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Is postprandial gastrointestinal hormone production different , depending on the type of reconstruction following total gastrectomy? | The present study examines the differences in gastrointestinal hormone production at 3 different reconstruction types after total gastrectomy. Total gastrectomy causes significant weight loss, mainly due to a reduced caloric intake probably because of a lack of initiative to eat or early satiety during meals. Behind this phenomenon a disturbed gastrointestinal hormone production can be presumed. Patients participating in a randomized study were recruited for the clinical experiment. Seven patients with simple Roux-en-Y reconstruction, 11 with aboral pouch (AP) construction, and 10 with aboral pouch with preserved duodenal passage (APwPDP) reconstruction, as well as 6 healthy volunteers were examined. Blood samples were taken 5 minutes before and 15, 30, and 60 minutes after ingestion of a liquid test meal. Plasma concentrations for insulin, cholecystokinin, and somatostatin were determined by radioimmunoassay analysis. Postprandial hyperglycemia was observed in patients after total gastrectomy most prominently in groups with duodenal exclusion (Roux-en-Y and AP) compared with healthy controls. Postprandial insulin curves reached significantly higher levels in all operated groups compared with controls, however, with no difference according to reconstruction type. Significantly higher cholecystokinin levels and higher integrated production of cholecystokinin were observed in Roux-en-Y and AP groups compared with APwPDP and control. Postprandial somatostatin levels were significantly different between the 4 groups, and highest levels and integrated secretions were reached in AP group, lowest in APwPDP and normal groups. | To compare single- and multiple-dose maraviroc exposures in cervicovaginal fluid (CVF) and vaginal tissue (VT) with blood plasma (BP) and quantify maraviroc protein binding in CVF. Open-label pharmacokinetic study. In 12 HIV-negative women, 7 paired CVF and BP samples were collected over 12 hours after 1 maraviroc dose. Subjects then received maraviroc twice daily for 7 days. After the last dose, subjects underwent CVF and BP sampling as on day 1, with additional sampling during terminal elimination. VT biopsies were obtained at steady state. Day 1 and day 7 median maraviroc CVF AUCtau were 1.9- and 2.7-fold higher, respectively, than BP. On day 1, 6 of 12 subjects had detectable maraviroc CVF concentrations within 1 hour; 12 of 12 were detectable within 2 hours, and all exceeded the protein-free IC90. On day 7, maraviroc CVF protein binding was 7.6% and the VT AUCtau was 1.9-fold higher than BP. Maraviroc CVF concentrations 72 hours after dose and BP concentrations 12 hours after dose were similar. |
Does a comparison of cancer burden and research spending reveal discrepancies in the distribution of research funding? | Ideally, the distribution of research funding for different types of cancer should be equitable with respect to the societal burden each type of cancer imposes. These burdens can be estimated in a variety of ways; "Years of Life Lost" (YLL) measures the severity of death in regard to the age it occurs, "Disability-Adjusted Life-Years" (DALY) estimates the effects of non-lethal disabilities incurred by disease and economic metrics focus on the losses to tax revenue, productivity or direct medical expenses. We compared research funding from the National Cancer Institute (NCI) to a variety of burden metrics for the most common types of cancer to identify mismatches between spending and societal burden. Research funding levels were obtained from the NCI website and information for societal health and economic burdens were collected from government databases and published reports. We calculated the funding levels per unit burden for a wide range of different cancers and burden metrics and compared these values to identify discrepancies. Our analysis reveals a considerable mismatch between funding levels and burden. Some cancers are funded at levels far higher than their relative burden suggests (breast cancer, prostate cancer, and leukemia) while other cancers appear underfunded (bladder, esophageal, liver, oral, pancreatic, stomach, and uterine cancers). | Medium composition and assay parameters for assessing human sperm hyperactivated motility (HA) were investigated during a time-course study. The incidence of HA was studied, in vitro, in sperm samples incubated in eight different media compositions. HA was assessed using the 7.1 version of the Hamilton Thorn Motion Analyzer (HTM). The HA expressed at four hours with human tubal fluid (HTF) was 21.5 +/- 1.1% (mean +/- SEM), and that in Ham's F10 medium was 20.1 +/- 1.4% when the media were supplemented with pregnant women's serum (PWS), a novel support for HA. When fetal cord serum (FCS) was used instead of PWS, the HA exhibited was 16.8 +/- 2.3% and 13.5 +/- 2.35% in HTF and Ham's F10, respectively. Addition of human serum albumin (HSA) to HTF or Ham's F10 media supported HA peak at the four-hour time point (HTF, 19.5 +/- 5.0%; Ham's F10, 10.6 +/- 3.2%). On the other hand, the peak HA expressed in synthetic tubal fluid (STF) supplemented with PWS was 6.0 +/- 0.7% at the two-hour time point. Intra-Menezo B2 medium (IMB2) supported HA at the two- and four-hour time points, but not at six hours. HA appeared much less when Biggers-Whitten-Whittingham (BWW) medium was used. |
Is motor cortical activity during motor tasks normal in patients with complex regional pain syndrome? | Motor dysfunction in complex regional pain syndrome (CRPS) is often considered a functional movement disorder. Earlier studies in patients with functional movement disorders found evidence of cortical inhibition during explicit but not implicit motor tasks, suggesting active inhibition from other brain areas. In this study, we explored whether active inhibition occurs in CRPS patients. We compared patients with CRPS with 2 control groups: healthy controls matched for age and sex, and patients whose hand was immobilized to treat a scaphoid fracture. We used transcranial magnetic stimulation to measure corticospinal excitability at rest and during motor imagery (explicit motor task) and motor observation (implicit motor task). Motor corticospinal excitation measured at rest and during implicit and explicit motor tasks was similar for CRPS patients and healthy controls. Patients with an immobilized hand showed an absence of motor cortical excitation of the corresponding hemisphere during motor imagery of tasks involving the immobilized hand, but not during motor observation. The normal motor cortical processing during motor imagery and motor observation found in the corresponding hemisphere of CPRS patients suggests that the nature of motor dysfunction in this condition differs from that described in literature for patients with functional paresis or under circumstances of limb immobilization. | Applications of the anticancer agent, ellipticine, have been limited by its hydrophobicity and toxicity. An efficient delivery system is required to exploit the enormous potential of this compound. Recently, EAK16-II, an ionic-complementary, self-assembling peptide, has been found to stabilize ellipticine in aqueous solution. Here, the anticancer activity of ellipticine encapsulated in EAK16-II (EAK-EPT) was evaluated in vitro and in vivo. Our cellular uptake, toxicity, and apoptosis results in an A549 human lung carcinoma cell line indicate that EAK-EPT complexes are significantly more effective than treatment with EAK16-II or ellipticine alone. This is due to the ability of EAK16-II to stabilize ellipticine in a protonated state in well formed nanostructures approximately 200 nm in size. In vivo observations in an A549 nude mouse tumor model show higher antitumor activity and lower cytotoxicity of EAK-EPT complexes than in the control group treated with ellipticine alone. Tumor growth in animals was significantly inhibited after treatment with EAK-EPT complexes, and without any apparent side effects. |
