeks, and twenty were immobilized for 6 weeks. The biomechanical parameters failure strength, stiffness, and relaxation were tested. Nine weeks after surgery, biomechanical parameters were still low compared to control tendons. Shrunken tendons did not reach levels of normal tissue at any time after surgery, regardless of whether the animals had been immobilized. According to time-related development, all biomechanical parameters had the lowest levels 3 weeks after surgery. Immobilized tendons demonstrated a better and faster recovery than nonimmobilized tendons compared to the immediate postoperative level.

Postoperative immobilization supports recovery of biomechanical properties after shrinkage. Despite immobilization, biomechanical properties of shrunken tissue did not completely reach levels of normal tissue.

Does structure of GlgS from Escherichia coli suggest a role in protein-protein interactions?

The Escherichia coli protein GlgS is up-regulated in response to starvation stress and its overexpression was shown to stimulate glycogen synthesis. We solved the structure of GlgS from E. coli, a member of an enterobacterial protein family. The protein structure represents a bundle of three alpha-helices with a short hydrophobic helix sandwiched between two long amphipathic helices.

GlgS shows structural homology to Huntingtin, elongation factor 3, protein phosphatase 2A, TOR1 motif domains and tetratricopeptide repeats, suggesting a possible role in protein-protein interactions.

Are nonsustained ventricular tachycardias predictive of major arrhythmias in patients with dilated cardiomyopathy on optimal medical treatment?

To evaluate the role of nonsustained ventricular tachycardias (NSVT) for the prediction of major ventricular arrhythmias (MVA) in patients with idiopathic dilated cardiomyopathy (DCM) after optimization of medical treatment. Three hundred nineteen consecutive DCM patients were evaluated after adequate stabilization on optimal angiotensin-converting enzyme (ACE) inhibitor (88%) and beta-blocker (82%) therapy. Frequency, length, and rate of NSVT at 24-hour Holter monitoring were analyzed to assess their values in predicting MVA (unexpected sudden death, SVT, ventricular fibrillation, and appropriate implantable cardioverter defibrillator interventions). During follow-up (median 96 months, 1(st)-3(rd) interquartile range 52-130), MVA incidence was low, and not statistically different between patients with and without NSVT (3 and 2 per 100 patient-years, respectively, P = nonsignificant [NS]at log-rank analysis). At multivariable analysis, the number of NSVT was predictive of MVA only if left ventricular ejection fraction (LVEF) was>0.35 (two NSVT/day vs no NSVT/day: hazard ratio [HR] 5.3, 95% confidence interval [CI]1.59-17.85 in LVEF>0.35 vs HR 0.93, 95% CI 0.3-2.81 in LVEF<or = 0.35). Consequently, in patients with LVEF<or = 0.35, MVA incidence rates were similar regardless of NSVT (3.6 and 4.1 patient-years, respectively, in those with and without NSVT, P = NS), while in patients with LVEF>0.35, MVA incidence (3.1 per 100 patient-years vs 0.9 per 100 patient-years, P = 0.003) was significantly higher when NSVT were present.

After medical stabilization, NSVT did not increase the risk of MVA in patients with DCM and LVEF<or = 0.35. Conversely, the number and length of NSVT runs were significantly related to the occurrence of MVA in the patients with LVEF>0.35.

Does the persistent release of HMGB1 contribute to tactile hyperalgesia in a rodent model of neuropathic pain?

High-mobility group box-1 protein (HMGB1) is a nuclear protein that regulates gene expression throughout the body. It can also become cytoplasmic and function as a neuromodulatory cytokine after tissue damage or injury. The manner in which HMGB1 influences the peripheral nervous system following nerve injury is unclear. The present study investigated the degree to which HMGB1 signaling contributes to the maintenance of neuropathic pain behavior in the rodent. Redistribution of HMGB1 from the nucleus to the cytoplasm occurred in both sensory neurons derived from a tibial nerve injured (TNI) rat and in a sensory neuron-like cell line following exposure to a depolarizing stimulus. We also observe that exogenous administration of HMGB1 to acutely dissociated sensory neurons derived from naïve or TNI rodents elicit increased excitability. Furthermore systemic injection of glycyrrhizin (50 mg/kg; i.p.), a known inhibitor of HMGB1, reversed TNI-induced mechanical hyperalgesia at fourteen days and three months following nerve injury.

We have identified that a persistent endogenous release of HMGB1 by sensory neurons may be a potent, physiologically relevant modulator of neuronal excitability. More importantly, the use of the anti-inflammatory compound and known inhibitor of HMGB1, glycyrrhizin, has the ability to diminish persistent pain behavior in a model of peripheral neuropathy, presumably through its ability to neutralize the cyotkine. The identification of HMGB1 as a potential therapeutic target may contribute to a better understanding of mechanisms associated with chronic pain syndromes.

Is postural orthostatic tachycardia syndrome an under-recognized condition in chronic fatigue syndrome?

It has been suggested that postural orthostatic tachycardia syndrome (POTS) be considered in the differential diagnosis of those with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Currently, measurement of haemodynamic response to standing is not recommended in the UK NICE CFS/ME guidelines. To determine prevalence of POTS in patients with CFS/ME. Observational cohort study. Fifty-nine patients with CFS/ME (Fukuda criteria) and 52 age- and sex-matched controls underwent formal autonomic assessment in the cardiovascular laboratory with continuous heart rate and beat-to-beat blood pressure measurement (Task Force, CNSystems, Graz Austria). Haemodynamic responses to standing over 2 min were measured. POTS was defined as symptoms of orthostatic intolerance associated with an increase in heart rate from the supine to upright position of >30 beats per minute or to a heart rate of >120 beats per minute on standing. Maximum heart rate on standing was significantly higher in the CFS/ME group compared with controls (106 +/- 20 vs. 98 +/- 13; P = 0.02). Of the CFS/ME group, 27% (16/59) had POTS compared with 9% (5) in the control population (P = 0.006). This difference was predominantly related to the increased proportion of those in the CFS/ME group whose heart rate increased to >120 beats per minute on standing (P = 0.0002). Increasing fatigue was associated with increase in heart rate (P = 0.04; r(2) = 0.1).

POTS is a frequent finding in patients with CFS/ME. We suggest that clinical evaluation of patients with CFS/ME should include response to standing. Studies are needed to determine the optimum intervention strategy to manage POTS in those with CFS/ME.

Do thrombocytopenia and thrombocytosis at time of hospitalization predict mortality in patients with community-acquired pneumonia?

Platelets are inflammatory cells with an important role in antimicrobial host defenses. We speculate that an abnormal platelet count may be a marker of severity in patients with community-acquired pneumonia (CAP). The objectives of this study were to evaluate if abnormal platelet count in hospitalized patients with CAP was associated with 30-day mortality and to compare platelet count and leukocyte count as predictors of 30-day mortality. We performed a retrospective cohort study of 500 consecutive patients hospitalized with CAP at the Veterans Hospital of Louisville, Kentucky, between June 2001 and March 2006 to investigate the association of platelet count and leukocyte count with 30-day mortality. Predictor variables were platelet count and leukocyte count. Abnormal platelet count was < 100,000/L (thrombocytopenia) and > 400,000/L (thrombocytosis). The outcome variable was 30-day mortality. To control for potential confounding, a propensity score that incorporated 33 variables was used. Platelet count was strongly associated (P = .0009) with 30-day mortality, whereas no association was observed for leukocyte count (P = .5114). High platelet counts resulted in a significantly increased risk of mortality.

Thrombocytopenia and thrombocytosis are associated with mortality in patients hospitalized with CAP. When evaluating an initial CBC test in patients with CAP, an abnormal platelet count is a better predictor of outcome than an abnormal leukocyte count.

Is cONSTANS a photoperiod regulated activator of flowering in sorghum?

Sorghum genotypes used for grain production in temperate regions are photoperiod insensitive and flower early avoiding adverse environments during the reproductive phase. In contrast, energy sorghum hybrids are highly photoperiod sensitive with extended vegetative phases in long days, resulting in enhanced biomass accumulation. SbPRR37 and SbGHD7 contribute to photoperiod sensitivity in sorghum by repressing expression of SbEHD1 and FT-like genes, thereby delaying flowering in long days with minimal influence in short days (PNAS_108:16469-16474, 2011; Plant Genome_in press, 2014). The GIGANTEA (GI)-CONSTANS (CO)-FLOWERING LOCUS T (FT) pathway regulates flowering time in Arabidopsis and the grasses (J Exp Bot_62:2453-2463, 2011). In long day flowering plants, such as Arabidopsis and barley, CONSTANS activates FT expression and flowering in long days. In rice, a short day flowering plant, Hd1, the ortholog of CONSTANS, activates flowering in short days and represses flowering in long days. Quantitative trait loci (QTL) that modify flowering time in sorghum were identified by screening Recombinant Inbred Lines (RILs) derived from BTx642 and Tx7000 in long days, short days, and under field conditions. Analysis of the flowering time QTL on SBI-10 revealed that BTx642 encodes a recessive CONSTANS allele containing a His106Tyr substitution in B-box 2 known to inactivate CONSTANS in Arabidopsis thaliana. Genetic analysis characterized sorghum CONSTANS as a floral activator that promotes flowering by inducing the expression of EARLY HEADING DATE 1 (SbEHD1) and sorghum orthologs of the maize FT genes ZCN8 (SbCN8) and ZCN12 (SbCN12). The floral repressor PSEUDORESPONSE REGULATOR PROTEIN 37 (PRR37) inhibits sorghum CONSTANS activity and flowering in long days.

Sorghum CONSTANS is an activator of flowering that is repressed post-transcriptionally in long days by the floral inhibitor PRR37, contributing to photoperiod sensitive flowering in Sorghum bicolor, a short day plant.

Doctors' responses to patients with medically unexplained symptoms who seek emotional support: criticism or confrontation?

Consultations about medically unexplained symptoms (MUSs) can resemble contests over the legitimacy of patients' demands. To understand doctors' motivations for speech appearing to be critical of patients with MUSs, we tested predictions that its frequency would be related to patients' demands for emotional support and doctors' patient-centered attitudes as well as adult attachment style. Twenty-four general practitioners identified 249 consecutive patients presenting with MUSs and indicated their own patient-centered attitudes as well as adult attachment style (positive models of self and others). Before consultation, patients self-reported their desire for emotional support. Consultations were audio recorded and coded utterance by utterance. The number of utterances coded as criticism was the response variable in the multilevel regression analyses. Frequency of criticism was positively related to patients' demands for emotional support, to doctors' belief in sharing responsibility with patients and to doctors' positive model of themselves. It was inversely associated with doctors' belief that patients' feelings were legitimate business for consultation and was unrelated to their model of others.

From the perspective of doctors, speech that appears to be critical probably reflects therapeutic intent and might therefore be better described as "confrontation." Understanding doctors' motivations for what they say to patients with MUSs will allow for more effective interventions to improve the quality of consultations.

Is 21-Hydroxylase-deficient nonclassic adrenal hyperplasia a progressive disorder : a multicenter study?

Our aim was to determine whether the clinical features of 21-hydroxylase-deficient nonclassic adrenal hyperplasia are correlated with either age at symptom onset or age at presentation, or both, and with the degree of adrenocortical abnormality. In a multicenter cohort design 220 women with nonclassic adrenal hyperplasia, with a basal or adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone level >30.3 nmol/L, were studied, either prospectively (n = 39) or retrospectively (n = 181). Patients were stratified by age of presentation into 5 groups: (1) <10 years (n = 25), (2) 10 to 19 years (n = 64), (3) 20 to 29 years (n = 83), (4) 30 to 39 years (n = 30), and (5) 40 to 49 years (n = 16). Two patients >50 years old were excluded from the analysis because of age. Ninety-two percent of patients <10 years old had premature pubarche at presentation, whereas clitoromegaly and acne were each present in only 20% of these younger subjects. With only patients > or =10 years old considered, presenting clinical features included hirsutism (59%), oligomenorrhea (54%), acne (33%), infertility (13%), clitoromegaly (10%), alopecia (8%), primary amenorrhea (4%), and premature pubarche (4%). Among the patients >/=10 years old, the prevalence but not the degree of hirsutism increased significantly with age. Basal levels of 17-hydroxyprogesterone in adolescents were significantly higher than the levels found either in children (<10 years old) or women 40 to 49 years old (P <.01 and P <.03, respectively), although no difference was noted in the stimulated 17-hydroxyprogesterone levels between age groups. The adrenocorticotropic hormone-stimulated levels but not the basal levels of 17-hydroxyprogesterone were significantly higher in patients with clitoromegaly than in women without clitoromegaly. Alternatively, there were no differences in either basal or stimulated 17-hydroxyprogesterone levels between patients with and those without hirsutism, acne, or alopecia.

In children <10 years old the most common presenting complaint was premature pubarche, whereas hirsutism and oligomenorrhea were more common in older patients. The prevalence of hirsutism increased with age, suggesting the progressive nature of nonclassic adrenal hyperplasia. Furthermore, the adrenocorticotropic hormone-stimulated levels of 17-hydroxyprogesterone were higher in patients with clitoromegaly, which suggests that the degree of adrenocortical dysfunction in nonclassic adrenal hyperplasia determines, at least in part, the clinical presentation.

Does delaying surgery after neoadjuvant chemoradiotherapy significantly influence postoperative morbidity or oncological outcome in patients with oesophageal adenocarcinoma?

Patients with resectable oesophageal cancer are treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery within 3-8 weeks. In practice, surgery is often delayed for various reasons. The aim of this study was to evaluate whether delaying surgery beyond 8 weeks has an effect on postoperative morbidity, long-term survival, and pathologic response in patients treated for oesophageal ADC. Patients who underwent nCRT followed by surgery, for cT1-3, N0-3, M0 ADC between 2001 and 2014 were retrospectively included from a prospectively obtained database. Patients with a time from the end of nCRT to surgery (TTS) ≤8 weeks were compared with patients with a TTS >8 weeks. Of 190 patients, 65 had a TTS ≤8 weeks, and 125 had a TTS >8 weeks. Patient characteristics were comparable for both groups, but patients with TTS >8 weeks exhibited higher ASA scores (p = 0.013) and more comorbidities (p = 0.007). Multivariate analysis revealed that TTS did not significantly influence postoperative morbidity, pathologic complete response rates, and five-year survival rates (42% in patients with TTS ≤8 weeks and 37% in patients with TTS >8 weeks).

Delaying surgery beyond 8 weeks after nCRT did not significantly influence postoperative morbidity, pathologic response, and survival in patients with non-metastatic ADC. Therefore, it appears reasonable to postpone surgery beyond 8 weeks in patients who have not yet recovered from nCRT. However, if the patient is fit for surgery, postponing surgery does not have any additional advantages.

Does endogenous renovascular hypertension combined with low shear stress induce plaque rupture in apolipoprotein E-deficient mice?

The development of a murine model of spontaneous atherosclerotic plaque rupture with luminal thrombus. Combined partial ligation of the left renal artery and left common carotid artery in 8-week-old apolipoprotein E-deficient mice induced endogenous renovascular hypertension and local low oscillatory shear stress in the left common carotid artery. After 8 weeks, a fresh left common carotid artery lumen thrombus associated with severe plaque burden was found in 50% (10/20) of the mice. Histological analyses indicated that all left common carotid artery lesions had vulnerable features, and 50% (5/10) of the mice showed plaque rupture with a lumen thrombus. Multiple layers with layering discontinuity and intraplaque hemorrhages were found in 80% (8/10) of the mice. Further experiments showed that both increased blood pressure, and angiotensin-II contributed to plaque progression and vulnerability. Decreased intimal collagen associated with increased collagenase activity and matrix metalloproteinase expression also resulted in plaque disruption.

We demonstrate a murine model of spontaneous plaque rupture with a high incidence of luminal thrombus. The model not only nicely recapitulates the pathophysiological processes of human plaque rupture but it is also simple, fast, and highly efficient to generate.

Placement of the peritoneal end of a ventriculoperitoneal shunt in the suprahepatic space: does it improve prognosis?

Hydrocephalus is a common pediatric problem. Ventriculoperitoneal shunts (VPS) are the most frequent operative procedures used to treat hydrocephalic children. The peritoneal end is usually placed in the general peritoneal cavity. We present an alternative site of peritoneal end placement in the suprahepatic space in an attempt to reduce the abdominal complications. All patients with a diagnosis of congenital hydrocephalus were included in the study. In group 1, the lower end of the VPS was placed in the suprahepatic space. Patients were evaluated for abdominal complications like pseudocyst formation, intestinal obstruction and blockage of the lower end of the VPS. The data were compared with those patients in whom the peritoneal end was placed in the general peritoneal cavity (group 2). The total number of patients in groups 1 and 2 was 133 and 175, respectively. Complications in group 1 were dislodgement of the shunt in the general peritoneal cavity in 28 (21.05%), suprahepatic pseudocyst formation in 2 (1.5%) and blocked lower end in 2 patients (1.5%). In group 2, complications noted were pseudocyst formation in 5 (2.8%), blocked lower end in 25 (14.2%), intestinal obstruction in 9 (5.1%), inguinoscrotal migration in 10 (5.7%) and perforation of viscera in 6 patients (3.4%). The overall follow-up period ranged from 1 to 7 years.

Placement of the lower end of the shunt in the suprahepatic space can be advantageous to placing it in the general peritoneal cavity. The procedure is simple and results can be rewarding.

Is treatment for alcohol use disorder associated with reductions in criminal offending?

This is the first English national study of change in criminal offending following treatment for alcohol use disorder (AUD). All adults treated for AUD by all publicly funded treatment services during April 2008-March 2009 (n=53,017), with data linked to the Police National Computer (April 2006-November 2011). Pre-treatment offender sub-populations were identified by Latent Profile Analysis. The outcome measure was the count of recordable criminal offences during two-year follow-up after admission. A mixed-effects, Poisson regression modelled outcome, adjusting for demographics and clinical information, the latent classes, and treatment exposure covariates. Twenty-two percent of the cohort committed one or more offences in the two years pre-treatment (n=11,742; crude rate, 221.5 offenders per 1000). During follow-up, the number of offenders and offences fell by 23.5% and 24.0%, respectively (crude rate, 69.4 offenders per 1000). During follow-up, a lower number of offences was associated with: completing treatment (adjusted incident rate ratio [IRR] 0.82; 95% confidence interval [CI]0.79-0.85); receiving inpatient detoxification (IRR 0.84; CI 0.80-0.89); or community pharmacological therapy (IRR 0.89; CI 0.84-0.96). Reconviction was reduced in the sub-population characterised by driving offences (n=1,140; 11.7%), but was relatively high amongst acquisitive (n=768; 58.3% reconvicted) and violent offending sub-populations (n=602; 77.6% reconvicted).

Reduced offending was associated with successful completion of AUD treatment and receiving inpatient and pharmacological therapy, but not enrolment in psychological and residential interventions. Treatment services (particularly those providing psychological therapy and residential care) should be alert to offending, especially violent and acquisitive crime, and enhance crime reduction interventions.

Do [ Superoxide anion inhibit endothelium-dependent relaxation in rat mesenteric artery ]?

To explore the resistant arterial effect of superoxide anion and its possible mechanisms. The third branch of the superior mesenteric artery in male Sprague-Dawley (200-300 g) rats was rapidly excised. Periadventitial fats and connective tissues were removed and the artery was dissected into about 2 mm rings. Each ring was dispensed between two stainless steel wires (diameter 0.0394 mm) in a 5 ml organ bath (DMT 610 M, Danish Myo Technology, Denmark). Isometric force recording studies in vitro of rat mesenteric arterial rings were recorded by Powerlab Syetem. Exposure of arteries to superoxide was accomplished through the auto-oxidation of pyrogallol added to the artery baths. Then endothelium-dependent or independent relaxation was investigated, respectively. Exposure to pyrogallol (10, 100, 300, and 1 000 micromol/L) which could produce superoxide anion for 15 min resulted in a dose-dependent manner in a decrease of acetylcholine(ACh)-induced relaxation in rat mesenteric artery. Especially, the two predominant components of acetylcholine(ACh)-induced endothelium-dependent relaxation, EDHF component and NO component were both inhibited by superoxide anion from pyrogallol. However, exposure to superoxide anion from pyrogallol had no effect on the endothelium-independent relaxations to pinacidil or sodium nitroprusside (SNP) in rat mesenteric artery.

These results indicate that superoxide anion can inhibit the endothelium-dependent relaxation in rat mesenteric artery, but has no effect on the endothelium-independent relaxation, in which the inhibited effect of EDHF and NO from endothelium is involved.

Does hepatocyte-targeted expression by integrase-defective lentiviral vectors induce antigen-specific tolerance in mice with low genotoxic risk?

Lentiviral vectors are attractive tools for liver-directed gene therapy because of their capacity for stable gene expression and the lack of preexisting immunity in most human subjects. However, the use of integrating vectors may raise some concerns about the potential risk of insertional mutagenesis. Here we investigated liver gene transfer by integrase-defective lentiviral vectors (IDLVs) containing an inactivating mutation in the integrase (D64V). Hepatocyte-targeted expression using IDLVs resulted in the sustained and robust induction of immune tolerance to both intracellular and secreted proteins, despite the reduced transgene expression levels in comparison with their integrase-competent vector counterparts. IDLV-mediated and hepatocyte-targeted coagulation factor IX (FIX) expression prevented the induction of neutralizing antibodies to FIX even after antigen rechallenge in hemophilia B mice and accounted for relatively prolonged therapeutic FIX expression levels. Upon the delivery of intracellular model antigens, hepatocyte-targeted IDLVs induced transgene-specific regulatory T cells that contributed to the observed immune tolerance. Deep sequencing of IDLV-transduced livers showed only rare genomic integrations that had no preference for gene coding regions and occurred mostly by a mechanism inconsistent with residual integrase activity.

IDLVs provide an attractive platform for the tolerogenic expression of intracellular or secreted proteins in the liver with a substantially reduced risk of insertional mutagenesis.

Is a small suberythemal ultraviolet B dose every second week sufficient to maintain summer vitamin D levels : a randomized controlled trial?

It is known that ultraviolet (UV) B radiation increases serum 25-hydroxyvitamin D(3) [25(OH)D] level. However, there is uncertainty about the relationship between the maintenance of vitamin D status and UVB. To define the frequency of UVB exposure necessary for maintaining summer 25(OH)D levels during the winter. In total, 60 participants were included from October 2008 to February 2009 (16weeks) and randomized for UVB exposure of 1 standard erythema dose (SED) to ∼88% body area once a week (n=15 completed), every second week (n=14 completed) or every fourth week (n=12 completed). The controls (n=14 completed) had no intervention. Vitamin D was measured at baseline, every fourth week before exposure, and 2days after the last UVB exposure. The 25(OH)D levels (mean) after UVB exposure once a week increased significantly (from 71·9 to 84·5nmolL(-1) ) (P<0·0001), whereas UVB exposure every second week maintained 25(OH)D levels (P=0·16). A significant decrease in mean 25(OH)D levels (from 56·4 to 47·8nmolL(-1) ) (P<0·0001) was found after UVB exposure once every fourth week and for the control group (from 64·8 to 40·1nmolL(-1) ) (P<0·0001). The development in 25(OH)D levels during the 16-week study period were negatively correlated with baseline 25(OH)D (P<0·0001). Further, the increase in 25(OH)D after the last UVB exposure was negatively correlated with the 25(OH)D level just before the last UVB exposure (P<0·0001).

Exposure to a UVB dose of 1 SED every second week to ∼88% body area is sufficient for maintaining summer 25(OH)D levels during the winter.

Does heart rate on admission independently predict in-hospital mortality in acute ischemic stroke patients?

Higher heart rate (HR) is associated with worse outcomes - in particular death - in long term follow-up of patients with vascular diseases. We investigated the association between HR measured on admission and early in-hospital mortality in acute ischemic stroke patients. Over a period of 30 months all patients admitted to our hospital with acute ischemic stroke but without atrial fibrillation were prospectively enrolled. Univariate and multiple logistic regression analyses were conducted to estimate the impact of HR on in-hospital mortality. HR was analyzed as continuous and categorical variable (tertiles). A total of 1335 patients (median age 73 (IQR 65-81), median National Institutes of Health Stroke Scale score 4 (IQR 2-8), median length of stay 5 days (IQR 4-7), female sex 46%) were studied. In-hospital mortality was 2.6%. When analyzed as categorical variable, HR ≥ 83 bpm was independently associated with in-hospital mortality after adjustment for predictors of poor outcome compared to the reference tertile (HR ≤ 69 bpm) (adjusted odds ratio 4.42, 95% CI 1.36-14.42, p=0.01). When HR was modeled as continuous variable, relative risk for in-hospital death was elevated by 40% for every additional 10-bpm (p=0.003). These results were not changed by including beta-blockers as covariate into the multiple regression model.

HR on admission is independently associated with in-hospital mortality in acute ischemic stroke patients suggesting early negative effects of autonomic imbalance. HR may represent a therapeutic target to improve outcome after ischemic stroke.

Does sPLA2-IIa amplify ocular surface inflammation in the experimental dry eye ( DE ) BALB/c mouse model?

sPLA2-IIa is a biomarker for many inflammatory diseases in humans and is found at high levels in human tears. However, its role in ocular surface inflammation remains unclear. An experimentally induced BALB/c mouse dry eye (DE) model was used to elucidate the role of sPLA2-IIa in ocular surface inflammation. BALB/c mice were subcutaneously injected with scopolamine and placed in a daytime air-drying device for 5 to 10 days. Control mice received no treatment. DE status was evaluated with tear production with a phenol-red thread method. Tear inflammatory cytokines were quantified by multiplex immunoassays. Ocular surface inflammation and sPLA2-IIa expression were examined by immune-staining and quantitative (q)RT(2)-PCR. Conjunctiva (CNJ) of the mice was cultured for prostaglandin E2 production induced by sPLA2-IIa with various amount of sPLA2-IIa inhibitor, S-3319. Treated mice produced fewer tears and heavier corneal (CN) fluorescein staining than the untreated controls (P < 0.001). They also revealed lower goblet cell density (P < 0.001) with greater inflammatory cell infiltration within the conjunctiva, and higher concentration of tear inflammatory cytokines than the controls. Moreover, treated mice showed heavier sPLA2-IIa immune staining than the controls in the CNJ epithelium, but not in the CN epithelium or the lacrimal gland. Treated mice exhibited upregulated sPLA2-IIa and cytokine gene transcription. Furthermore, CNJ cultures treated with sPLA2-IIa inhibitor showed significantly reduced sPLA2-IIa-induced inflammation.

This is the first report regarding sPLA2-IIa in the regulation of ocular surface inflammation. The findings may therefore lead to new therapeutic strategies for ocular surface inflammation, such as DE disease.

Does adult-age inflammatory pain experience enhance long-term pain vigilance in rats?

Previous animal studies have illustrated a modulatory effect of neonatal pain experience on subsequent pain-related behaviors. However, the relationship between chronic pain status in adulthood and future pain perception remains unclear. In the current study, we investigated the effects of inflammatory pain experience on subsequent formalin-evoked pain behaviors and fear conditioning induced by noxious stimulation in adult rats. Our results demonstrated an increase of the second but not the first phase of formalin-induced pain behaviors in animals with a history of inflammatory pain that have recovered. Similarly, rats with persistent pain experience displayed facilitated acquisition and prolonged retention of pain-related conditioning. These effects of prior pain experience on subsequent behavior were prevented by repeated morphine administration at an early stage of inflammatory pain.

These results suggest that chronic pain diseases, if not properly and promptly treated, may have a long-lasting impact on processing and perception of environmental threats. This may increase the susceptibility of patients to subsequent pain-related disorders, even when chronic pain develops in adulthood. These data highlight the importance of treatment of chronic pain at an early stage.

Does oil coating affect internal quality and sensory acceptance of selected attributes of raw eggs during storage?

Four (coconut, palm, rice bran, and soybean) edible oils and glycerol were applied on eggshell. All noncoated and coated eggs were stored for 5 wk at 25 ± 2 °C and drawn weekly for quality evaluation. All oil coatings were more effective in preserving internal quality of eggs than was glycerol coating. As storage time increased, the preservative effects of edible oil coating on weight loss, and albumen and yolk quality were significantly noticed. Oil-coated eggs had significantly lower weight loss (<0.43%) than did noncoated (3.87%) and glycerol-coated (3.73%) eggs after 5 wk of storage. Based on the Haugh unit, oil-coated eggs maintained AA grade up to 3 wk. After 5 wk of storage, noncoated, glycerol-coated, and oil-coated eggs changed from AA grade to below B, below B and A grade, respectively. The albumen pH of noncoated and glycerol-coated eggs considerably increased from 8.23 to 9.51 and 9.42, respectively, while those of oil-coated eggs either maintained or slightly increased to 8.32. The albumen viscosity of all eggs decreased with increased storage time. Consumers (N = 120) could differentiate surface glossiness of oil-coated eggs from uncoated eggs (R-index of 81.42% to 86.99%). All oil-coated eggs were acceptable for surface glossiness (liking scores of 6.22 to 6.77) and surface odor (liking scores of 6.20 to 6.55) with overall liking scores of 6.34 to 7.03. Overall, this study demonstrated that edible oil (coconut, palm, rice bran, and soybean) coating could preserve internal quality of eggs (maintaining grade A) at least 4 wk longer than noncoated eggs.

 Freshness is a major contribution to the egg quality. The internal quality of eggs begins to deteriorate after they have been laid due to loss of moisture and carbon dioxide via the eggshell pores. Refrigeration is very effective in preserving egg quality. Surface coating is an alternative method to preserve egg quality, although it is much less effective than refrigeration. This study demonstrated that coconut, rice bran, soybean, and palm oils, which are abundant and commonly consumed in many parts of the world, could preserve the internal quality and reduce weight loss of oil-coated eggs during room temperature storage.

Are plantar fasciitis and calcaneal spur formation associated with abductor digiti minimi atrophy on MRI of the foot?

To determine the association of atrophy of the abductor digiti minimi muscle (ADMA), an MRI manifestation of chronic compression of the inferior calcaneal nerve suggesting the clinical diagnosis of Baxter's neuropathy, with MRI markers of potential etiologies, including calcaneal spur formation, plantar fasciitis, calcaneal edema, Achilles tendinosis and posterior tibial tendon dysfunction (PTTD). Prevalence of calcaneal spur formation, plantar fasciitis, calcaneal edema, Achilles tendinosis and PTTD was assessed retrospectively on 100 MRI studies with ADMA and 100 MRI studies without ADMA. Patients ranged in age from 10-92 years. Pearson chi-square analyses and Fisher's exact test were used to compare prevalence of the above findings in patients with and without ADMA. Logistic regression was used to determine which variables were significantly associated with ADMA. Among patients with ADMA, there was significantly greater age (57.2 years vs 40.8 years, p<0.001), presence of Achilles tendinosis (22.0% vs 3.0%, P<0.001), calcaneal edema (15.0% vs 3.0%, P=0.005), calcaneal spur (48.0% vs 7.0%, P<0.001), plantar fasciitis (52.5% vs 11.0%, P<0.001), and PTTD (32.0% vs 11.0%, P<0.001). After multivariate logistic regression analysis, only age [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.03, 1.09], calcaneal spur (OR 3.60, 95% CI 1.28, 10.17), and plantar fasciitis (OR 3.35, 95% CI 1.31, 8.56) remained significant.