Do uterine leiomyomas express a molecular pattern that lowers retinoic acid exposure? | To analyze expression of the retinoic acid signaling pathway genes that are involved in retinol metabolism, transport, transcriptional activation, and transcriptional products in spontaneous human leiomyomas. Laboratory study of human leiomyoma and patient-matched myometrial tissue. Eight women undergoing hysterectomy for symptomatic leiomyomas. Confirmation of an altered retinoic acid pathway analyzed by microarray, real time reverse transcription-polymerase chain reaction, Western blot, immunohistochemistry, and high-performance liquid chromatography (HPLC). Gene and protein expression. Regardless of patient demographics and leiomyoma location and size, we found decreased expression of the major genes involved in retinoic acid pathway including alcohol dehydrogenase-1 (-3.97- +/- 0.03-fold), aldehyde dehydrogenase-1 (-3.1- +/- 0.07-fold), cellular retinol binding protein-1 (-2.62- +/- 0.04-fold), and cellular retinoic acid binding protein-1 (-2.42- +/- 0.20-fold). Cytochrome P450 (CYP 26A1), which is responsible for retinoic acid metabolism, was highly up-regulated in leiomyomas (+5.4- +/- 0.53-fold). Nuclear receptors demonstrated a complex pattern of under-expression (RARalpha, RARbeta, RXRalpha, RXRgamma) and over-expression (RARgamma, RXRbeta) at both the mRNA and protein level. Differences in protein amounts were confirmed by Western blot. Finally, a reduced amount of cellular ATRA and 9-cis retinoic acid was confirmed by HPLC in leiomyomas compared with myometrial tissues. | There is a lot of evidence that angina during the 24-48 h before a reperfused myocardial infarction improves the evolution of the patients. However, there are studies that failed to demonstrate this protective effect of preinfarction angina in an interventional reperfusion setting. To compare the effect of preinfarction angina (PIA) on inhospital evolution of thrombolysis vs. interventionally reperfused acute myocardial infarction (AMI). There were prospectively studied 133 consecutive AMI patients, eligible for reperfusion (thrombolysis or interventional). History of PIA under 48 hours was obtained. Evolution of AMI was evaluated considering the following end-points: the ratio between the number of ECG leads with final pathologic Q wave and the number of leads with initial ST elevation, CK-MB values, separate and composite incidence of death, heart failure, shock and incidence of serious arrhythmia (sustained VT or ventricular fibrillation). ECG ratio was lower in patients with PIA (0.511 +/- 0.281 vs. 0.646 +/- 0.274, p=0.02) in thrombolysed patients, but it was higher in interventionally reperfused patients (0.740 +/- 0.418 vs. 0.554 +/- 0.295 p=0.11). CK-MB values were lowered by PIA in thrombolysed AMI (122 +/- 74 vs. 190 +/- 89, p=0.0003), but they were not in the interventional group. Clinical end-points were slightly less frequent in patients with PIA, in both reperfusion groups, but not statistically significant. Major arrhythmia occurred less frequently in interventionally reperfused patients with PIA (9.5% vs. 31.6%, p=0.12). |
Does sucrose concentration influence the rate of human oocytes with normal spindle and chromosome configurations after slow-cooling cryopreservation? | Recently described slow-cooling cryopreservation protocols involving elevated sucrose concentration have improved survival frequencies of human oocytes, potentially overcoming a major hurdle that has limited the adoption of oocyte storage. Because implantation rates of embryos from frozen oocytes remain generally low, it is still debated whether, irrespective of survival rates, this form of cryopreservation leads inevitably to the disruption or complete loss of the metaphase II (MII) spindle. Human oocytes with an extruded polar body I (PBI) were cryopreserved using a slow-cooling method including 1.5 mol/l propane-1,2-diol (PrOH) and alternative sucrose concentrations (either 0.1 or 0.3 mol/l) in the freezing solution. Fresh control and frozen-thawed survived oocytes were analysed by confocal microscopy to evaluate MII spindle and chromosome organizations. Of the 104 oocytes included in the unfrozen group, 76 (73.1%) displayed normal bipolar spindles with equatorially aligned chromosomes. Spindle and chromatin organizations were significantly affected (50.8%) after cryopreservation involving lower sucrose concentration (61 oocytes), whereas these parameters were unchanged (69.7%) using the 0.3 mol/l sucrose protocol (152 oocytes). | High anxiety has been reported in patients with drug hypersensitivity reaction (DHR); however, its relationship with the test results was not studied previously. We aimed to investigate the association of patient anxiety with the results of drug tests together with the other contributing factors. Sixty-seven patients were included in the study between November 2012 and April 2013, in whom drug tests were performed after clinical evaluation and application of the Penn State Worry Questionnaire (PSWQ). The mean ± standard deviation (SD) age was 43.5 ± 12.9 years, and 73.1% of the patients were females. The patient group had significantly higher mean ± SD PSWQ score than 35 control subjects without histories of DHRs and major psychiatric disorders (47.95 ± 14.64 versus 40.22 ± 11.86, p = 0.008). However, the mean ± SD. PSWQ score of the patients with positive drug test results was not significantly different from the patients with negative drug test results (46.06 ± 13.41 versus 50.47 ± 18.02, p = 0.32). Panic attack symptoms were more common in the reactions with positive test results than in the reactions with negative test results (74.0% versus 48.9%, p = 0.01). However, presence of panic attack symptoms [odds ratio (OR): 1.25, 95% confidence interval (CI): 0.44-3.54; p = 0.67] was not found independently associated with positive test results in the multiple logistic regression model. |