Advancing age, calcaneal spur, and plantar fasciitis are significantly associated with ADMA. Their high odds ratios support the notion of a possible etiologic role for calcaneal spur and plantar fasciitis in the progression to Baxter's neuropathy.

To Cast, to Saw, and Not to Injure: Can Safety Strips Decrease Cast Saw Injuries?

Placement and removal of fiberglass casts are among the more-common interventions performed in pediatric orthopaedic surgery offices. However, cast removal is associated with abrasive injuries and burns from the oscillating cast saw, and these injuries can occur even when the cast is removed by experienced personnel. It is unknown whether an added barrier, such as a safety strip, can mitigate injuries from blade-to-skin contact during cast removal with the oscillating saw.QUESTIONS/ We asked: (1) Can a safety strip provide a physical barrier during cast removal, decreasing blade-to-skin contact? (2) Does the safety strip lessen heat transfer? (3) Will the use of the safety strip prevent cast pressure from being released when the cast is split? Standard long-arm fiberglass casts were removed by experienced and inexperienced healthcare personnel (n = 35) from life-sized pediatric models. A commercially available woven cast saw safety strip, commonly incorporated in waterproof cast constructs, was chosen as the protective strip. Each participant removed a cast with and without the safety strip present. All participants were blinded to the presence or absence of the safety strip at the time of cast removal. The number of touches was compared between cast removal with and without protective strips. A separate model was designed to assess prevention of heat transfer. Temperatures were recorded, using thermocouples, for three designated temperatures. Five to six trials were conducted at each designated temperature for each of two conditions, with and without the safety strip. Finally, to assess if the safety strip would prevent cast pressure from being released, a third model was used. Thirty standard short-arm casts were applied and removed from the arm models by one of the authors. Pressure data were collected from between the padding layers, in casts with and without the safety strip present, after application, univalving and bivalving each cast. Use of the safety strip reduced the number of simulated skin touches compared with casts removed without the safety strip, among experienced users (mean, 9.0 [range, 1-28] versus 0.1 [range, 0-1], mean ratio, 0.0012; 95% CI, 0.002-0.063; p<0.001) and inexperienced users (mean, 8.5 [range, 0-31] versus 0.6 [range, 0-3], mean ratio, 0.07; 95% CI, 0.03-0.15; p<0.001). The safety strips decreased heat transfer, preventing temperatures at the cast-skin interface from reaching 50 °C. Finally, after splitting the cast, with the numbers available, there was no increase in the pressure beneath the casts in those with the safety strip present (mean without, 0.23 [SD, 0.070] versus safety strip in the padding 0.20 [SD, 0.091]and safety strip on top padding, 0.21 [SD, 0.090]; p = 0.446 and p = 0.65 respectively).

Our study showed the effectiveness of a safety strip in reducing simulated touches with the oscillating cast saw during cast splitting. Additional studies are warranted to investigate the clinical use and utility of the safety strip in practice.

Does chondrocyte dedifferentiation increase cell stiffness by strengthening membrane-actin adhesion?

Chondrocyte dedifferentiation is known to influence cell mechanics leading to alterations in cell function. This study examined the influence of chondrocyte dedifferentiation in monolayer on cell viscoelastic properties and associated changes in actin organisation, bleb formation and membrane-actin cortex interaction. Micropipette aspiration was used to estimate the viscoelastic properties of freshly isolated articular chondrocytes and the same cells after passage in monolayer. Studies quantified the cell membrane-actin cortex adhesion by measuring the critical pressure required for membrane detachment and bleb formation. We then examined the expression of ezrin, radixin and moesin (ERM) proteins which are involved in linking the membrane and actin cortex and combined this with theoretical modelling of bleb dynamics. Dedifferentiated chondrocytes at passage 1 (P1) were found to be stiffer compared to freshly isolated chondrocytes (P0), with equilibrium modulus values of 0.40 and 0.16 kPa respectively. The critical pressure increased from 0.59 kPa at P0 to 0.74 kPa at P1. Dedifferentiated cells at P1 exhibited increased cortical F-actin organisation and increased expression of total and phosphorylated ERM proteins compared to cells at P0. Theoretical modelling confirmed the importance of membrane-actin cortex adhesion in regulating bleb formation and effective cellular elastic modulus.

This study demonstrates that chondrocyte dedifferentiation in monolayer strengthens membrane-actin cortex adhesion associated with increased F-actin organisation and up-regulation of ERM protein expression. Thus dedifferentiated cells have reduced susceptibility to bleb formation which increases cell modulus and may also regulate other fundamental aspects of cell function such as mechanotransduction and migration.

Beginning hemodialysis: do patients with a failed renal transplant start in worse condition?

Predialysis management of patients with kidney transplant failure is a topic of growing interest. Herein we have reviewed a group of patients with a failed kidney transplant who returned to dialysis to compare them with patients with native kidney failure. We analyzed 25 patients who returned to dialysis after a failed renal transplant (group A) and 38 patients initiating dialysis after native kidney failure (group B). We did not observe significant differences in the glomerular filtration rate (GFR), potassium, calcium, phosphorus, albumin, and hemoglobin levels between the 2 groups at the beginning of dialysis. Erythropoietin resistance index (ERI) was higher in group A. Progression of renal disease in the 2 years before dialysis was faster in group A, with a greater monthly decline in GFR and higher levels of systolic blood pressure. Renal transplant patients needed more evaluations in the 6 months before initiating dialysis: 1.75 +/- 0.97 vs 0.70 +/- 2.61 evaluations/month (P = .000). Also, the number of hospitalizations during the years before and after dialysis initiation was higher among group A. Patient survival after return to dialysis at 1 year was 75% in group A and 97% in group B (log-rank; P = .09).

Patients with a failed kidney allograft initiated dialysis in similar condition to those with native kidney failure. The faster GFR decline may be related to immunosuppressive treatment. Transplant patients needed more frequent evaluations and more hospitalizations before and after dialysis initiation, indicating a higher morbidity rate.

Proposal for a novel methodology to screen and score cost versus survival for anticancer drugs in metastatic disease: could cost weigh in evaluation?

Rising costs of anticancer drugs prompt concerns about their approval, use, and affordability. A methodology was developed to evaluate cost versus survival for anticancer drugs in metastatic breast cancer and non-small-cell lung cancer (NSCLC). Costs of evaluated drugs were calculated by using average wholesale prices in US dollars. Ratios of cost to day of survival (cost/survival/d) were obtained by dividing costs of the entire treatment by reported median survival gain in days. A crude score of 100% was assigned to a cost/survival/d of less than $25, and 0% to a cost/survival/d of more than $750. A strategy was designed to correct for overall survival (OS) versus progression-free survival (PFS), adverse effects, and quality of life. In breast cancer, PFS scores of bevacizumab varied between 0% and 60%. In NSCLC, OS scores of bevacizumab improved from 0% to 50%, as a result of histology, lower prices, and extended therapy. Gefitinib and erlotinib PFS scores were 80% and 70%, respectively. Correction for longer survival with erlotinib resulted in similar scores. In maintenance therapy, the OS score for pemetrexed was 70% as compared with 25% for erlotinib. Generic drugs scored 70% to 90%.

Cost/survival varied with the number of cycles. In breast cancer, bevacizumab scores failed to justify its use. In NSCLC, 10 cycles of bevacizumab scored 0%. Scores improved with extended treatment and lower prices. Scores for gefitinib and erlotinib would support their approval. Erlotinib was preferred because of longer PFS. Results tended to endorse maintenance pemetrexed but not erlotinib. Generic drugs demonstrated high scores. Cost/survival could weigh in drug evaluation.

Does celecoxib inhibit meningioma tumor growth in a mouse xenograft model?

Treatments for recurrent meningiomas are limited. We previously demonstrated universal expression of COX-2 in meningiomas and dose-dependent growth inhibition in vitro with celecoxib, a COX-2 inhibitor. We therefore tested the effects of celecoxib on meningioma growth in a mouse xenograft model. Meningioma cell lines (IOMM-Lee, CH157-MN, WHO grade I primary cultured tumor) were transplanted into flanks of nude mice fed mouse chow with celecoxib at varying concentrations (0, 500, 1000, 1500 ppm) ad libitum. Tumors were measured biweekly and processed for MIB-1, Factor VIII, COX-2, and VEGF, and assayed with transferase-mediated dUTP-biotin nick-end labeling (TUNEL). Celecoxib reduced growth of mean tumor volume by 66% (P < .05), 25% (P > .05), and 65% (P < .05) compared with untreated controls in IOMM-Lee, CH157-MN, and benign tumors, respectively. IOMM-Lee tumors removed from celecoxib treatment regained a growth rate similar to the control. Blood vessel density decreased and apoptotic cells increased in treated flank tumors. Diminished COX-2 expression and VEGF were observed in treated IOMM-Lee tumors. Mean plasma celecoxib levels were 845, 1540, and 2869 ng/mL, for low-, medium-, and high-dose celecoxib, respectively.

Celecoxib inhibits meningioma growth in vivo at plasma levels achievable in humans. Celecoxib-treated tumors were less vascular with increased apoptosis. IOMM-Lee tumors treated with celecoxib showed decreased COX-2 and VEGF expression. COX-2 inhibitors may have a role in the treatment of recurrent meningiomas.

Are mitotic rate and subcutaneous involvement prognostic factors for survival after recurrence in patients with only locoregional skin metastasis as the first site of recurrence from cutaneous melanoma?

Few reports on literature give detailed figures on prognostic factors of locoregional skin recurrence in cutaneous melanoma. The aim of this study was to evaluate clinical and histological prognostic factors following development of locoregional cutaneous metastasis as the only progression site from melanoma. Data from 1327 stage I and II melanoma patients who visited Instituto Valenciano de Oncología and Consorcio Hospital General Universitario de Valencia from 2000 to 2010 were documented in a prospective manner. During follow up, 112 (8.4%) of them developed recurrent disease. A retrospective analysis revealed a subset of 36 patients with locoregional cutaneous metastases as a first event. Significant prognostic factors in the univariate analysis were Breslow thickness, tumor mitotic rate and the presence subcutaneous involvement of the skin metastasis. After multivariate analysis the independent predictive factors for survival after recurrence were tumor mitotic rate (hazard ratio [HR]: 8.6; 95% CI: 1.0-77.2) and subcutaneous involvement of the skin metastasis (HR: 4.3; 95% CI: 1.0-18.5).

The survival after recurrence of melanoma patients that has relapsed with only locoregional cutaneous metastasis depends on the mitotic rate of the primary tumor and the subcutaneous involvement of the metastasis.

Attitudes of nurse professionals and nursing students towards children with disabilities. Do nurses really overcome children's physical and mental handicaps?

Many health professionals and nurses, who are involved in the care of disabled children, do not exhibit the essential sensitivity and appropriate attitudes towards them, resulting in a poor quality of nursing care.AIM: The objective of this study was to investigate the attitudes of nurse professionals (paediatric nurses) and nursing students towards disabled children. The present study is a comparative study. The sample consisted of 228 first-year nursing students, 90 post-diploma nurses attending MSc degree course and 123 nurse professionals who are employed in paediatric hospitals. After obtaining permission from the hospitals and the educational settings and informing about the subjects of the study, data were collected using the paediatric Attitude Towards Disabled Person Scale (ATDP). Overall nurses' attitudes appeared to be poor (mean ATDP score 61.7 +/- 14.2). However, the post-diploma nurses had significantly higher ATDP scores than first-year students and paediatric nurses (P<0.001). In addition, first-year students had significantly higher scores than paediatric nurses (P = 0.047). Across the sample, females hold significantly more positive attitudes than males (F = 9.5, P = 0.002), while age did not have any significant effect.

Carefully designed curricula can influence the attitudes of nursing students towards children with disabilities. Special courses for treating disabled children should be integrated to the basic nursing studies. Moreover, continuing hospital education can change paediatric nurses' attitudes towards children with disabilities.

Does the presence and mix of destinations influence walking and physical activity?

Local destinations have previously been shown to be associated with higher levels of both physical activity and walking, but little is known about how specific destinations are related to activity. This study examined associations between types and mix of destinations and both walking frequency and physical activity. The sample consisted of 2349 residents of 50 urban areas in metropolitan Melbourne, Australia. Using geographic information systems, seven types of destinations were examined within three network buffers (400 meters (m), 800 m and 1200 m) of respondents' homes. Multilevel logistic regression was used to estimate effects of each destination type separately, as well as destination mix (variety) on: 1) likelihood of walking for at least 10 min ≥ 4/week; 2) likelihood of being sufficiently physically active. All models were adjusted for potential confounders. All destination types were positively associated with walking frequency, and physical activity sufficiency at 1200 m. For the 800 m buffer: all destinations except transport stops and sports facilities were significantly associated with physical activity, while all except sports facilities were associated with walking frequency; at 400 m, café/takeaway food stores and transport stops were associated with walking frequency and physical activity sufficiency, and sports facilities were also associated with walking frequency. Strongest associations for both outcomes were observed for community resources and small food stores at both 800 m and 1200 m. For all buffer distances: greater mix was associated with greater walking frequency. Inclusion of walking in physical activity models led to attenuation of associations.

The results of this analysis indicate that there is an association between destinations and both walking frequency and physical activity sufficiency, and that this relationship varies by destination type. It is also clear that greater mix of destinations positively predicts walking frequency and physical activity sufficiency.

Does a Genetic Variant in the Distal Enhancer Region of the Human Renin Gene affect Renin Expression?

The high heritability of plasma renin activity was confirmed in recent investigations. A variation located near the strong enhancer of the human renin gene (REN), C-5312T, has been shown to have different transcription activity levels depending on its allele: the 5312T allele shows transcription levels that are 45% greater than those of the 5312C allele. The purpose of this study was to confirm the hypothesis that variations in the enhancer region of the REN gene are involved in regulating renal expression of renin. Sixty-four subjects with biopsy-proven renal diseases were included in this study (male/female: 35/29, age 41.9 ± 20.9 years, SBP/DBP 123.1 ± 23.7/73.4 ± 14.8 mmHg, s-Cr 0.93 ± 0.63 mg/dl). A genetic variant of REN, C-5312T, was assayed by PCR-RFLP and the TaqMan method. Total RNAs from a small part of the renal cortex were reverse-transcribed and amplified for REN and GAPDH with a real-time PCR system. Logarithmically transformed expression values of the relative ratio of REN to GAPDH (10-3) were as follows (mean ± SE): CC (26 cases), 0.016 ± 0.005; CT (33 cases), 0.047 ± 0.021 (p = 0.41 vs. CC); TT (5 cases), 0.198 ± 0.194 (p = 0.011 vs. CC, p < 0.031 vs. CT). Thus, significant differences in REN expression were observed among the genetic variants.

The results suggest that variants in the enhancer region of the human renin gene have an effect on the expression levels of renin in renal tissue; this observation is in good accordance with the results of the transcriptional assay.

Is evaluation of early dynamic changes of intracranial arterial occlusion useful for stroke etiology diagnosis?

The etiologic diagnosis of intracranial arterial occlusion is sometimes challenging because of the dynamic nature of acute stroke. We investigated whether short-term follow-up vascular imaging adds additional information to the differential diagnosis between intracranial atherosclerotic and embolic occlusion. Acute ischemic stroke patients with symptomatic middle cerebral artery (MCA) occlusion on MR angiography (MRA) within 24h of symptom onset were included. Follow-up MRA was performed 5-7days after stroke onset. Stroke subtypes were independently determined at baseline and follow-up MRAs based on clinical, laboratory and imaging findings. In the 108 included patients, the most common etiologic subtype of initial stroke was intracranial large artery atherosclerosis (ICLAA) in 70 patients, followed by cardioembolism in 29 and other causes in 9. On follow-up MRA, 32 (29.6%) patients showed either significant or complete recanalization. Of these, 10 had been originally diagnosed with ICLAA, but were reclassified as a cryptogenic mechanism after follow-up MRA. Multiple logistic regression analysis showed that the presence of coexisting arterial atherosclerosis (odds ratio [OR], 6.91; 95% confidence interval [CI], 2.67-17.91; p<0.001); the absence of large territorial infarction (OR, 4.06; 95% CI, 1.39-11.85; p=0.010); and smoking (OR, 2.54; 95% CI, 1.028-6.29; p=0.043) were significantly associated with a final diagnosis of ICLAA.