Does general anesthesia affect the serum complexed and free prostate specific antigen levels? | Serum prostate-specific antigen (PSA) level is a widely used serum marker for diagnosis and management of prostate cancer. Although not well-defined, liver appears to be the most likely site of PSA metabolism. However, general anaesthesia usually changes hepatic blood flow, therefore it may affect the metabolism of PSA. In this study we investigated the affect of general anaesthesia on the serum total PSA, free PSA and free to total PSA levels. 30 male patients who were hospitalised in the internal medicine clinic (non-surgery group) and 30 male patients who would undergo operation under general anaesthesia (15 for cholecystectomy and 15 for inguinal hernia repair) enrolled into the study. PSA measurement was done on the day of the hospitalisation (which was also the day of operation for surgery group), on the 24th hour following the first measurement and on the 21st day. Anaesthesia was standardized for all patients. There was no statistically significant difference in serum total PSA (p >0.05), free PSA levels (p >0.05) and free to total PSA ratio (p >0.05) between the surgery and non-surgery groups. There were statistically significant decreases in the 24th hour total PSA levels (13.8% in surgery group, p <0.05, and 13.1% in non-surgery group, p <0.05) and in the free PSA levels (4.0% in surgery group, p <0.05, and 8.2% in non-surgery group, p <0.05). There was no statistically significant difference in the free to total PSA ratios (p >0.05 and p >0.05, respectively). | This work aimed to identify altered pathways in congenital heart defects (CHD) in Down syndrome (DS) by systematically tracking the dysregulated modules of reweighted protein-protein interaction (PPI) networks. We performed systematic identification and comparison of modules across normal and disease conditions by integrating PPI and gene-expression data. Based on Pearson correlation coefficient (PCC), normal and disease PPI networks were inferred and reweighted. Then, modules in the PPI network were explored by clique-merging algorithm; altered modules were identified via maximum weight bipartite matching and ranked in non-increasing order. Finally, pathways enrichment analysis of genes in altered modules was carried out based on Database for Annotation, Visualization, and Integrated Discovery (DAVID) to study the biological pathways in CHD in DS. Our analyses revealed that 348 altered modules were identified by comparing modules in normal and disease PPI networks. Pathway functional enrichment analysis of disrupted module genes showed that the 4 most significantly altered pathways were: ECM-receptor interaction, purine metabolism, focal adhesion, and dilated cardiomyopathy. |
Does radial forearm free tissue transfer reduce complications in salvage skull base surgery? | Patients who undergo skull base resection after prior surgery or radiation may be at high risk for complications when local flaps alone are used for reconstruction. To determine whether the complication rate could be reduced, fasciocutaneous free tissue transfer was used to reinforce the dural closure in patients who had prior skull base surgery or radiation. This study is a case series of 20 patients (14 males, 6 females, aged 8-79 years of age with a mean of 47.7 years) from 1997 to 2001 who had prior skull base surgery or radiation, and underwent salvage skull base resection without large volume defects. All patients had a radial forearm free tissue transfer to reinforce the dural closure. Six patients had an osseous component to the forearm flap to provide vascularized bone to the orbital rim. The overall local complication rate was 35%. Three patients (15%) had major complications including 1 case of meningitis, 1 case of cerebrospinal fluid leak, and 1 case of a flap requiring venous salvage. There were no flap failures, 1 idiopathic median nerve palsy, and no pathologic radius bone fractures. | In the rat, two forms of the pancreatic secretory trypsin inhibitor, PSTI-I and PSTI-II, are secreted into pancreatic juice. It is assumed that their role is to protect the pancreas from premature activation of the protease-rich pancreatic juice. In the small intestine, PSTI-I, also called 'monitor peptide', is thought to have a different role: PSTI-I competes with protein for activated trypsin. In the presence of a protein-rich meal, free PSTI induces a release of cholecystokinine from the intestine. To investigate whether its role as monitor peptide is compatible with the inhibitory, protective function in the pancreas, PSTI-I was chemically synthesized and then renatured. The peptide was almost completely trypsin resistant and exhibited a dose-dependent inhibitory activity to bovine and partially purified rat trypsin. Furthermore, experiments with trypsin- and endopeptidase-activated pancreatic juice demonstrated that its inhibitory capacity was sufficient to prevent premature activation. Binding studies of (125)I-labeled PSTI-I with the putative intestinal receptor using isolated membranes indicated the presence of high-affinity binding sites (k(d) = 5 x 10(-8)M). Binding of PSTI-I could be competed with excess PSTI-I or trypsin. In a biological assay system, injections of PSTI-I displayed monitor peptide activity by inducing a dose-dependent trypsinogen release from the pancreas. |
Is viral mRNA expression but not DNA replication required for lipogenic effect of human adenovirus Ad-36 in preadipocytes? | Human adenovirus Ad-36 causes adiposity in animal models and shows association with human obesity. Ad-36 enhances differentiation of 3T3-L1 and human preadipocytes, without cell lysis, a characteristic that may contribute to its adipogenic effect observed in vivo. Ad-2, another human adenovirus is nonadipogenic in animals and in 3T3-L1 cells and shows no correlation with human obesity. The objective of this study was to determine the adipogenic roles of viral mRNA and DNA, which may explain the differential effects of Ad-36 and Ad-2 on preadipocyte differentiation. This study determined the duration of selected Ad-36 gene expression in 3T3-L1 cells, and the effect on preadipocytes differentiation, when Ad-36 gene expression was attenuated by Cidofovir, an antiadenoviral agent. The results showed that Ad-36, but not Ad-2, expresses viral mRNA. Ad-36 gene expression peaked at 2-4 days postinoculation and very low levels persisted after day 7. Despite the viral mRNA expression, Ad-36 infection of 3T3-L1 cells was abortive as indicated by a progressive decrease in viral DNA quantity. Attenuation of Ad-36 mRNA expression by Cidofovir reduced the adipogenic effect of the virus. | High mobility group box 1 (HMGB1) is a late mediator of systemic inflammation. Extracellular HMGB1 play a central pathogenic role in critical illness. The purpose of the study was to investigate the association between plasma HMGB1 concentrations and the risk of poor outcomes in patients with severe blunt chest trauma. The plasma concentrations of HMGB1 in patients with severe blunt chest trauma (AIS ≥ 3) were measured by a quantitative enzyme-linked immunosorbent assay at four time points during seven days after admission, and the dynamic release patterns were monitored. The biomarker levels were compared between patients with sepsis and non-sepsis, and between patients with multiple organ dysfunction syndrome (MODS) and non-MODS. The related factors of prognosis were analyzed by using multivariate logistic regression analysis. The short-form 36 was used to evaluate the quality of life of patients at 12 months after injury. Plasma HMGB1 levels were significantly higher both in sepsis and MODS group on post-trauma day 3, 5, and 7 compared with the non-sepsis and non-MODS groups, respectively. Multivariate analysis showed that HMGB1 levels and ISS were independent risk factors for sepsis and MODS in patients with severe blunt chest trauma. |
Does a lifetime psychiatric history predict a worse seizure outcome following temporal lobectomy? | To identify the psychiatric and epilepsy variables predictive of postsurgical seizure outcome after anterotemporal lobectomy (ATL). Retrospective study of 100 consecutive patients with temporal lobe epilepsy (TLE) who underwent ATL. The mean (+/- SD) follow-up period was 8.3 (+/- 3.1) years. Three types of surgical outcomes were examined at 2 years after surgery and at last contact: class IA (no disabling seizures no auras), class IA + IB (no disabling seizures), and class IA + IB + IC (no or rare disabling seizures in the first postsurgical year). Logistic regression analyses were performed separately for the three types of surgical outcomes. The epilepsy-related independent variables included age at onset, cause of TLE (mesial temporal sclerosis, lesional and cryptogenic TLE), extent of resection of mesial structures, neuropathologic abnormalities, having only complex partial seizures, and duration of the seizure disorder. The psychiatric independent variables included a postsurgical and presurgical lifetime history of mood, anxiety, attention deficit hyperactivity, and psychotic disorders. The absence of a psychiatric history was an independent predictor of all three types of surgical outcomes. In addition, a larger resection of mesial structures was a predictor for class IA outcome, and having only complex partial seizures (vs generalized tonic-clonic seizures) was a predictor for class IA + IB and IA + IB + IC. Having mesial temporal sclerosis (vs other causes of TLE) was a predictor for class IA + IB + IC as well. | The counterbalance of macrophage migration inhibitory factor (MIF) and Gremlin-1 is a useful tool to predict the acuity of coronary artery disease (CAD) and plaque stability. Gremlin1 is an endogenous antagonist of MIF and therefore influences plaque vulnerability. This study was designed to elucidate the mechanistic basis determining the biophysical binding of Gremlin-1 to MIF. An in silico model suggested that several charged C-terminal amino acids are crucial in mediating Gremlin-1/MIF-binding. We produced several single amino acid exchange mutants of Gremlin-1 by site-directed mutagenesis. These Gremlin-1 mutants were tested for their ability to reduce MIF effects on monocytes. We observed that the critical element of the Gremlin-1 molecule for regulating MIF-induced chemotactic activity lies at the C-terminal region. A single amino acid exchange of an arginine to an alanine residue is sufficient to abolish the antagonistic effect of Gremlin-1 on MIF. Therefore, the Gremlin-1 mutant R172A failed to reduce MIF-induced monocyte differentiation into macrophages. |
Are action potentials in retinal ganglion cells initiated at the site of maximal curvature of the extracellular potential? | The initiation of an action potential by extracellular stimulation occurs after local depolarization of the neuronal membrane above threshold. Although the technique shows remarkable clinical success, the site of action and the relevant stimulation parameters are not completely understood. Here we identify the site of action potential initiation in rabbit retinal ganglion cells (RGCs) interfaced to an array of extracellular capacitive stimulation electrodes. We determine which feature of the extracellular potential governs action potential initiation by simultaneous stimulation and recording RGCs interfaced in epiretinal configuration. Stimulation electrodes were combined to areas of different size and were presented at different positions with respect to the RGC. Based on stimulation by electrodes beneath the RGC soma and simultaneous sub-millisecond latency measurement we infer axonal initiation at the site of maximal curvature of the extracellular potential. Stimulation by electrodes at different positions along the axon reveals a nearly constant threshold current density except for a narrow region close to the cell soma. These findings are explained by the concept of the activating function modified to consider a region of lower excitability close to the cell soma. | This study aims to assess whether the associations between burnout and sick leave due to stress-related mental disorders, other mental disorders, and somatic conditions are influenced by familial (genetic and shared environmental) factors. In this prospective cohort study, 23,611 Swedish twins born between 1959 and 1985, who answered a web-based questionnaire, including the Pines Burnout Measure 2004-2006, were included. Registry data on sick leave spells from the response date until December 31, 2010 were obtained from the Swedish Social Insurance Agency. Logistic regression analysis was performed to assess odds ratios with 95% confidence intervals for the association between burnout and sick leave for the whole sample, while conditional logistic regression of the same-sex discordant twin pairs was used to estimate the association between burnout and sick leave, adjusting for familial confounding. The Bivariate Cholesky models were used to assess whether the covariation between burnout and sick leave was explained by common genetic and/or shared environmental factors. Burnout was a risk factor for sick leave due to stress-related and other mental disorders, and these associations were explained by familial factors. The phenotypic correlation between burnout and sick leave due to somatic conditions was 0.07 and the association was not influenced by familial factors. The phenotypic correlations between burnout and sick leave due to stress-related (0.26) and other mental disorders (0.30) were completely explained by common genetic factors. |
Does triheptanoin dramatically reduce paroxysmal motor disorder in patients with GLUT1 deficiency? | On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7-47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional (31)P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. Patients with GLUT1-DS experienced a mean of 30.8 (± 27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (± 2.9, 76% motor events) during the treatment phase (p = 0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (± 21.9, 52% motor events; p = 0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p = 0.021), and deteriorated when triheptanoin was withdrawn. | The purpose of the current study was to determine whether there is any incremental benefit to routine intravascular ultrasound (IVUS) guidance of percutaneous coronary intervention. We compared the outcome of 796 patients who underwent an IVUS study (IVUS group) during the index stent procedure with 8274 patients who did not have an IVUS study (angiography group). The primary end point was the composite end point of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months of the index stent procedure. There were statistically significant differences in multiple procedural characteristics. Most importantly, those patients who underwent an IVUS study had a larger postprocedural minimal lumen diameter and smaller postprocedural percent diameter stenosis. However, there was no significant difference between the IVUS group and the angiography group with respect to the primary end point (RR 1.10, 95% CI 0.91, 1.32) or any of the individual clinical end points. Adjustment for multiple clinical and procedural characteristics did not significantly alter these findings. |