In the absence of follow-up vascular imaging, a substantial proportion of patients with intracranial middle cerebral arterial occlusion may be misdiagnosed as ICLAA. Evaluation of early dynamic changes in intracranial middle cerebral arterial occlusion may provide useful information for the differential diagnosis of intrinsic atherosclerosis and embolic occlusion.

Are folate pathway genetic polymorphisms related to attention disorders in childhood leukemia survivors?

To test the hypothesis that 5,10-methylenetetrahydroreductase (MTHFR) polymorphisms can partially explain the individual variation in developing attention-deficit/hyperactivity disorder (ADHD) after acute lymphoblastic leukemia (ALL) therapy. Parents of 48 survivors of childhood ALL completed a clinical diagnostic process to identify subtypes of ADHD. Genotyping was performed with peripheral blood DNA for MTHFR (C677T and A1298C) polymorphisms. Eleven of the 48 patients (22.9%) had scores consistent with the inattentive symptoms of ADHD. Patients with genotypes related to lower folate levels (11 out of 39; 39.2%) were more likely to have ADHD. The A1298C genotype appeared to be the predominant linkage to the inattentive symptoms, leading to a 7.4-fold increase in diagnosis, compared with a 1.3-fold increase for the C677T genotype. Age at diagnosis and sex were not associated with inattentiveness.

Preliminary data imply a strong relationship between MTHFR polymorphisms and the inattentive symptoms of ADHD in survivors of childhood ALL.

Are cognitive deficits associated with poorer simulated driving in older adults with heart failure?

Cognitive impairment is prevalent in older adults with heart failure (HF) and associated with reduced functional independence. HF patients appear at risk for reduced driving ability, as past work in other medical samples has shown cognitive dysfunction to be an important contributor to driving performance. The current study examined whether cognitive dysfunction was independently associated with reduced driving simulation performance in a sample of HF patients. 18 persons with HF (67.72; SD = 8.56 year) completed echocardiogram and a brief neuropsychological test battery assessing global cognitive function, attention/executive function, memory and motor function. All participants then completed the Kent Multidimensional Assessment Driving Simulation (K-MADS), a driving simulator scenario with good psychometric properties. The sample exhibited an average Mini Mental State Examination (MMSE) score of 27.83 (SD = 2.09). Independent sample t-tests showed that HF patients performed worse than healthy adults on the driving simulation scenario. Finally, partial correlations showed worse attention/executive and motor function were independently associated with poorer driving simulation performance across several indices reflective of driving ability (i.e., centerline crossings, number of collisions, % of time over the speed limit, among others).

The current findings showed that reduced cognitive function was associated with poor simulated driving performance in older adults with HF. If replicated using behind-the-wheel testing, HF patients may be at elevated risk for unsafe driving and routine driving evaluations in this population may be warranted.

Are pterygia measurements more accurate with anterior segment optical coherence tomography - a pilot study?

Slit-lamp beam measurements of a pterygium can be difficult to reproduce accurately. To compare standard slit-lamp beam measurements of pterygia to computer caliper measurements of Anterior Segment Optical Coherence Tomography (OCT)images. Thirteen pterygia often patients were evaluated. Two physicians independently measured each pterygium using the slit lamp beam. Caliper measurements of two different OCT images of each pterygium were obtained. All measurements determined the distance from the limbus to the pterygium apex. The difference in the slit lamp beam measurements of each pterygium was calculated and the mean of the differences was 0.3 and the standard deviation was 0.32.The difference in the two OCT measurements of each pterygium was also calculated and the mean of the differences was 0.1 and the standard deviation was 0.12. A two-tailed t-test demonstrated a statistically significant difference in these measurements (p = 0.0256).

Anterior Segment Optical Coherence Tomography (OCT) gives significantly more reproducible results than the slit lamp beam for measurements of the distance of a pterygium's apex from the limbus. This tool may provide more accurate clinical assessment of extension of pterygia onto the cornea and may be useful for research purposes.

Do study of the feasible size of a bone conduction implant transducer in the temporal bone?

The aim was to assess the temporal bone volume to determine the suitable size and position of a bone conduction implant (BCI) transducer. A BCI transducer needs to be sufficiently small to fit in the mastoid portion of the temporal bone for a majority of patients. The anatomical geometry limits both the dimension of an implanted transducer and its positions in the temporal bone to provide a safe and simple surgery. Computed tomography (CT) scans of temporal bones from 22 subjects were virtually reconstructed. With an algorithm in MATLAB, the maximum transducer diameter as function of the maximum transducer depth in the temporal bone, and the most suitable position were calculated in all subjects. An implanted transducer diameter of 16 mm inserted at a depth of 4 mm statistically fitted 95% of the subjects. If changing the transducer diameter to 12 mm, a depth of 6 mm would fit in 95% of the subjects. The most suitable position was found to be around 20 mm behind the ear canal.

The present BCI transducer casing, used in ongoing clinical trials, was designed from the results in this study, demonstrating that the present BCI transducer casing (largest diameter [diagonal]: 15.5 mm, height: 6.4 mm) will statistically fit more than 95% of the subjects. Hence, the present BCI transducer is concluded to be sufficiently small to fit most normal-sized temporal bones and should be placed approximately 20 mm behind the ear canal.

Does colonic inflammation increase the contribution of muscarinic M2 receptors to carbachol-induced contraction of the rat colon?

Carbachol-induced contraction of the rat colon is impaired in rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis. The main objective of this study was to examine the effect of colitis on the expression and function of muscarinic (M) receptor subtypes in the rat colon. Rats (n = 80) were treated with TNBS and used 5 days later for measurement of contractility, myeloperoxidase activity, histology and expression of muscarinic receptor isoforms using Western blot analysis. Carbachol produced concentration-dependent contractions of colonic segments from control (n = 40) and TNBS-treated (n = 40) rats with no significant difference in potency. However, the maximum response to carbachol was significantly reduced in colon segments of TNBS-treated rats. The selective muscarinic receptor antagonists 4-diphenylacetoxy-N-methyl piperidine (4-DAMP, M(3)), pirenzepine (M(1)) and methoctramine (M(2)) antagonized carbachol-induced contraction in control (9.1 ± 0.1, 6.7 ± 0.3 and 6.0 ± 0.1, respectively) and TNBS-treated rats (9.2 ± 0.2, 6.9 ± 0.2, 6.7 ± 0.2). The -logK(B) values in control rats are consistent with an action of carbachol on muscarinic M(3) receptors. There was no significant difference in -logK(B) values for 4-DAMP and pirenzepine in control and TNBS-treated rats, but methoctramine was fivefold more potent in TNBS-treated rats, possibly indicating an increased contribution of muscarinic M(2) receptors to carbachol-induced contraction in the inflamed colon. The expression of M(2) receptors was also significantly increased in colon segments from TNBS-treated rats, confirming the increased role of muscarinic M(2) receptors in the inflamed colon.

The data show that while only M(3) receptors appeared to mediate carbachol-induced contraction in control segments, expression of both M(2) and M(3) receptors was increased in the inflamed rat colon.

Do donor hematopoietic cells from transgenic mice that express GFP are immunogenic in immunocompetent recipients?

To study the immunogenicity of hematopoietic cells marked with green fluorescence protein (GFP) while avoiding the potentially confounding effects of viral gene transduction, marked cells from GFP+ transgenic mice were tracked after transplantation into unconditioned immunocompetent recipients. Marrow was harvested from GFP+ transgenic mice that had been crossed onto a BALB/cByJ background. Unconditioned marrow transplantation involved infusion of sex-matched or sex-mismatched cells into female BALB/cByJ hosts. Engraftment and contribution to circulating nucleated blood cells were compared to recipients of donor cells that were not GFP-marked. Donor cells were detected by flow cytometry (GFP) and fluorescence in situ hybridization (FISH) for Y-chromosome sequences. Donor cells from mice of the same genetic background that did not express GFP were detected for more than four-weeks in unconditioned recipients. In contrast, GFP-marked cells in the blood peaked at one-week, declined to undetectable levels by two-weeks and were not detected in the marrow at sacrifice. In sex-mismatched studies, detection of male GFP+ donor cells by FISH yielded levels similar to those observed by flow cytometry, in contrast to the levels detected for many weeks in mice infused with male cells that did not express GFP. In immunocompetent recipients immunized with irradiated GFP-expressing cells, rechallenge with GFP+ cells resulted in the accelerated loss of donor cells.

Donor marrow cells from GFP+ transgenic mice were lost after infusion into unconditioned immunocompetent mice and sensitization studies infer an immunologic mechanism. These results are similar to studies of virally transduced cells. Thus, infusion of cells with optimum engraftment potential could not compensate for the loss of donor cells due to immunogenicity.

Is the fourth port routinely required for laparoscopic cholecystectomy?

There have been many changes in number and place of trocars that have been described, since the first laparoscopic cholecystectomy (LC), but, in fact, all authors agree that laparoscopic procedure is accepted as gold standard. However, four trocars use in standard laparoscopic cholecystectomy, it has been argued that the fourth port is not necessary for grasping fundus of gallbladder so as to expose Calot's triangle. The aim of this study is to establish the safety of three-trocar LC in symptomatic gallbladder disease and also to determine the ratio of technical requirements of the fourth trocar. Between August 2010 and January 2016, 291 cases were operated in Kocaeli Derince Education and Research Hospital, department of general surgery for symptomatic gallbladder disease with three-port LC, and their records were examined retrospectively. Two hundred and twenty patients were female (75.6 %) and seventy one (24.4 %) were male. Two hundred and eighteen of two hundred and ninety-one cases (74.92 %) were operated with three- port LC in a secure way. In seventy-three cases (25.08 %), one more port was needed to use. Mean operative time was 33.76 ± 11:18 min. (15-90 min). In these cases, major complications, such as main bile duct injury or bile leakage, that may increase the mortality and morbidity, did not occur. Only in one case (0.34 %) postoperative bleeding was seen from the liver bed, which was required exploration.

We concluded that in experienced hand, LC with three ports is safe and feasible technique if it is not endanger the course of the surgery.

Is teaching of the Society for Fetal Urology grading system for pediatric hydronephrosis improved by e-Learning using Computer Enhanced Visual Learning ( CEVL ) : A multi-institutional trial?

It is unclear how clinicians learn to grade pediatric hydronephrosis (HN) and how effective their training has been. We sought to: 1. Assess how clinicians learn to grade HN and their confidence in their training and abilities and 2. To assess Computer Enhanced Visual Learning (CEVL) e-Learning to learn the Society for Fetal Urology (SFU) grading system for pediatric HN. A multi-institutional online survey was distributed to pediatric urologists, nephrologists, and radiologists. Respondents used a 6-point Likert scale (0 = not confident to 5 = very confident) to assess their confidence in knowledge of the criteria, indications, and ability to grade HN, and how they learned to grade. Participants assigned SFU grades to 15 neonatal ultrasounds (US). A CEVL module on the SFU grading system was accessed and a post-CEVL survey completed. Changes in confidence and accuracy of grading were compared before and after CEVL e-Learning. The most common method of learning was "casually during training" (44.5%). Significant increases in confidence in knowledge of criteria, indications, and ability to grade, as well as the accuracy of grading were seen following CEVL e-Learning (Figure A and B).

Although the SFU grading system is considered the predominant grading system for HN, its application in clinical practice has been inconsistent. While this may be due to the grading system itself, it is possible that deficient training and confidence are the root causes. Our data supports this by demonstrating that most clinicians receive only casual training and accordingly, report low confidence in their knowledge and ability to grade HN. Therefore, we conclude that there exists a strong need to improve the teaching of the SFU grading system. e-Learning has been shown to be effective in teaching difficult topics and skills. We demonstrate that e-Learning with CEVL is effective in increasing both the confidence and accuracy of SFU grading of pediatric HN. Limitations of our study include a small sample size, low response rate, and discrepant participation. Furthermore, we did not assess the extent to which the CEVL module was used or include a control group learning through traditional means. Therefore, we were unable to evaluate the efficiency of learning or be certain that the improvements seen were derived exclusively from CEVL.

Are lung recruitment manoeuvres effective in regaining lung volume and oxygenation after open endotracheal suctioning in acute respiratory distress syndrome?

Lung collapse is a contributory factor in the hypoxaemia that is observed after open endotracheal suctioning (ETS) in patients with acute lung injury and acute respiratory distress syndrome. Lung recruitment (LR) manoeuvres may be effective in rapidly regaining lung volume and improving oxygenation after ETS. A prospective, randomized, controlled study was conducted in a 15-bed general intensive care unit at a university hospital. Eight consecutive mechanically ventilated patients with acute lung injury or acute respiratory distress syndrome were included. One of two suctioning procedures was performed in each patient. In the first procedure, ETS was performed followed by LR manoeuvre and reconnection to the ventilator with positive end-expiratory pressure set at 1 cmH2O above the lower inflexion point, and after 60 min another ETS (but without LR manoeuvre) was performed followed by reconnection to the ventilator with similar positive end-expiratory pressure; the second procedure was the same as the first but conducted in reverse order. Before (baseline) and over 25 min following each ETS procedure, partial arterial oxygen tension (PaO2) and end-expiratory lung volume were measured. After ETS, PaO2 decreased by 4.3(0.9-9.7)kPa (median and range; P < 0.005). After LR manoeuvre, PaO2 recovered to baseline. Without LR manoeuvre, PaO2 was reduced (P = 0.05) until 7 min after ETS. With LR manoeuvre end-expiratory lung volume was unchanged after ETS, whereas without LR manoeuvre end-expiratory lung volume was still reduced (approximately 10%) at 5 and 15 min after ETS (P = 0.01).

A LR manoeuvre immediately following ETS was, as an adjunct to positive end-expiratory pressure, effective in rapidly counteracting the deterioration in PaO2 and lung volume caused by open ETS in ventilator-treated patients with acute lung injury or acute respiratory distress syndrome.

Are there distinctive inflammatory flares after hylan g-f 20 intraarticular injections?

This survey was designed to examine features of a group of patients with acute painful joint effusions following hylan G-F 20 (Synvisc) knee injections. Eight patients with painful local reactions after intraarticular hylan G-F 20 injections for knee osteoarthritis were evaluated clinically, with detailed synovial fluid analysis, and followed for outcome. Leukocyte counts ranged from 3150 to 103,000/mm3. Crystals were seen in one patient. Inflammatory knee effusions occurred from 1 to 48 h after injections, but never with first injections. Synovial fluid volumes were 30 to 71 mm(3). Three patients had shiny clumps (not further characterized) that were noted in leukocytes on Wright stained smears. Most patients were treated with aspiration and depot steroids. Five of the 8 patients had moderate or greater improvement at 6 months.

The majority of the occasional dramatic episodes of inflammation after hylan G-F 20 injection do not seem to be related to crystals. No detrimental lasting results were noted. The absence of post-hylan flares following the first intraarticular injection in this small series suggests that sensitization to or accumulation of hylan G-F 20 or its breakdown products may play an etiologic role in these flares.

Does stereotactic vacuum-assisted core biopsy result for non-palpable breast lesions?