Does molecular characterisation of parvoviruses from domestic cats reveal emergence of newer variants in India? | The present study was undertaken to characterise the viral polypeptide 2 (VP2) gene of parvovirus from domestic cats in India. The faecal samples from diarrhoeic/healthy domestic cats were collected from different geographical regions of India for screening by PCR assay followed by sequence analysis of the VP2 gene. Canine parvovirus (CPV)/feline panleukopenia virus (FPV) infections were found in 12 samples (11.3%) of 106 faecal samples tested. Two new CPV-2a (297Ala and Asn426) and three FPV strains were identified by VP2 gene analysis. Several unique and existing amino acid mutations were found suggesting continuous evolution and emergence of newer variants. The phylogenetic analysis of the CPV sequences revealed that the two new CPV-2a strains from Mumbai (MC8) and Puducherry (P15) were clustered together in a single clade but had evolved independently and were ancestrally related to Chinese CPV-2a isolates. The FPV sequences (T-C-6 and T-C-1) from Thrissur, Kerala, formed a different clade (FPV clade) and were closely related to each other and had an ancestral relationship with an FPV isolate from the USA. Another FPV isolate from Goa (GC1) was positioned in the same clade but had evolved independently. | Treatment-resistant depression (TRD) is a pervasive and difficult to treat condition for which deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCwm) is an emerging therapeutic option. However, neuropsychological safety data for this novel treatment have only been published for a small number of subjects. Moreover, little is known regarding the neuropsychological profile present in TRD patients at baseline, prior to initiation of DBS therapy. This report describes the neuropsychological effects of TRD and acute and chronic DBS of the SCCwm in patients with unipolar and bipolar TRD. Patients with TRD (N = 17) were compared to a healthy control group (N = 15) on subtests from the Cambridge Neuropsychological Test Automated Battery and the Stroop Task. Patients were then tested again at subsequent time points of 1 and 6 months following the initiation of chronic DBS of the SCCwm. Patients with TRD showed similar levels of performance to healthy controls on most neuropsychological measures, with the exception that the TRD group had slower processing speed. Patients with bipolar TRD, relative to those with unipolar TRD, obtained lower scores on measures of executive function and memory only at baseline. With acute and chronic SCCwm DBS, neuropsychological function improved in multiple domains including processing speed and executive function (planning, set shifting, response inhibition), and memory remained stable. |
Is chronic hyperglycemia associated with acute kidney injury in patients undergoing CABG surgery -- a cohort study? | Chronic hyperglycemia (CHG) with HbA1c as an indicator affects postoperative mortality and morbidity after coronary artery bypass grafting surgery (CABG). Acute kidney injury (AKI) is one of the frequent postoperative complications after CABG impacting short-and long-term outcomes. We investigated the association between CHG and postoperative incidence of AKI in CABG patients with and without history of diabetes mellitus (DM). This cohort study consecutively enrolled patients undergoing CABG in 2009 at the department for cardiovascular surgery. CHG was defined as HbA1c ≥ 6.0%. Patients with advanced chronic kidney disease (CKD) were excluded. The incidence of postoperative AKI and its association with CHG was analyzed by univariate and multivariate logistic regression modeling. Three-hundred-seven patients were analyzed. The incidence of AKI was 48.2%. Patients with CHG (n = 165) were more likely to be female and had greater waist circumference as well as other comorbid conditions, such as smoking, history of DM, CKD, hypertension, pulmonary hypertension, and chronic obstructive pulmonary disease (all p ≤ 0.05). Preoperative eGFR, atrial fibrillation (AF), history of DM and CHG were associated with an increased risk of postoperative AKI in univariate analyses. In multivariate modelling, history of DM as well as preoperative eGFR and AF lost significance, while age, CHG and prolonged OP duration (p < 0.05) were independently associated with postoperative AKI. | Although serine proteases and agonists of protease-activated receptor 2 (PAR2) cause inflammation and pain, the spectrum of proteases that are activated by proinflammatory and algesic stimuli and their contribution to inflammatory pain are uncertain. Enzymic assays and selective inhibitors were used to characterize protease activity in mice after intraplantar injections of formalin, bradykinin, PAR2 activating peptide (AP) or vehicle. The capacity of these proteases and of recombinant mouse trypsin 4 to cleave fragments of PAR2 and to activate PAR2 in cell lines was determined. Protease inhibitors and par2 (-/-) mice were used to assess the contributions of proteases and PAR2 to pain and inflammation. Intraplantar injection of formalin, bradykinin or PAR2-AP led to the activation of proteases that were susceptible to the serine protease inhibitor melagatran but resistant to soybean trypsin inhibitor (SBTI). Melagatran inhibited mouse trypsin 4, which degraded SBTI. Proteases generated in inflamed tissues cleaved PAR2-derived peptides. These proteases and trypsin 4 increased [Ca(2+) ]i in PAR2-transfected but not in untransfected cells, and melagatran suppressed this activity. Melagatran or PAR2 deletion suppressed oedema and mechanical hypersensitivity induced by intraplantar formalin, bradykinin and PAR2-AP, but had no effect on capsaicin-induced pain. |
Does glucose infusion suppress surgery-induced muscle protein breakdown by inhibiting ubiquitin-proteasome pathway in rats? | It appears to have been well established that after surgery, protein catabolism is accelerated and glucose infusion suppresses the catabolic reactions. However, in the early postoperative period, the effects of surgical stress and glucose infusion on muscle protein catabolism and the related mechanisms remain unclear. Rats undergoing laparotomy were infused with acetated Ringer's solution (10 ml x kg(-1) x h(-1)) without glucose (control) or containing 1% or 5% glucose. The infusion was continued for a further 4 h after the surgical treatment. The catabolic index, excretion of urinary nitrogen and 3-methylhistidine, and release of tyrosine and 3-methylhistidine from isolated muscle were determined. Furthermore, muscular mRNA expression of proteolytic-related genes (atrogin-1/MAFbx, muscle ring finger-1, mu- and m-calpain, and cathepsin L and H) and phosphorylation of components of insulin signaling (forkhead box O3 and protein kinase B) were evaluated. Surgery increased the catabolic index, and this increase was suppressed by glucose infusion (both 1% and 5%). In the control group, mRNA expression of atrogin-1/MAFbx and muscle ring finger-1 was increased, and they were suppressed in the two glucose groups. Furthermore, insulin signaling (phosphorylation of protein kinase B and forkhead box O3) in muscles was stimulated by glucose infusion. | In Europe, extracts of Equisetum arvense (common horsetail) have a long tradition in the treatment of inflammatory disorders. To understand the molecular basis for its use, we investigated the immunomodulatory capacity of a standardized commercially available common horsetail extract on human primary lymphocyte function in vitro. The standardized extract of Equisetum arvense was phytochemically characterized. Effects on proliferation, viability and activity of mitogen-activated human lymphocytes were assessed in comparison to cyclosporine A using annexin V/propidium iodide staining assays and flow cytometry-based surface receptor characterization, respectively. Intracellular levels of effector molecules (IL-2, IFN-γ and TNF-α) were analyzed with cytokine assays. T cell proliferation was inhibited dose dependently by the Equisetum extract without induction of apoptosis or necrosis. This effect was mediated through inhibition of lymphocyte activation, specifically by diminishing CD69 and IL-2 surface receptor expression and intracellular IL-2 production. Furthermore, treatment with Equisetum arvense inhibited effector functions, as indicated by reduced production of IFN-γ and TNF-α. |
Does retinopathy in galactosemic dogs continue to progress after cessation of galactosemia? | Progression of diabetic retinopathy in human subjects and animal models is difficult to halt promptly by intensified insulin therapy and strict glycemic control. To learn whether this resistance to arrest is peculiar to diabetes and insulin therapy or is a characteristic of hyperglycemia itself, we have determined the effect of intervention on diabetic-like retinopathy in a non-diabetic animal model, the galactose-fed dog. Dogs were given a 30% galactose diet. At the end of 24 months, the dogs were divided into two groups, one of which continued to receive the galactose diet, while the second immediately began receiving the diet minus galactose. All animals were killed after 60 months of study. Consumption of the galactose-rich diet resulted, as expected, in galactosemia evident by elevated hemoglobin A1, plasma nonenzymatically glycated protein, and erythrocyte polyol concentrations, each of which decreased to normal levels following withdrawal of dietary galactose. Retinopathy was found to be equivocal at the end of 24 months of the galactose diet and subsequently progressed significantly despite cessation of the galactose diet. | Aluminum potroom exposure is associated with increased mortality of COPD but the association between potroom exposure and annual decline in lung function is unknown. We have measured lung volumes annually using spirometry from 1986 to 1996. The objective was to compare annual decline in forced expiratory volume in 1 s (dFEV1) and forced vital capacity (dFVC). The number of aluminum potroom workers was 4,546 (81% males) and the number of workers in the reference group was 651 (76% males). The number of spirometries in the index group and the references were 24,060 and 2,243, respectively. After adjustment for confounders, the difference in dFEV1 and dFVC between the index and reference groups were 13.5 (P < 0.001) and -8.0 (P = 0.060) ml/year. |
Do propofol and magnesium attenuate isoflurane-induced caspase-3 activation via inhibiting mitochondrial permeability transition pore? | The inhalation anesthetic isoflurane has been shown to open the mitochondrial permeability transition pore (mPTP) and induce caspase activation and apoptosis, which may lead to learning and memory impairment. Cyclosporine A, a blocker of mPTP opening might attenuate the isoflurane-induced mPTP opening, lessening its ripple effects. Magnesium and anesthetic propofol are also mPTP blockers. We therefore set out to determine whether propofol and magnesium can attenuate the isoflurane-induced caspase activation and mPTP opening. We investigated the effects of magnesium sulfate (Mg2+), propofol, and isoflurane on the opening of mPTP and caspase activation in H4 human neuroglioma cells stably transfected to express full-length human amyloid precursor protein (APP) (H4 APP cells) and in six day-old wild-type mice, employing Western blot analysis and flowcytometry. Here we show that Mg2+ and propofol attenuated the isoflurane-induced caspase-3 activation in H4-APP cells and mouse brain tissue. Moreover, Mg2+ and propofol, the blockers of mPTP opening, mitigated the isoflurane-induced mPTP opening in the H4-APP cells. | To identify injured cells in the liver of patients with primary biliary cirrhosis (PBC) and to determine the effects of ursodeoxycholic acid (UDCA) on these cells, we examined the cellular expression of heat shock proteins (HSPs) in PBC both before and after treatment with UDCA. Expression of HSP70 and ubiquitin in PBC livers (n=34) was evaluated immunohistochemically as well as by immunoblot analysis, and compared with chronic viral hepatitis type C (n= 9), primary sclerosing cholangitis (n=8), and controls (n=7). Immunoblot analysis demonstrated a marked expression of HSP70 and ubiquitin in PBC. Immunohistochemical staining for both HSP70 and ubiquitin was observed to be strong in biliary epithelial cells (BECs) and moderate in both hepatocytes and arteries in PBC. Cellular labelling rates for HSP70 and ubiquitin of bile ducts in PBC were significantly higher (p<0.01) than those in chronic viral hepatitis type C, primary sclerosing cholangitis, or controls. The labelling rates for HSP70 and ubiquitin in bile ducts and in hepatocytes were significantly decreased (p<0.01) after treatment with UDCA in PBC. |
Does hyperleptinaemia and chronic inflammation after peritonitis predict poor nutritional status and mortality in patients on peritoneal dialysis? | The serum leptin level is elevated in patients undergoing peritoneal dialysis (PD) and associated with a loss of lean body mass. The nutritional status of PD patients may further be worsened following peritonitis. We investigated the association between hyperleptinaemia, inflammation and malnourishment in PD-related peritonitis. We conducted a prospective study on PD patients who developed peritonitis. Blood samples were obtained as baseline (D0) before the onset of peritonitis, and once peritonitis developed, leptin, adiponectin (ADPN) and other inflammatory markers were collected, on day 1 (D1), day 7 (D7) and day 42 (D42) of peritonitis. Patients were followed-up for any censor event or 1 year after peritonitis. Forty-two patients with a mean age of 62.9+/-13.2 years were recruited. Fourteen (33.3%) were diabetic. The serum leptin levels increased significantly from baseline to day 1 and 7, but fell back to the premorbid state at day 42. In contrast, the ADPN level decreased from a baseline value of 15.60+/-10.4 microg/ml to 13.01+/-8.1 microg/ml on day 1 (P=0.01) but rose to 14.39+/-8.9 microg/ml on day 7 (P=0.28) and 13.87+/-7.9 microg/ml on day 42 (P=0.21). High-sensitivity C-reactive protein (hs-CRP) increased significantly from baseline to day 1, 7 and even at day 42. The lean body mass (LBM) and nutritional