The increase in breast cancer awareness and widespread use of mammographic screening has led to an increased detection of (non-palpable) breast cancers that cannot be discovered through physical examination. One of the methods used in the diagnosis of these cancers is vacuum-assisted core biopsy, which prevents a considerable number of patients from undergoing surgical procedures. The aim of this study was to present the results of stereotactic vacuum-assisted core biopsy for suspicious breast lesions. Files were retrospectively scanned and data on demographic, radiological and pathological findings were recorded for patients who underwent stereotactic vacuum-assisted core biopsy due to suspicious mammographic findings at the Interventional Radiology Centre of the Florence Nightingale Hospital between January 2010, and April 2013. Statistical analysis was carried out using Pearson's Chi-square, continuity correction, and Fisher's exact tests. The mean age of the patients was 47 years (range: 36-70). Biopsies were performed due to BIRADS 3 lesions in 8 patients, BIRADS 4 lesions in 77 patients, and BIRADS 5 lesions in 3 patients. Mammography elucidated clusters of microcalcifications in 73 patients (83%) and focal lesions (asymmetrical density, distortion) in 15 patients (17%). In terms of complications, 1 patient had a hematoma, and 2 patients had ecchymoses (3/88; 3.3%). The histopathologic results revealed benign lesions in 63 patients (71.6%) and malignant lesions in 25 patients (28.4%). The mean duration of the procedure was 37 minutes (range: 18-55). Although all of the BIRADS 3 lesions were benign, 22 (28.6%) of the BIRADS 4 lesions and all of the BIRADS 5 lesions were malignant. Among the malignant cases, 80% were in situ, and 20% were invasive carcinomas. These patients underwent surgery.

In cases where non-palpable breast lesions are considered to be suspicious in mammography scans, the vacuum-assisted core biopsy method provides an accurate histopathologic diagnosis thus preventing a significant number of patients undergoing unnecessary surgical procedures.

Does sigh improve gas exchange and respiratory mechanics in children undergoing pressure support after major surgery?

Children undergoing major surgery can develop lung de-recruitment and gas exchange impairment in the postoperative period. The aim of this study was to assess the effect of periodic sigh breaths (Sighs) during pressure support ventilation (PSV) on gas exchange and respiratory pattern in children after major surgery. Twenty children were enrolled and received PSV alone and with Sighs in a randomized order. Sighs were administered once per minute by adding to baseline pressure support a pressure controlled breath set at 30 cm H2O of peak airway pressure. At the end of each study period air flow, pressure traces, and compliance of respiratory system, together with hemodynamic parameters and venous and arterial blood gas tensions, were recorded. PaO2/FiO2 improved from baseline to Sigh group (312.6 ± 137.4 vs. 394.2 ± 127.0; P<0.01) and PaCO2 decreased from baseline to Sigh group (39.3 ± 3.3 vs. 34.3 ± 4.6 mmHg; P<0.001), without any change in minute expiratory volume. Indexed to body weight compliance of respiratory system improved from baseline to Sigh group (0.85 ± 0.35 vs. 1.01 ± 0.30 mL/kg/cm H2O; P<0.01). There were no significant differences between the two groups for the hemodynamic parameters.

The addition of one Sigh per minute during PSV in the post-operative period of children that underwent major surgery improved gas exchange and decreased respiratory drive without producing major short-term complications. Further long-term studies are necessary to evaluate the efficacy and safety of Sigh in pediatric patients.

Is proapoptotic gene BAX frequently mutated in hereditary nonpolyposis colorectal cancers but not in adenomas?

The p53 and BAX genes have been linked to apoptosis. p53 was not frequently found to be mutated in colorectal carcinomas with a microsatellite mutator phenotype, but frame-shift mutations in a tract of eight guanines within BAX were frequently found in these carcinomas. To understand the roles of these genes in hereditary nonpolyposis colorectal cancer (HNPCC) tumorigenesis, we examined whether BAX mutations occur in adenoma and carcinoma specimens from patients with HNPCC and also determined the frequencies of p53 mutations. Thirteen colorectal adenomas and 24 adenocarcinomas from patients with HNPCC showing a microsatellite instability phenotype were screened by polymerase chain reaction followed by denaturing polyacrylamide gel electrophoresis and direct sequencing. Two of the 13 adenomas (15.4%) and 13 of the 24 adenocarcinomas (54.2%) showed mutation patterns and were confirmed to have frame-shift mutations at the BAX repeat site by direct sequencing. For p53, only 1 of the 24 adenocarcinomas (4.2%) showed a missense mutation.

In HNPCC colorectal carcinomas, BAX was significantly (P = 0.024) more mutated than in adenomas. p53 was not frequently found to be mutated in these carcinomas. These data suggest that mutations in BAX, rather than mutations in p53, may contribute to the adenoma-carcinoma transition in HNPCC tumorigenesis.

Does [ Ceramide participate in cell programmed death induced by Type II anti-CD20 mAb ]?

To explore the exact mechanisms of programmed cell death (PCD) induced by Type II anti-CD20 mAb in CD20+ non-Hodgkin lymphoma (NHL) cells, and to provide theoretical basis for anti-tumor ability of new CD20 mAb.
 After incubation with Rituximab (a Type I anti-CD20 mAb) and Tositumomab (a Type II anti-CD20 mAb), Raji cells were stained by annexin V & propidium iodide (PI). The ratio of programmed death cells were measured by two channel flow cytometry (FCM). Before the treatment of anti-CD20 mAbs, Raji cells was incubated with a caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (Z-VAD-FMK) and a dihydroceramide synthase inhibitor fumonisin B1 (FB1) for 30 minutes to assess their inhibitory effect on PCD. High performance liquid chromatography (HPLC) was utilized to compare the ratio of programmed death cells between the pretreatment group (treated by Rituximab and Tositumomab) and the non-pretreatment group. The anti-CD20 mAbs-treated Raji cells were collected, and the ceramide levels in the Raji cells in the different pretreatment groups were also examined by HPLC, and the inhibitory effect of FB1 on the changes of ceramide levels in the Raji cells was measured. The Raji cells were incubated with different concentration C2-ceramide, C2-Ceramide-induced PCD was also evaluated by annexin V & PI staining after 16 hours. 
 Tositumomab (10 µg/mL) but not Rituximab (10 µg/mL) can induce significant PCD (28.6±4.2)% in Raji cells, with significant difference (t=26.48, P<0.01), which cannot be blocked by Z-VAD-FMK with a concentration range from 10 to 30 µmol/L (F=3.01, P>0.05). The cellular ceramide levels in Raji cells were significantly elevated after the treatment of Tositumomab (t=28.48, P<0.01). C2-ceramide can significantly induce PCD in Raji cells in a dose-dependent manner with a concentration range from 5 to 40 µmol/L (F=2.71, P>0.05). The dihydroceramide synthase inhibitor FB1 can significantly inhibit the elevated cellular ceramide levels (F=20.18, P<0.01) and cell programmed death induced by Tositumomab (F=17.02, P<0.01).


Type II but not Type I anti-CD20 mAbs can induce caspase independent PCD in CD20+ NHL cells through the elevation of cellular ceramide levels. The PCD is not associated with classic caspase pathway.

Do the common consensus criteria have high predictive values for long-term postoperative acromegaly remission?

The aim of this work was to retrospectively study the long-term reliability of the common consensus endocrinological criteria for the assessment of postoperative remission of acromegaly. In 96 consecutive patients, surgical remission of acromegaly following transsphenoidal surgery was considered to be present when, without adjuvant treatment, 3 months postoperatively there was no clinical evidence of persisting disease, and, according to the common consensus criteria for acromegaly remission, GH was suppressed to < 1 μg/l during the oral glucose tolerance test (OGTT) and insulin like growth factor-1 (IGF-1) was within normal limits. The results of the second postoperative week, 3 months postoperative, and the most recent follow-up OGTT and IGF-1 measurements were used to calculate the positive and negative predictive values of the following endocrinological criteria of acromegaly remission: the common consensus criteria for acromegaly remission, GH suppression to < 1 μg/l during OGTT and IGF-1 within normal limits. Sensitive IRMA (≤ 0.3 μg/l) and RIA (≤ 32 μg/l) assays for GH and IGF-1 were used. The surgical remission rate of acromegaly was 72.9%. At a median follow-up of 5.06 years, the recurrence rate of acromegaly was 2.08%. Overall, the common consensus criteria for acromegaly remission were the most reliable tests, with the following positive and negative predictive values at 2 weeks postoperatively, 3 months postoperatively and at the most recent follow-up: 68%, 100% and 100%, and 98%, 100% and 100%, respectively. The negative likelihood ratio confirmed that the test qualities of the common consensus criteria for acromegaly remission were superior to the other tests.

The common consensus criteria were the most reliable tests for the diagnosis of postoperative acromegaly remission. The positive and negative predictive values of the common consensus criteria for acromegaly remission increased from the second postoperative week to 3 months postoperatively, thereafter reliably indicating the long-term results of transsphenoidal surgery.

Are [ Low testosterone levels inversely correlated with carotid artery plaque formation in elderly women ]?

To study the relationship between serum testosterone levels and the plaque formation of the carotid artery in a population-based cohort of independently living healthy women above 60 years of age. Analysis of the healthy elders from a population-based cohort study in 9 communities of Beijing. Carotid intima-media thickness and atherosclerotic plaques were determined ultrasonographically. Serum testosterone levels were measured by immunoassay. The data were analyzed with ANOVA and logistic regression analysis. There was an inverse correlation between testosterone and plaque formation in old females (P < 0.01), while no association was found in males. Female with testosterone levels in the lowest quartile (< 0.49 nmol/L) had more risk of plaque formation (OR = 3.805, P < 0.01) after adjusted with age and other traditional factors of atherosclerosis.

Testosterone concentrations are negatively associated with carotid artery atherosclerosis in old women in Beijing, experimental and prospective studies are needed to determine the possible therapeutic role of testosterone in atherosclerosis.

Is escherichia coli sequence type 131 a dominant , antimicrobial-resistant clonal group associated with healthcare and elderly hosts?

To determine prevalence, predictors, and outcomes of infection due to Escherichia coli sequence type ST131. Retrospective cohort. All healthcare settings in Olmsted County, Minnesota (eg, community hospital, tertiary care center, long-term care facilities, and ambulatory clinics). Ambulatory and hospitalized children and adults with extraintestinal E. coli isolates. We analyzed 299 consecutive, nonduplicate extraintestinal E. coli isolates submitted to Olmsted County laboratories in February and March 2011. ST131 was identified using single-nucleotide polymorphism polymerase chain reaction and further evaluated through pulsed-field gel electrophoresis. Associated clinical data were abstracted through medical record review. Most isolates were from urine specimens (90%), outpatients (68%), and community-associated infections (61%). ST131 accounted for 27% of isolates overall and for a larger proportion of those isolates resistant to fluoroquinolones (81%), trimethoprim-sulfamethoxazole (42%), gentamicin (79%), and ceftriaxone (50%). The prevalence of ST131 increased with age (accounting for 5% of isolates from those 11-20 years of age, 26% of isolates from those 51-60 years of age, and 50% of isolates from those 91-100 years of age). ST131 accounted for a greater proportion of healthcare-associated isolates (49%) than community-associated isolates (15%) and for fully 76% of E. coli isolates from long-term care facility (LTCF) residents. Multivariable predictors of ST131 carriage included older age, LTCF residence, previous urinary tract infection, high-complexity infection, and previous use of fluoroquinolones, macrolides, and extended-spectrum cephalosporins. With multivariable adjustment, ST131-associated infection outcomes included receipt of more than 1 antibiotic (odds ratio [OR], 2.54 [95% confidence interval (CI), 1.25-5.17]) and persistent or recurrent symptoms (OR, 2.53 [95% CI, 1.08-5.96]). Two globally predominant ST131 pulsotypes accounted for 45% of ST131 isolates.

ST131 is a dominant, antimicrobial-resistant clonal group associated with healthcare settings, elderly hosts, and persistent or recurrent symptoms.

Is the entire dural sinus tree compressed in patients with idiopathic intracranial hypertension : a longitudinal , volumetric magnetic resonance imaging study?

The objective of this study was to explore the volumetric alterations of dural sinuses in patients with idiopathic intracranial hypertension (IIH). Standardized cranial magnetic resonance imaging (MRI) was used in 17 patients prior to and following treatment of IIH and in seven controls. Magnetic resonance venographies (MRV) were employed for (a) judgement of circumscript dural sinus stenoses and (b) computation of sinus volumes. Cross-sectional areas (CSA) of the superior sagittal sinuses (SSS) were measured on T2-weighted images. Results of the initial MRIs were compared to those on follow-up MRIs and to results of controls. Stenoses of the transverse sinuses (TS) resulting in cranial venous outflow obstruction (CVOO) were present in 15/17 (88%) patients, normalizing in 7/15 cases (47%) after treatment of IIH. CVOO was not detected in the control group. Segmentation of MRV revealed decreased dural sinus volumes in patients with IIH as compared to controls (P = 0.018). Sinus volumes increased significantly with normalization of intracranial pressure independent from disappearing of TS stenoses (P = 0.007). The CSA of the SSS were normal on the initial MRIs of patients with IIH and increased on follow-up after treatment (P < 0.001). However, volumetries displayed overlap in patients and controls.

Patients with IIH not only exhibit bilateral stenoses of the TS as has been reported, but volume changes of their entire dural sinus system also occur. The potential etiopathological and diagnostic roles of these changes are discussed.

Is high-normal blood pressure associated with visit-to-visit blood pressure variability in the US adults?

High-normal blood pressure and visit-to-visit blood pressure variability are common in clinical settings. They are associated with cardiovascular outcomes. No population based studies have assessed the association between these two phenomena. Our objective was to test the relationship of high-normal blood pressure with visit-to-visit blood pressure variability. A cross-sectional study. We used data from the cross-sectional Third National Health and Nutrition Examination Survey to test the relationship between high-normal blood pressure and visit-to-visit blood pressure variability; we conducted multivariable regression analyses to evaluate the relationship between these two variables. The analysis included 6,071 participants. The participants' mean age was 37.16 years. The means of visit-to-visit systolic and diastolic blood pressure variability were 5.84 mmHg and 5.26 mmHg. High-normal blood pressure was significantly associated with systolic and diastolic blood pressure variability (p values <0.05).

High-normal blood pressure is associated with visit-to-visit blood pressure variability. Additional research is required to replicate the reported results in prospective studies and evaluate approaches to reduce blood pressure variability observed in clinical settings among patients with high-normal blood pressure to reduce the subsequent complications of blood pressure variability.

Lipopolysaccharide binding protein in a surgical intensive care unit: a marker of sepsis?

We investigated the time course of lipopolysaccharide binding protein (LBP) plasma concentrations in patients in the surgical intensive care unit (ICU), their value in discriminating sepsis from systemic inflammatory response syndrome, and their association with severity of sepsis and outcome in these patients compared with interleukin (IL)-6, C-reactive protein, and procalcitonin. Prospective, observational, cohort study. Academic ICU. All 327 consecutively admitted patients. Serum LBP concentrations were higher in patients who had severe sepsis/septic shock on ICU admission than in patients who never had sepsis (20.5 [8.1-38.8] vs. 14.2 [7.7-22.2]microg/mL, p<.05) but were similar in patients with sepsis without organ failure and those who never had sepsis. After 3 days, LBP levels were similar in all groups. In a receiver operating characteristic curve analysis, LBP concentrations moderately discriminated sepsis from systemic inflammatory response syndrome (area under curve [AUC] = .66) and severe sepsis from sepsis without organ failure (AUC = .71). IL-6 had the highest AUC in discriminating sepsis from other conditions (AUC = .76) and procalcitonin had the highest AUC for discrimination of severe sepsis from sepsis (AUC = .86). LBP concentrations on admission and during the first week were similar in patients with gram-positive and those with gram-negative infections (15.9 [11-26.7]and 37.2 [25.1-62.4] vs. 16.3 [5.3-31.6]and 31.6 [13.4], microg/mL, p>.2). LBP concentrations on admission were similar in nonsurvivors and survivors and did not discriminate ICU mortality. However, the maximum LBP concentration during the first 3 days in the ICU discriminated moderately between survivors and nonsurvivors.