markers decreased significantly after peritonitis. For patients with high hs-CRP (>3.0 mg/l) at day 42, there was a higher mortality rate than for those with lower hs-CRP (<3.0 mg/l, P=0.02), even if they were in clinical remission of peritonitis. | An in vitro study was carried out to determine the effect of UHRF1 overexpression on radiosensitivity in human cervical cancer HeLa cells using adenovirus-mediated UHRF1 gene transfer (Ad5-UHRF1). Cell survival was evaluated using the clonogenic survival assay and the MTT assay; apoptosis and cell cycle distribution were monitored by flow cytometry. Protein levels were measured by Western blotting. Silencing XRCC4 expression was performed by transfection of small interfering RNA (siRNA). Increased expression of UHRF1 by Ad5-UHRF1 significantly reduced the radiosensitivity of HeLa cells. The UHRF1-mediated radioresistance was correlated with increased DNA repair capability and increased expression of the DNA damage repair protein, XRCC4. Knocking down XRCC4 expression in the cells using XRCC4 siRNA markedly reduced the UHRF1-mediated radioresistance. |
Does passive electrode effect reduce defibrillation threshold in bi-filament middle cardiac vein defibrillation? | To investigate whether a passive electrode effect decreases defibrillation threshold (DFT) in multi-filament middle cardiac vein (MCV) defibrillation. Twelve pigs underwent active housing (AH) insertion, with defibrillation coils placed transvenously in right ventricular apex and superior vena cava. The MCV was cannulated, and 1.12F, 50 mm coil electrodes (Ela Medical SA, France) were deployed in its right and left branches. Lead placement was possible in 11 of 12 animals. DFT (J, mean +/- SD) was determined by three-reversal binary search and compared between the MCV monofilament (single filament deployed) and the AH (25.9 +/- 10.9) and the MCV mono + passive filaments (both filaments deployed, one connected) and the AH (19.9 +/- 11.4); 24% DFT reduction P = 0.008. | To simultaneously study the effect of a selective cyclooxygenase-2 (COX-2) inhibitor and that of a classic non-steroidal anti-inflammatory drug (NSAID) on the expression of pro-inflammatory genes in the cartilage of patients with severe knee osteoarthritis (OA) and in cultured human OA chondrocytes. A 3-month clinical trial was carried out on 30 patients with severe knee OA scheduled for knee replacement surgery. Patients were randomized into two groups: patients treated with celecoxib (CBX) and patients treated with aceclofenac (ACF). OA patients who did not want to be treated served as the control group. After surgery, cartilage was processed for molecular biology studies. We also employed cultured chondrocytes from different OA patients to examine NSAID effects on pro-inflammatory gene expression in cells stimulated with interleukin (IL)-1beta. Both CBX and ACF inhibited COX-2, microsomal prostaglandin E synthase-1 (mPGES-1) and inducible nitric oxide synthase (iNOS) synthesis in the articular cartilage of OA patients. In cultured chondrocytes, both NSAID decreased COX-2 and mPGES-1 synthesis and prostaglandin E2 (PGE2) release induced by IL-1beta, while no effect was observed on nitric oxide or iNOS synthesis. In OA patients, only CBX decreased tumor necrosis factor alpha and IL-1beta expression in the cartilage, while both NSAID diminished IL-1beta induced cytokine synthesis in cultured OA chondrocytes. |
Does lL37 induce VEGF expression in dental pulp cells through ERK signalling? | To examine the in vitro effects of LL37 on the expression of vascular endothelial growth factor (VEGF) in human pulp cells and to identify the intracellular signalling pathway involved. Pulp cells at passage 6 were treated with 10 μg mL(-1) synthesized LL37, and an inhibition assay was performed with MAPK or NF-κB inhibitors to determine the possible signalling pathway. VEGF mRNA, VEGF protein and phosphorylated ERK1/2 levels were determined by real-time PCR, ELISA and Western blot, respectively. Data were analysed using t-tests. LL37 significantly increased both the mRNA and protein levels of VEGF in pulp cells (P < 0.01). However, pre-treatment with an ERK kinase inhibitor suppressed these increases. Furthermore, the inhibitor blocked LL37-induced ERK1/2 phosphorylation. | The existence of health disparities in military populations has become an important topic of research. However, to our knowledge, this is the first study to examine health disparities, as related to access to care and health status, among active duty soldiers and their families. Specifically, the purpose of this analysis was to evaluate whether health disparities exist in access to care and health outcomes of patient satisfaction, physical health status, and mental health status according to race, gender, and sponsor rank in the population of active duty soldiers and their family members. In this cross-sectional study, active duty army soldiers and family members were recruited from either one particular army health clinic where they received their health care or from an adjacent shopping center frequented by eligible participants. Data were collected using validated measures to assess concepts of access to care and health status. Statistical analysis, including one-way analysis of variance (ANOVA) was performed to investigate differences in study outcome measures across four key demographic subgroups: race, gender, sponsor rank, and component (active soldier or family member). A total of 200 participants completed the study questionnaires. The sample consisted of 45.5 % soldiers and 54.5 % family members, with 88.5 % reporting a sponsor rank in the category of junior or senior enlisted rank. Mean scores for access to care did not differ significantly for the groups race/ethnicity (p = 0.53), gender (p = 0.14), and sponsor rank (p = 0.10). Furthermore, no significant differences were observed whether respondents were active soldiers or their family members (p = 0.36). Similarly, there were no statistically significant subgroup (race/ethnicity, gender, sponsor rank, or component) differences in mean patient satisfaction, physical health, and mental health scores. |
Does eUS clarify the natural history and ideal management of GISTs? | Gastrointestinal stromal tumors (GISTs) are mesenchymal gastrointestinal tumors expressing C-kit (CD117). Endoscopic ultrasonography (EUS) evaluations of GISTs can help determine optimal therapy and follow-up care. The current study assesses the natural history of 100 GISTs evaluated by EUS, and the impact of EUS on their management. Retrospective review of 2600 EUS files performed over 11 years identified 100 patients with GISTs. Relevant data from all appropriate files and interviews with patients or family of deceased patients were tabulated regarding the GISTs. Every GIST had definitive cytology (n=43) or histology. Seventy of the 100 patients underwent more than one evaluation. Size of the GISTs at initial diagnosis averaged 20.5 mm and at follow-up examination 23.2 mm. Fourteen of 70 GISTs showed significant enlargement (> 1 mm/month). Enlargement during follow-up of GISTs was significantly more common with GISTs over 17 mm at initial diagnosis (p<0.018). Thirty-four were excised (7 endoscopically). Clinically asymptomatic