In the surgical ICU, LBP moderately discriminated patients without infection from patients with severe sepsis but not from patients with sepsis without organ dysfunction. LBP concentrations did not distinguish between gram-positive and gram-negative infections. The correlation of LBP concentrations with disease severity and outcome is weak compared with other markers and its use as a biomarker is not warranted in this patient population.

Is target blood pressure for patients with type 2 diabetes difficult to achieve in the setting of a busy diabetes clinic?

Target blood pressure control in patients with type 2 diabetes should be 130/85 mmHg or less; however, it is not clear how achievable this target is in clinical practice. To assess the adequacy of blood pressure control in patients with type 2 diabetes attending a busy outpatient clinic. One hundred and eight patients with type 2 diabetes were assessed for the presence of hypertension using a cut-off value of 130/85 mmHg. Antihypertensive treatment and diabetic complications were evaluated. Hypertension was present in 67% of patients, in whom 90% were receiving anti-hypertensive treatment. Forty-nine per cent of the treated patients achieved target blood pressure. Of the undertreated patients, 55% were on one antihypertensive agent, 30% were on two agents and 15% were on three or more agents. The corresponding figures for the adequately treated patients were 28%, 31% and 41%, respectively (p=0.03).

Adequate blood pressure control was underachieved in this patient group underlying the difficulty in treating blood pressure to target values in patients with type 2 diabetes in the setting of outpatient diabetes clinics. A more aggressive strategy, in particular the use of multiple antihypertensive agents should be adopted.

Does primary WWOX phosphorylation and JNK activation during etoposide induce cytotoxicity in HEK293 cells?

Etoposide is an antineoplastic agent used in multiple cancers. It is known that etoposide induce cell death via interaction with topoisomerase II; however, the etopoisde cellular response is poorly understood. Upon etoposide induced DNA damage, many stress signaling pathways including JNK are activated. In response to DNA damage, it has been shown that WWOX, a recently introduced tumor suppressor, can be activated. In this study the activation of WWOX and JNK and their interaction following etoposide treatment were evaluated. HEK293 cells treated with etoposide were lysed in a time course manner. The whole cell lysates were used to evaluate JNK and WWOX activation pattern using Phospho specific antibodies on western blots. The viability of cells treated with etoposide, JNK specific inhibitor and their combination was examined using MTT assay. Findings of this study indicate that WWOX and JNK are activated in a simultaneous way in response to DNA damage. Moreover, JNK inhibition enhances etoposide induced cytotoxicity in HEK293.

Taken together, our results indicate that etoposide induces cytotoxicity and WWOX phosphorylation and the cytotoxicty is augmented by blocking JNK pathway.

Are vasomotor symptoms associated with depression in perimenopausal women seeking primary care?

To compare the relationship between vasomotor symptoms (hot flushes and night sweats) and depression in perimenopausal women with that in postmenopausal and older premenopausal women. Questionnaire data assessing current depressive symptoms (Center for Epidemiologic Studies Depression Scale), hot flushes, night sweats, menopausal status, depression history, hormonal therapy use, and demographic characteristics were collected from women aged 40 to 60 years seeking primary care. Multivariable logistic regression models were used to examine the relationship between vasomotor symptoms and depression. Depression (defined by a Center for Epidemiologic Studies Depression Scale score >/= 25) was observed in 14.9% of 141 perimenopausal women, 13.9% of 151 postmenopausal women, and 7.6% of 184 older premenopausal women. Recent vasomotor symptoms were reported by 53.9% of perimenopausal women, 43.7% of postmenopausal women, and 20.7% of older premenopausal women. Perimenopausal women with vasomotor symptoms were 4.39 times more likely to be depressed than those without vasomotor symptoms (95% CI, 1.40-13.83), an association that did not change after controlling for depression history. In contrast with perimenopausal women, postmenopausal and older premenopausal women with vasomotor symptoms did not have a significantly greater risk for depression than women of the same menopausal status without vasomotor symptoms (adjusted odds ratios, 1.28 and 1.77; 95% CI, 0.47-3.46 and 0.53-5.89, respectively).

Hot flushes and night sweats are associated with depression in perimenopausal women. Further investigation is warranted to elucidate the mechanism by which hot flushes may be associated with depression in perimenopausal women and not in postmenopausal or older premenopausal women.

Is heart-type fatty acid binding protein associated with proteinuria in obesity?

Lipid metabolism contributes to the formation of obesity-related glomerulopathy (ORG). Heart-type fatty acid binding protein (H-FABP or FABP3) is involved in lipid metabolism and was predicted to relate to renal lesions in obesity. A total of 28 patients with ORG were investigated, and renal tissue from 7 kidney donors served as controls. Db/db mice with albuminuria were treated with Simvastatin for 12 weeks. Immunohistochemistry demonstrated the H-FABP staining in glomerular and tubular areas of patients with ORG, and the percentage of H-FABP in the glomerular area was significantly higher than in controls (15.8±1.62 versus 4.51±0.56%, P<0.001). Moreover, H-FABP expression correlated with proteinuria, high-density lipoprotein (HDL) cholesterol, waist circumference and the homeostatic model assessment - insulin resistance (HOMA-IR) among patients with ORG. Enhanced expression of H-FABP was also detected in the db/db mice, and expression increased from 8 to 20 weeks of age and was weakly related to increased albuminuria (r = 0.433; P = 0.020). Furthermore, H-FABP was co-localized with synaptopodin and demonstrated a podocyte pattern distribution. After Simvastation treatment, the urine albumin levels decreased with lipid levels and H-FABP expression in the glomeruli. The expression of H-FABP was related to Simvastatin treatment, albuminuria and triglycerides, while it was only linked with triglycerides and albuminuria (r = 0.643, P = 0.036).

This study confirmed an association of H-FABP with the pathogenesis of clinical and experimental ORG, and suggests that such a process might be related to podocytes and lipid dysmetabolism.

Is nF-κB-direct activation of microRNAs with repressive effects on monocyte-specific genes critical for osteoclast differentiation?

Monocyte-to-osteoclast conversion is a unique terminal differentiation process that is exacerbated in rheumatoid arthritis and bone metastasis. The mechanisms implicated in upregulating osteoclast-specific genes involve transcription factors, epigenetic regulators and microRNAs (miRNAs). It is less well known how downregulation of osteoclast-inappropriate genes is achieved. In this study, analysis of miRNA expression changes in osteoclast differentiation from human primary monocytes revealed the rapid upregulation of two miRNA clusters, miR-212/132 and miR-99b/let-7e/125a. We demonstrate that they negatively target monocyte-specific and immunomodulatory genes like TNFAIP3, IGF1R and IL15. Depletion of these miRNAs inhibits osteoclast differentiation and upregulates their targets. These miRNAs are also upregulated in other inflammatory monocytic differentiation processes. Most importantly, we demonstrate for the first time the direct involvement of Nuclear Factor kappa B (NF-κB) in the regulation of these miRNAs, as well as with their targets, whereby NF-κB p65 binds the promoters of these two miRNA clusters and NF-κB inhibition or depletion results in impaired upregulation of their expression.

Our results reveal the direct involvement of NF-κB in shutting down certain monocyte-specific genes, including some anti-inflammatory activities, through a miRNA-dependent mechanism for proper osteoclast differentiation.

Are nurses adequately prepared for end-of-life care?

To determine end-of-life (EOL) care core competencies and educational needs from practicing oncology nurses and to describe the characteristics of the respondents that are associated with selection of the leading core competencies. A researcher-developed mailed descriptive survey to members of the Oncology Nursing Society in Georgia, Virginia, Washington, and Wisconsin in late 1999. Nearly all respondents indicated that EOL care was a part of their practice and that continuing education was important, but one-third of the respondents had less than 2 hours of continuing education in 2 years. How to talk to patients and families about dying was the top-rated core competency, consistent across age, educational level, practice role, and practice setting. Pain control and comfort care were also frequently selected as important EOL care issues about which more education is needed.

Results show guidelines for improving educational curricula and considering characteristics of nurses when planning EOL educational programs.

Does pitavastatin improve glycated hemoglobin in patients with poorly controlled type 2 diabetes?

To investigate the effect of pitavastatin on glucose control in patients with type 2 diabetes. Medical records of 340 patients with type 2 diabetes treated with pitavastatin or atorvastatin between 1 August 2013 and 31 May 2014 were reviewed. A total of 96 patients who had not received statins were treated with pitavastatin (N to P group). A total of 100 patients who had previously used atorvastatin were switched to pitavastatin (A to P group). A total of 144 patients continued with atorvastatin treatment. Data were collected at baseline, 3 and 6 months of treatment. Changes in glycated hemoglobin (HbA1c) level were analyzed in 222 patients who did not change their antidiabetic agent during 6 months of treatment. A negative correlation between baseline HbA1c and delta HbA1c at 6 months was found in the pitavastatin-treated patients (N to P group: ρ = -0.329, P = 0.006; A to P group: ρ = -0.480, P < 0.001). The correlation remained similar after adjusting for age, body mass index, dose of pitavastatin, estimated glomerular filtration rate and high-density lipoprotein cholesterol. After 6 months of treatment, the benefit of pitavastatin on HbA1c in the patients with poorly controlled diabetes was significant in both the N to P (8.1 vs 7.4%, P = 0.018) and A to P (9.7 vs 9.0%, P = 0.015) groups.

Pitavastatin decreases HbA1c in patients with type 2 diabetes with a higher baseline HbA1c level. The benefit on HbA1c was also observed in patients with previous use of atorvastatin.

Dose adjustment guidelines for medications in patients with renal impairment: how consistent are drug information sources?

It is known that patients with renal disease are often administered inappropriate dosages of drugs. A lack of quantitative data in the available drug information sources and inconsistency in dosing information may augment the problem of dosing error. To determine the concordance among five drug information sources regarding the dosing recommendations provided for drugs considered problematic in patients with renal impairment and to determine the consistency among the sources regarding the definition of renal impairment and categorisation of chronic kidney disease. Five standard drug information sources were reviewed for 61 drugs recommended to be used with caution in renal impairment. Information on recommendations for dosage adjustment in renal impairment was extracted and analysed. Further, the definition and classification of renal impairment were recorded. The recommendation for each drug was coded into six different categories and the intersource reliability was calculated. Only slight agreement was observed among the sources (Fleiss Kappa: 0.3). Qualitative data were not well defined, and there was a lack of consistency in quantitative values. Some drugs marked as contraindicated in one source were not mentioned as such in others. Also, drugs considered as not requiring dosage adjustment in one source had explicit recommendations in other sources. The definition and classification of renal impairment differed among the five information sources.

There should be an evidence-based approach to drug dosage adjustment in order to bring uniformity to the recommendations. Regular updating of the content of the drug information sources is also important.

Are periplakin and envoplakin target antigens in canine and human paraneoplastic pemphigus?

On the basis of clinical and histopathologic similarities to human paraneoplastic pemphigus (PNP), we recently identified the first case of PNP in a nonhuman species, the dog. To determine a similar pathogenesis in both species, the present study aimed to define whether common antigens are targeted in dog and man. Canine and human PNP sera were used in parallel to immunoprecipitate 14C-labeled human keratinocyte antigens. The immunoreactive proteins were then identified by immunoprecipitation of canine keratinocyte extracts with specific antibodies to the antiplakin family members follwed by immunoblot analysis using canine and human PNP sera. Protein bands of 210, 190, 170, and 130 kd were identified in dogs and humans. In both species, envoplakin and periplakin were demonstrated as antigens. Anti-desmoglein 3 antibodies could not be demonstrated in canine PNP, but in human PNP.

These results demonstrate that canine PNP closely correlates to the human counterpart and may therefore represent an excellent model for the human disease.

Do volatile anesthetics alter bradykinin-induced release of nitric oxide or L-citrulline in crystalloid perfused guinea pig hearts?

Nitric oxide (NO) and L-citrulline (L-cit) are released by endothelial NO synthase (eNOS) to induce vasodilation via guanylyl cyclase and cyclic guanosine monophosphate (cGMP). Volatile anesthetics directly reduce vascular muscle tone, but their effects on the eNOS cGMP pathway is controversial. The aim of this study was to examine the effects of anesthetics on bradykinin-induced increases in flow, NO, and L-cit in isolated hearts. Guinea pig hearts were isolated, perfused at 55 mmHg with a crystalloid or erythrocyte perfusate at 37 degrees C, and heart rate, left ventricular pressure, coronary flow (CF), effluent pH, and oxygen tension were monitored. Effluent [NO] was measured by a Clark-type electrode (sensitivity > or = 1 nM = 3 pA) with a selectively permeable membrane. Effluent [L-cit] was measured by chromatography. Before, during, and after exposure to halothane, isoflurane, or sevoflurane, hearts were infused with as much as 100 nM bradykinin to induce increases in CF and effluent release of NO and L-cit. In crystalloid-perfused hearts, 10 nm bradykinin produced maximal concentration-dependent increases in CF (87+/-2%), [NO] (24+/-4 nM), NO release (128+/-18 pmol x g(-1) x min(-1)), and [L-cit] (58+/-8 nM). Isoflurane slightly increased CF but not NO. Anesthetics did not alter the bradykinin-induced CF, NO slope relationship, or change [L-cit]. In erythrocyte-perfused hearts, isoflurane also did not alter the bradykinin-induced increase in CF and decrease in percentage of oxygen extracted.

This is the first study to simultaneously measure CF with bradykinin-induced changes in [NO] and [L-cit] in the presence of halothane, isoflurane, and sevoflurane in intact hearts. The study shows for the first time that volatile anesthetics do not alter the CF to NO relationship and suggests that NO production, NO release, and NO vasodilatory effects mediated by the eNOS cGMP pathway are not significantly affected by anesthetics in crystalloid or erythrocyte-perfused guinea pig hearts.

Do community pharmacists ' attitudes towards medicines use reviews and factors affecting the numbers performed?

Medicines use review and prescription intervention ('MUR services') is the first advanced service within the NHS community pharmacy contract and is a structured review that is undertaken by a pharmacists with patients on multiple medicines. The objective of this study was to investigate factors that influence the number of Medicines use reviews (MURs) performed by community pharmacists and to explore community pharmacists' attitudes towards the service. Setting This study was conducted with pharmacists who were employed by one UK community pharmacy chain. A questionnaire was developed to investigate factors that influence the number of MURs performed and pharmacists' attitudes towards MURs. It consisted of a series of attitudinal statements together with brief demographic data. Questionnaires were distributed to a sample of 280 pharmacists accredited to provide the service during April and May 2006. Factors affecting the number of MURs performed and community pharmacists' attitudes towards MURs. Sixty per cent (167/280) of pharmacists returned a completed questionnaire. Twenty-seven per cent of respondents had not performed any MURs, 43% had conducted one to 14 reviews and 31% had conducted 15 or more. Job title affected the number of reviews performed; respondents categorised as 'Store based' pharmacists performed significantly more MURs than those working as 'Locums' but not significantly more than 'Managing' pharmacists. Pharmacists reporting access to an accredited consultation area performed significantly more MURs than those who did not. Those working more than 20 h per week performed significantly more MURs than those working less. Gender, time since qualification, the pharmacy size and those having or currently undertaking a clinical diploma were not found to be associated with the number of MURs performed. Most respondents reported that MURs were an opportunity for pharmacist to use their professional skills in an extended role and patients would benefit from the service. However they reported concerns about GPs opinion of the service, lack of time and support staff to conduct MURs and were unhappy about consultation areas.

This study demonstrates that pharmacists perceive MURs to be an opportunity for an extended role and of value to patients. However, this study has identified perceived barriers, including the availability of a consultation area suitable for performing MURs, time to perform MURs and support staff. The number of MURs performed by pharmacists appears to be affected by the pharmacists' job title, their working hours and the presence of a consultation area. Additional support for 'locum' pharmacists was also highlighted and may be needed.

Does connexin hemichannel blockade improve outcomes in a model of fetal ischemia?

Connexin hemichannels can open during ischemia, resulting in loss of membrane potential, calcium influx, and release of glutamate. In this study, we tested the hypothesis that opening of hemichannels after cerebral ischemia may contribute to delayed evolution of injury. We infused a mimetic peptide that blocks connexin 43 hemichannels into the lateral ventricle of chronically instrumented fetal sheep in utero at 128 ± 1 days gestation (term is 147 days), starting 90 minutes after 30 minutes of severe ischemia induced by reversible bilateral carotid artery occlusion, for either 1 or 25 hours. Sheep were killed 7 days later. Peptide infusion was associated with a graded improvement in recovery of electroencephalographic power after 7 days recovery, from -13 ± 1.9 dB (n = 7) after ischemia-vehicle to -9 ± 1.6 dB (n = 7) after ischemia-short infusion and -5 ± 1.6 dB after ischemia-long infusion (n = 6, p < 0.05). Peptide infusion was associated with reduced seizure activity after ischemia, less frequent status epilepticus (p < 0.05), and earlier return of sleep state cycling (p < 0.05). Ischemia-long infusion (but not ischemia-short infusion) was associated with improved survival of oligodendrocytes in intragyral and periventricular white matter (p < 0.05) and increased brain weight (p < 0.05). Ischemia-long infusion was associated with an intermediate estimate of surviving neurons in the parasagittal cortex of 2.9 ± 0.8 × 10(6), in comparison to sham control (4.3 ± 0.9 × 10(6)) or ischemia-vehicle (1.5 ± 0.4 × 10(6); p < 0.05 vs sham control).

These data support the hypothesis that opening of connexin hemichannels is a significant mediator of postischemic white and gray matter dysfunction and injury.

Is human placental growth hormone increased in maternal serum in pregnancies affected by Down syndrome?

To evaluate the relationship between maternal serum levels of human placental growth hormone (hPGH) and fetal Down syndrome at gestational midtrimester. We retrospectively analyzed samples of serum from 21 women with Down syndrome pregnancies detected at gestational midtrimester. The samples were obtained at 16-23 weeks' gestation during amniocentesis for fetal karyotyping. Sixty-two serum samples were used as controls, which were obtained at 16-23 weeks' gestation from women with singleton, uncomplicated pregnancies, who gave birth to healthy neonates with a birth weight appropriate for gestational age. The hPGH levels were measured by a solid-phase immunoradiometric assay using 2 different epitopes. The median hPGH values in the serum of the Down-syndrome-affected pregnancies were significantly higher (p < 0.05) than those of the normal pregnancies at 16-23 weeks' gestation: the median value in the serum was 9.4 ng/ml (5th to 95th percentiles = 1.49-39.03) versus 4.7 ng/ml (0.53-7.88).

The hPGH levels in maternal serum were found to be higher at 16-23 weeks' gestation in pregnancies affected by fetal Down syndrome. Further investigation is needed to examine if maternal serum hPGH could be used as an additional marker in prenatal screening of Down syndrome at gestational midtrimester.

Does interleukin-6 ( IL-6 ) change the expression of Bcl-2 protein in the prevention of cisplatin-induced apoptosis in ovarian cancer cell lines?

To study whether interleukin-6 (IL-6) changes the expression of the anti-apoptic Bcl-2 protein in the prevention of cis-diaminedichloroplatinum (II) (CDDP)-induced apoptosis of human ovarian cancer cells. Comparative studies were performed on 3 ovarian cancer cell lines after 48 hours of exposure to 0.5-50 ng/ml IL-6, 2 micrograms/ml anti-IL-6 monoclonal antibody (anti-IL-6 mAb), 10 microM CDDP, 10 microM CDDP + 0.5-50 ng/ml IL-6, and 10 microM CDDP + 2 micrograms/ml anti-IL-6 mAb. Apoptosis was measured morphologically and by a DNA fragmentation assay. Bcl-2 protein levels were measured by an ELISA. An increase in apoptosis was observed for each cell line after 48 hours of exposure to 10 microM CDDP. Although high doses of IL-6 decreased the percentage of apoptotic cells, this cytokine did not change the expression of the Bcl-2 protein.

CDDP-induced apoptosis was negatively controlled by IL-6. However, the anti-apoptic Bcl-2 protein level was not changed by IL-6 in the process of apoptosis in the ovarian cancer cell lines.

Does tMEM106B regulate progranulin levels and the penetrance of FTLD in GRN mutation carriers?

To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to determine whether TMEM106B modulates GRN expression. We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD-TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls. In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, p(allelic) = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected p(allelic) = 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected p(recessive) = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = -0.63, p = 7.7 × 10(-5)) and controls (r = -0.49, p = 2.2 × 10(-10)).

In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD.

A population-based study of tuberculosis case fatality in Canada: do Aboriginal peoples fare less well?

The Province of Alberta, Canada. To explore trends in tuberculosis (TB) case fatality, compare TB case-fatality rates by population group and determine prognostic factors associated with TB-related death in Alberta from 1996 to 2012. Retrospective cohort analysis. During the study years, all-cause TB case fatality fell from 10.7% to 6.3%; the fall was attributable to a change in population structure, as there were more foreign-born and fewer older cases with time. A stable 2% of TB cases died without treatment. Compared to other population groups, Canadian-born Aboriginal case patients were more likely to die without treatment and to die younger. Of TB deaths that were TB-related, 68.9% occurred before or during the initial phase of treatment; of these, TB was a contributory cause of death in 77.5%, i.e., another medical condition was the primary cause of death. In multivariate analysis, age>64 years, aboriginality and miliary/disseminated or central nervous system disease were independent predictors for TB-related death.

Preventive therapy for those with latent tuberculous infection and a high-risk medical condition, early diagnosis of disease, and special support of older, Aboriginal or comorbid cases, once diagnosed, are necessary to further minimise TB case fatality in Alberta, Canada.

Does sMURF1 silencing diminish a CD44-high cancer stem cell-like population in head and neck squamous cell carcinoma?

Bone morphogenetic protein (BMP) signaling is thought to play key roles in regulating the survival and maintenance of cancer stem cells (CSCs), which contribute to disease recurrences and treatment failures in many malignances, including head and neck squamous cell carcinoma (HNSCC). Intracellular BMP signaling is regulated by SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) during cellular development. However, little is known about the role or regulation of BMP signaling in HNSCC CSCs. Two CSC-like populations, CD44(high)/BMI1(high) and CD44(high)/ALDH(high), were enriched from HNSCC cell lines and evaluated for the expression of SMURF1 by qRT-PCR, flow cytometry, and immunoblotting. The activation status of BMP signaling in these populations was determined by using immunoblotting to detect phosphorylated SMAD1/5/8 (pSMAD1/5/8) levels. Knockdown of SMURF1 transcripts by RNA interference was used to assess the role of SMURF1 in BMP signaling and CSC maintenance. Loss of CSC-like phenotypes following SMURF1 knockdown was determined by changes in CD44(high) levels, cellular differentiation, and reduction in colony formation. Populations of enriched CSC-like cells displayed decreased levels of pSMAD1/5/8 and BMP signaling target gene ID1 while SMURF1, CD44, and BMI1 were highly expressed when compared to non-CSC populations. Stable knockdown of SMURF1 expression in CSC-like cells increased pSMAD1/5/8 protein levels, indicating the reactivation of BMP signaling pathways. Decreased expression of SMURF1 also promoted adipogenic differentiation and reduced colony formation in a three-dimensional culture assay, indicating loss of tumorigenic capacity. The role of SMURF1 and inhibition of BMP signaling in maintaining a CSC-like population was confirmed by the loss of a CD44(high) expressing subpopulation in SMURF1 knockdown cells.

Our findings suggest that inhibition of BMP signaling potentiates the long-term survival of HNSCC CSCs, and that this inhibition is mediated by SMURF1. Targeting SMURF1 and restoring BMP signaling may offer a new therapeutic approach to promote differentiation and reduction of CSC populations leading to reduced drug resistance and disease recurrence.

Do p66 Shc tumor levels show a strong prognostic correlation with disease outcome in stage IIA colon cancer?

Most stage IIA colon cancer patients receive no adjuvant therapy despite an estimated 15% risk of disease-related death within 5 years of resection. Prognostication of disease outcome would benefit the clinician by categorizing patients with stage IIA disease by risk. The abundance of the signal transduction proteins p66 Shc and tyrosine-phosphorylated (PY)-Shc in tumor cells is a prognostic indicator of disease outcome in breast cancer, suggesting that Shc analysis may provide prognostic information in stage IIA colon cancer. Immunohistochemical staining of p66 Shc and PY-Shc was examined in resection specimens from 240 chemotherapy-naïve patients with stage IIA (T(3)N(0)M(0)) colon cancer from two independent (130 and 110 cases, respectively) retrospective cohorts. Staining was scored on a 0 to 5 scale and correlated with relapse-free survival and disease-specific survival in a multivariate analysis to obtain hazard ratios (HR) for both outcomes. In a pooled analysis of both cohorts, p66 Shc score was a significant prognostic indicator of relapse-free survival (full-range HR, 13.0; P = 0.012) and disease-specific survival (full-range HR, 36.6; P = 0.004) when analyzed as a continuous variable in a multivariate Cox proportional hazards model stratified by study site and adjusted for age, sex, grade, and lymphovascular involvement. PY-Shc in this multivariate Cox model, however, did not achieve statistical significance for either outcome.

Measuring p66 Shc tumor levels provides a unique and simple tool for stratifying stage IIA colon cancer patients by risk of recurrence and disease-specific death and may assist in determining treatment strategies for these patients.

Does longitudinal mechanical tension induce growth in the small bowel of juvenile rats?

The aim of our study was to apply longitudinal force to the small bowel to increase the length of intestine in juvenile rats. Fifty juvenile rats had double barrelled, blind loop ostomies created using an isolated segment of bowel. Our intestinal lengthening device was inserted into one of the loops and the second loop served as a control. Once the device was deployed, the experimental, control, and in situ segments of bowel were evaluated for length, weight, histology, and disaccharidase enzyme activity. Mechanical tension increased intestinal length by 149%. The lengthened bowel also exhibited a greater total weight (218%), greater mucosal weight (122%), and increased protein mass (164%) compared with the control limb of bowel. Histologically, there was a markedly increased thickness of the muscularis propria in the lengthened bowel (200% increase compared with the control limb). Functionally, we found increased total disaccharidase activity in the lengthened bowel (between 47% and 350%, depending on the particular enzyme tested; p<0.01).

Mechanical tension induces intestinal growth by increasing length, weight of the bowel and mucosa, and protein mass. Histological changes, such as increases in Paneth cells, suggest that increased proliferation and reorganisation of the mucosa and muscularis propria are a response to mechanical tension. Functionally, increased intestinal length corresponds with increased disaccharidase activity, thus implying potential increased absorptive capacity of the lengthened bowel.

Does [ Bicyclol protect rat thoracic aorta from superoxide anion-induced inhibition of vascular relaxation ]?

To investigate the effect of bicyclol on vascular oxidative stress injury induced by superoxide anion. Rat thoracic aortic rings were isolated for isometric tension recording using organ bath technique. Superoxide arterial injury was induced by pyrogallol exposure, and the effect of bicyclol on endothelium-dependent relaxation was evaluated. Bicyclol (10(-8) - 10(-5) mol/L) relaxed endothelium-intact aortic rings precontracted by phenylephrine. This effect was abolished by L-NAME, an inhibitor of nitric oxide synthase and indomethacin, an inhibitor of cyclooxygenase. Exposure to pyrogallol (500 micromol/L) resulted in decrease of acetylcholine(ACh)-induced endothelium-dependent relaxation in aortic rings, and pre-incubation of bicyclol (10(-5) mol/L) for 45 min improved the relaxation attenuated by pyrogallol. In aortic rings pre-treated with indomethacin, bicyclol increased the ACh-induced relaxation that was inhibited by pyrogallol (500 micromol/L). This effect was not found in aortic rings pre-treated with L-NAME.

Bicyclol has endothelium-dependent vasodilating effect on rat thoracic aorta and improves vascular function by attenuating oxidative stress. Nitric oxide from endothelium is involved in the anti-oxidative effect of bicyclol.

Does exercise reduce inflammation and cell proliferation in rat colon carcinogenesis?

There is evidence that the risk of colon cancer is reduced by appropriate levels of physical exercise. Nevertheless, the mechanisms involved in this protective effect of exercise remain largely unknown. Inflammation is emerging as a unifying link between a range of environment exposures and neoplastic risk. The carcinogen dimethyl-hydrazine (DMH) induces an increase in epithelial cell proliferation and in the expression of the inflammation-related enzyme cyclooxigenase-2 (COX-2) in the colon of rats. Our aim was to verify whether these events could be attenuated by exercise. Four groups of eight Wistar rats were used in the experiment. The groups G1 and G3 were sedentary (controls), and the groups G2 and G4 were submitted to 8 wk of swimming training, 5 d.wk. The groups G3 and G4 were given subcutaneous injections of DMH immediately after the exercise protocols. Fifteen days after the neoplasic induction, the rats were sacrificed and the colon was processed for histological examination and immunohistochemistry staining of proliferating cell nuclear antigen (PCNA) and COX-2. We found a significant increase in the PCNA-labeling index in both DMH-treated groups of rats. However, this increase was significantly attenuated in the training group G4 (P < 0.01). Similar results were observed in relation to the COX-2 expression.

From our findings, we conclude that exercise training exerts remarkable antiproliferative and antiinflammatory effects in the rat colonic mucosa, suggesting that this may be an important mechanism to explain how exercise protects against colonic cancer.

Does laparoscopic colorectal surgery modify risk factors for postoperative morbidity?

The aim of this study was to evaluate whether laparoscopic colorectal surgery can modify the risk factors for the occurrence of postoperative morbidity. A total of 384 consecutive patients with colorectal disease were randomized to laparoscopic resection (n = 190) or open resection (n = 194). On admission, demographics, comorbidity, and nutritional status were recorded. Operative variables, patient outcome, and length of stay were also recorded. Postoperative complications were registered by four members of staff not involved in the study. The overall morbidity rate was 27.1 percent, with the rate in the laparoscopic group (18.7 percent) being less than that in the open group (31.5 percent; P = 0.003). Patients who underwent laparoscopic resection had a faster recovery of bowel function (P = 0.0001) and a shorter length of stay (P = 0.0001). In the whole cohort of patients, multivariate analysis identified open surgery (P = 0.003), duration of surgery (P = 0.01), and homologous blood transfusion (P = 0.01) as risk factors for postoperative morbidity. In the open group, blood loss (P = 0.01), homologous blood transfusion (P = 0.01), duration of surgery (P = 0.009), weight loss (P = 0.06), and age (P = 0.08) were related to postoperative morbidity. In the laparoscopic group the only risk factor identified was duration of surgery (P = 0.005).

In the laparoscopic group, both postoperative morbidity and length of stay were significantly reduced and most risk factors for postoperative morbidity disappeared.

Does vEGF stimulate the ERK 1/2 signaling pathway and apoptosis in cerebral endothelial cells after ischemic conditions?

Cerebral endothelial cells that line microvessels play an important role in maintaining blood flow homeostasis within the brain-forming part of the blood-brain barrier. These cells are injured by hypoxia-induced reperfusion, leading to blood-brain barrier breakdown and exacerbation of ischemic injury. We investigated the roles of vascular endothelial growth factor (VEGF) and the downstream extracellular signal-regulated kinase (ERK) protein after oxygen-glucose deprivation (OGD) in primary endothelial cells. Primary mouse endothelial cells were isolated and subjected to OGD. Western analysis of VEGF and ERK 1/2 protein levels was performed. Cells were transfected with VEGF small interference RNA. A terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL) assay and DNA fragmentation assay were used on mouse endothelial cells that overexpress copper/zinc-superoxide dismutase (SOD1). VEGF protein expression was induced and its receptor, Flk-1, was stimulated by OGD. Phosphorylation of ERK 1/2 protein levels was upregulated. Inhibition of phosphorylated ERK (pERK) expression by U0126 reduced endothelial cell death by OGD. Transfection of small interfering RNA for VEGF also inhibited an increase in pERK, suggesting that VEGF acts via ERK. The TUNEL and DNA fragmentation assays showed a significant decrease in TUNEL-positivity in the SOD1-overexpressing endothelial cells compared with wild-type cells after OGD.

Our data suggest that OGD induces VEGF signaling via its receptor, Flk-1, and activates ERK via oxidative-stress-dependent mechanisms. Our study shows that in cerebral endothelial cells the ERK 1/2 signaling pathway plays a significant role in cell injury after OGD.

Does addition of an aminopeptidase N-binding sequence to human endostatin improve inhibition of ovarian carcinoma growth?

Blood vessels in tumors express higher level of aminopeptidase N (APN) compared with normal tissues. It has been reported that peptides that contain asparagine-glycine-arginine (NGR) sequence home to APN in tumor vasculature. Increased expression of APN in tumor vascular endothelium, therefore, offers an opportunity to target NGR peptide-linked therapeutic reagents to tumors. To determine whether an additional NGR sequence could improve endothelial homing and biologic activity, human endostatin was modified genetically to introduce an NGR motif (NGR-endostatin) and was expressed in yeast. In vitro biologic activity of NGR-endostatin was compared with the native protein in endothelial cell proliferation and migration. NGR-modified endostatin was used in tumor localization studies. Finally, the effects of endostatin and NGR-endostatin on tumor growth were determined in two model systems. Human endostatin has an internal NGR sequence, which is not accessible to bind APN. However, the addition of an NGR-sequence at the amino terminus resulted in strong binding and inhibition of endothelial cell APN. NGR-endostatin showed increased binding to endothelial cells compared with the native protein. Increased binding of endostatin also coincided with improved antiangiogenic properties of endostatin. NGR modification improved tumor localization and, as a consequence, effectively inhibited ovarian carcinoma growth in athymic nude mice.

These studies demonstrated that human endostatin can be modified genetically to improve its ability to inhibit tumor growth.

Does combination therapy of gamma-aminobutyric acid derivative promote proton pump inhibitor based healing of reflux esophagitis in animal model?

The present study was undertaken to elucidate the effect of omeprazole and baclofen on experimental esophagitis in albino rats. Groups of rats, fasted overnight received normal saline (3 ml/kg, ip; sham control) or toxic control (3 ml/kg, ip) or omeprazole (30 mg/kg, ip) or baclofen (20 mg/kg, ip) or their combinations, were subjected to the pylorus and forestomach ligation. Animals were sacrificed after 6 h and evaluated for the gastric pH, volume of gastric juices, total acidity, esophagitis index and free acidity. Esophageal tissues were further subjected to estimations of TBARS, GSH, catalase and SOD. Treatment with omeprazole and baclofen significantly inhibited the gastric secretion, total acidity and esophagitis index. The treatment also helped to restore the altered level's oxidative stress parameters to normal.

The beneficial effect of omeprazole and baclofen against GERD could be conglomerately attributed to the antisectretory action of omeprazole and reduction in the tracheal lower esophageal sphincter release rate by baclofen.

Does psychological stress exert effects on pathogenesis of hepatitis B via type-1/type-2 cytokines shift toward type-2 cytokine response?

Psychological and physical stress has been demonstrated to have an impact on health through modulation of immune function. Despite high prevalence of stress among patients with hepatitis B virus (HBV) infection, little is known about whether and how stress exerts an effect on the course of hepatitis B. Eighty patients with chronic hepatitis B(CHB) completed the Perceived Stress Scale-10(PSS-10) and State-Trait Anxiety Inventory(STAI). Fresh whole blood was subject to flow cytometry for lymphocytes count. Plasma samples frozen at -80 °C were thawed for cytokines, alanine aminotransferase (ALT), and virus load. These patients were grouped into high or low perceived stress, state anxiety and trait anxiety groups according to the scale score. Sociodemographic, disease-specific characteristics, lymphocytes count and cytokines were compared. Firstly, a negative association between ALT and stress (t =  -4.308; p =  .000), state anxiety (t =  -3.085; p =  .003) and trait anxiety (t =  -4.925; p =  .000) were found. As ALT is a surrogate marker of hepatocytes injury, and liver injury is a consequence of immune responses. Next, we tested the relationship between stress/anxiety and lymphocytes. No statistical significance were found with respect to counts of total T cells, CD4+ T cell, CD8+ T cell, NK cell, and B cell count between high and low stress group. Type-2 cytokine interleukin-10 (IL-10) level was significantly higher in high stress group relative to lower counterpart (t = 6.538; p = 0.000), and type-1 cytokine interferon-gamma (IFN-γ) level shown a decreased tendency in high stress group (t =  -1.702; p = 0.093). Finally, INF-γ:IL-10 ratio displayed significant decrease in high perceived stress(t =  -4.606; p = 0.000), state anxiety(t =  -5.126; p = 0.000) and trait anxiety(t =  -4.670; p = 0.000) groups relative to low counterparts.

Our data show stress is not related to the lymphocyte cells count in CHB patients, however, stress induces a shift in the type-1/type-2 cytokine balance towards a type-2 response, which implicated a role of psychological stress in the course of HBV related immune-pathogenesis.

Does 4-Aminopyridine restore impaired hypoxic pulmonary vasoconstriction in endotoxemic mice?

Hypoxic pulmonary vasoconstriction (HPV) is impaired during inflammatory lung processes such as pneumonia or the acute respiratory distress syndrome. Voltage-gated potassium channels play a central role in mediating HPV. The aim of this study was to determine whether 4-aminopyridine (4-AP), a known voltage-gated potassium channel inhibitor, may restore HPV in sepsis. The effects of 0.01, 0.1, and 1.0 mm 4-AP on HPV responsiveness were assessed in isolated lungs of untreated mice and of mice 18 h after lipopolysaccharide injection (20 mg/kg intraperitoneal Escherichia coli 0111:B4 lipopolysaccharide). HPV was quantified as the increase in perfusion pressure in response to hypoxic ventilation in percent of baseline perfusion pressure. Intrinsic pulmonary vascular resistance (R0) and pulmonary vascular distensibility (alpha) were determined by nonlinear regression analysis of pulmonary vascular pressure-flow curves generated during normoxic and hypoxic ventilation, respectively. HPV was impaired in lungs isolated from lipopolysaccharide-challenged mice. Addition of 4-AP to the perfusate did not alter HPV responsiveness in untreated mice but dose dependently restored HPV in endotoxemic mice. Analysis of pulmonary vascular pressure-flow curves revealed that 4-AP (1) counteracted the observed lipopolysaccharide-induced changes in alpha and R0 under normoxic conditions and (2) augmented the hypoxia-induced increase in R0 in lungs of endotoxemic mice.

This study demonstrates that lipopolysaccharide-induced pulmonary vascular hyporesponsiveness to hypoxia can be restored by 4-AP in murine endotoxemia and, thus, may be a new therapeutic approach to treat patients with hypoxemia due to impaired HPV.

Do pancreatic duct stents cause or prevent pancreatic sepsis?

Pancreatic sepsis can occur after contrast injection into an obstructed or disrupted pancreatic duct. Whether stents cause or prevent pancreatic sepsis is unknown. Accordingly, the pancreatic duct bacteriology in patients with pancreatic duct stents was retrospectively reviewed and contrasted with biliary cultures taken from patients at the time of bile duct stent retrieval and/or exchange. Of 61 patients (29 men, 32 women; 72 stents; mean age 51 [16] years, range 14-88 years), 36 with pancreatic duct stents had pancreatic duct cultures obtained at the time of stent exchange and/or retrieval. The results of these cultures were compared with bile duct cultures taken from 36 patients at the time of biliary stent exchange/retrieval. Eleven of the 36 patients with pancreatic duct stents also had bile duct stents. Data collected included stent patency, clinical sepsis at initial stent placement or retrieval, administration of antibiotics before the procedure, indication for stent placement, stent duration, and culture results. At stent retrieval and/or exchange, all 61 patients with pancreatic and/or biliary stents had contamination of the respective ducts with multiple enteric bacteria (mean 3.4 organisms in patients with pancreatic duct stents vs. 3.3 in those with bile duct stents). Clostridium perfringens was found in 17% and 0% of patients with, respectively, bile duct and pancreatic duct stents. Among the most common indications for pancreatic duct stent placement were stricture (28), sphincterotomy (9), leak (7), stones (3), and dilated pancreatic duct (1). Indications for a biliary stent included benign stricture (29), malignancy (6), stones (2), cholangitis (1), chronic pancreatitis (1), and dilated common bile duct (1). Pancreatic cultures were taken at a median of 85 days (interquartile range 60-126; range 13-273) and biliary cultures at a median of 87 days (interquartile range 45-149; range 19-927) after stent placement. Eleven patients, 6 with a bile duct stent, 4 with a pancreatic duct stent, and one with dual stents, developed pre-exchange/retrieval clinical sepsis; 3 had pancreatic sepsis. All had received antibiotics at initial placement. In the 11 patients with sepsis (12 stents), 8 stents were completely occluded at exchange/retrieval, 3 were partially occluded, and one was patent. In 50 patients (60 stents), no clinical sepsis developed; 7 stents were patent, 31 partially occluded, and 22 completely obstructed.

(1) Comparable to patients with biliary stents, all patients with pancreatic stents had contamination of the pancreatic ductal system by enteric flora. (2) In contrast to the 17% of patients with bile duct stents who had intraductal Clostridium perfringens, there were no instances of contamination with this organism in patients with pancreatic stent (p = 0.025), although, after adjusting for multiple comparisons, statistical significance was lost. (3) There was a tendency for stent occlusion to predispose to pancreatic sepsis, but occlusion by itself was insufficient (p = 0.106). (4) Further investigation is required to define the additional variables that are associated with the development of pancreatic sepsis.

Do multiplicity in the high-frequency signals during the short-latency somatosensory evoked cortical activity in humans?

Recent studies using electroencephalography or magnetoencephalography have shown that peripheral nerve stimulations produce short-latency high-frequency signals in the human somatosensory cortex. The present study tested whether they consist of more than one distinct type of signal. Somatic evoked magnetic fields (SEFs) elicited by electrical stimulation of the median nerve were measured in 12 healthy volunteers. They were analyzed using a time-frequency analysis method based on Gabor filters and another based on autoregressive moving average, and also with bispectrum and bicoherence techniques and a new dispersion curve method. Signals in two separate high-frequency bands (200 and 600 Hz) were distinguished from the main signal in the low frequency (LF) range during the time period of N20m and P25m. The novel 200 Hz-band signal was seen reliably in those channels where the LF band signal was weak, so that the former was not masked by the latter. The 600 Hz signal consisted of two distinct components or parts (p1 and p2) in 10 out of 12 subjects, one peaking during ascending slope and the second during the descending slope of the N20m. The latency of the p1 was shorter than the latencies of the 200 Hz and LF signals according to the dispersion curve analysis. The inter-peak interval of p1 became shorter for later peaks in all 12 subjects. Bicoherence analysis revealed a significant phase coupling between the 200 and 600 Hz bands.

There are three distinct types of signal during the time period of the short-latency cortical components of the SEF -- LF which gives rise to the commonly seen waveform of the SEF, the newly found 200 Hz signal and the 600 Hz signal which consists of two components. The possible origins of the high frequency signals are discussed in light of the new set of evidence found in the present study.

Does range of motion physiotherapy reduce the force deficit in antagonists to denervated rat muscles?

We used a rat hindlimb model of tibial nerve transection to determine if a loss of mechanical function exists in innervated antagonists compared with denervated muscles. We tested two hypotheses: (1) denervation of the rat ankle plantar flexors results in decreased force production of the ankle dorsiflexors, and (2) daily passive ankle range of motion (ROM) physiotherapy prevents or reduces the force deficit. Adult Lewis rats were assigned to one of three groups: (1) a sham (S) group, in which the tibial nerve was exposed but not transected; (2) a no rehabilitation (NR) group, in which a 2-cm segment of tibial nerve was excised at midthigh to denervate the ankle plantar flexors; or (3) a rehabilitation (R) group, in which a 2-cm segment of tibial nerve was excised and the animals were subjected to ankle passive ROM physiotherapy for two 5-min sessions each day. After 14 days, maximum isometric tetanic force (F(0)) and specific force (sF(0)) were measured in the extensor digitorum longus (EDL) muscle, an ankle dorsiflexor. Compared with those from animals in the S group, EDL muscles from animals in the NR group demonstrated a 22% decrease in both F(0) and sF(0). In the EDL from animals in the R group, daily passive ROM physiotherapy diminished the deficit in F(0) but not in sF(0).

These data support the hypotheses that nerve injuries result in impaired mechanical function in the innervated antagonists to denervated muscles and that passive ROM physiotherapy can improve force production in these muscles.

Does intermittent pneumatic compression prevent venous stasis in the lower extremities in the lithotomy position?

To investigate the interactions of a new lithotomy positioning device (LPD) with two intermittent pneumatic compression (IPC) devices by measuring femoral venous flow velocity. Subjects were divided into three groups: 1) supine position as a control, 2) lithotomy position using a conventional LPD, and 3) lithotomy position using a new LPD, Levitator(TM). These three groups were further divided in two according to the type of IPC device used: AV-impulse(TM) (rapid IPC) and SeQuel(TM) (standard IPC). Peak femoral venous flow velocity was measured by using an ultrasonic echo diagnostic device. Data were analyzed by one-way ANOVA with Fisher's test or by the unpaired two-tailed t test. Moving to the conventional lithotomy position from the supine position, venous flow velocity was decreased by 38% in both IPC device groups. Even when the new LPD was used to support the lithotomy position, the flow velocity was decreased by 24%, but the velocity was significantly higher than in the conventional lithotomy position. Both rapid and standard IPC devices increased flow velocity to 77% and 107% (first compression) and to 71% and 84% (fifth compression) of the control values during compression, respectively. In the lithotomy position group using the new LPD, similar increases in flow were seen with the use of IPC devices.

Both rapid and standard IPC devices are useful for maintaining venous flow of the lower extremities in the lithotomy position.

Do phenolic diterpenes derived from Hyptis incana induce apoptosis and G ( 2 ) /M arrest of neuroblastoma cells?

Neuroblastoma is one of the most commonly encountered solid tumors in the pediatric age group, and the prognosis of patients with advanced neuroblastoma is very poor. In this study, the antitumor effects of five phenolic diterpenes derived from Hyptis incana (Lamiaceae), a Brazilian medicinal plant, were examined on neuroblastoma cells. Cytotoxicity was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptotic nuclear shrinkage was monitored by Hoechst 33342 staining. The cell-cycle status was evaluated by flow cytometry and protein alterations were monitored by western blotting. Differentiated cells were photographed and counted in a randomized fashion. All of the examined compounds exhibited significant cytotoxicity towards the neuroblastoma cells. In particular, 7-ethoxyrosmanol had a high degree of efficacy. Nuclear condensation and degradation of procaspase-3 and -9 were observed after treatment of the cells with these compounds. Moreover, phenolic diterpenes induced cell-cycle arrest in the G(2)/M phase. Rosmanol and epirosmanol tended to induce differentiation.

Phenolic diterpenes isolated from H. incana have multiple antitumor effects on neuroblastoma cells.