GISTs tended to be smaller. Thirteen percent of GIST patients had second primary malignancy. | Oxidant stress contributes to vascular injury and atherosclerosis. We hypothesized that estrogen treatment of ovariectomized rats decreases O(2)(-) by decreasing the activity of NAD(P)H oxidase and this reduction in O(2)(-) could have a vasculoprotective effect. Ovariectomized rats were treated with 17-beta-estradiol E2 (0.25mg) or oil placebo for 21 days. Aorta were removed for contractility studies and O(2)(-) production was measured by lucigenin enhanced chemiluminescence (230 and 5microM). E2 treatment decreased basal O(2)(-) production but did not alter NADH or NADPH stimulated O(2)(-) production. Total p47phox and p47phox in membrane fractions of cardiac tissue were decreased, which suggests less activation of NAD(P)H oxidase in E2 treated rats. E2 did not change expression of other components of NAD(P)H oxidase in heart, lung, spleen and diaphragm. Expression of eNOS was also lower in E2 treated rats. E2 did not affect the contractile response to phenylepherine, dilation with acetylcholine, dilation with superoxide dismutase or constriction with l-NAME. This argues against changes in bioavailable NO. |
Do maternal and childhood psychological factors predict chronic disabling fatigue at age 13 years? | To investigate whether premorbid maternal and childhood psychological problems are risk factors for chronic disabling fatigue at age 13 years among children in the Avon Longitudinal Study of Parents and Children birth cohort. Chronic disabling fatigue was defined as fatigue of at least 3-month, and up to 5-year, duration that prevented school attendance or hobbies/sport/leisure activities, and for which other causes were not identified. Maternal psychological factors were symptoms of anxiety and depression assessed up to eight times between pregnancy and age 6 years. We investigated critical periods for maternal effects and effects of paternal depression at three time points. Child psychological factors included internalizing and externalizing problems and upsetting life events occurring at age 7-8 years. Of 5,657 children, 110 (1.9%) had chronic disabling fatigue at age 13 years. Maternal anxiety (adjusted odds ratio [AOR], 1.19; 95% confidence interval [CI], 1.09-1.31 per episode), maternal depression (AOR, 1.24; CI, 1.11-1.39 per episode), child psychological problems (AOR, 1.19; CI, 1.00-1.41 per problem), and upsetting events (AOR, 1.22; CI, .99-1.58 per event) were associated with chronic disabling fatigue. Associations of child psychological problems and upsetting events were attenuated (AOR, 1.12; CI, .93-1.33 per problem; AOR, 1.19; CI, .94-1.52 per event) after further adjusting for maternal anxiety and depression. | A new ferric ammonium citrate-cellulose mixture for use in MRI of the esophagus was evaluated for its ability to opacify the esophageal lumen. Thirty-two patients with esophageal disorders and ten patients with normal esophagus undergoing MRI at 1.5 T were given approximately 100 ml of the newly developed high-viscosity esophageal contrast preparation. Moreover, six of the patients with esophageal cancer were subjected to a second examination after radiation therapy. A total of 48 MR imagings were performed. Of the patients examined, successful esophageal opacification, graded as excellent, was obtained in 84.2, 78.9, and 57.9%, of the sagittal, axial, and coronal images, respectively. In cases of extrinsic disease involving the esophagus the contrast medium administration allowed the easy differentiation of the esophagus from adjacent mass lesions and proved very useful in identifying displacement and compression. In cases of esophageal carcinoma the contrast medium administration assisted in the measurement of wall thickness and length of the lesion as well as in the identification of the site of origin of the tumor. |
Does dual trigger for final oocyte maturation improve the oocyte retrieval rate of suboptimal responders to gonadotropin-releasing hormone agonist? | To identify the risk factors for suboptimal response to GnRH agonist (GnRH-a) trigger and evaluate the effect of hCG on the outcome of patients with suboptimal response to GnRH-a. A retrospective data analysis. A tertiary-care academic medical center. A total of 8,092 women undergoing 8,970 IVF/intracytoplasmic sperm injection (ICSI) treatment cycles. All women underwent hMG + medroxyprogesterone acetate (MPA)/P treatment cycles during IVF/ICSI, which were triggered using a GnRH-a alone or in combination with hCG (1,000, 2,000, or 5,000 IU). Viable embryos were cryopreserved for later transfer. The rates of oocyte retrieval, mature oocytes, fertilization, and the number of oocytes retrieved, mature oocytes, and embryos frozen. In total, 2.71% (243/8,970) of patients exhibited a suboptimal response to GnRH-a. The suboptimal responders (LH ≤15 mIU/mL) had a significantly lower oocyte retrieval rate (48.16% vs. 68.26%), fewer mature oocytes (4.10 vs. 8.29), and fewer frozen embryos (2.32 vs. 3.54) than the appropriate responders. Basal LH levels served as the single most valuable marker for differentiating suboptimal responders with the areas under the receiver operating curve of 0.805. Administering dual trigger (GnRH-a and hCG 1,000, 2,000, 5,000 IU) significantly increased oocyte retrieval rates (60.04% vs. 48.16%; 68.13% vs. 48.16%; and 65.76% vs. 48.16%, respectively) in patients with a suboptimal response. | Physical activity and sedentary behavior measurement tools need to be validated in free-living settings. Direct observation (DO) may be an appropriate criterion for these studies. However, it is not known if trained observers can correctly judge the absolute intensity of free-living activities. To compare DO estimates of total MET-hours and time in activity intensity categories to a criterion measure from indirect calorimetry (IC). Fifteen participants were directly observed on three separate days for two hours each day. During this time participants wore an Oxycon Mobile indirect calorimeter and performed any activity of their choice within the reception area of the wireless metabolic equipment. Participants were provided with a desk for sedentary activities (writing, reading, computer use) and had access to exercise equipment (treadmill, bike). DO accurately and precisely estimated MET-hours [% bias (95% CI) = -12.7% (-16.4, -7.3), ICC = 0.98], time in low intensity activity [% bias (95% CI) = 2.1% (1.1, 3.2), ICC = 1.00] and time in moderate to vigorous intensity activity [% bias (95% CI) -4.9% (-7.4, -2.5), ICC = 1.00]. |
Does beta-carotene supplementation attenuate cardiac remodeling induced by one-month tobacco-smoke exposure in rats? | The objectives were to analyze the cardiac effects of exposure to tobacco smoke (ETS), for a period of 30 days, alone and in combination with beta-carotene supplementation (BC). Rats were allocated into: Air (control, n = 13); Air + BC (n = 11); ETS (n = 11); and BC + ETS (n = 9). In Air + BC and BC + ETS, 500 mg of BC were added to the diet. After three months of randomization, cardiac structure and function were assessed by echocardiogram. After that, animals were euthanized and morphological data were analyzed post-mortem. One-way and two-way ANOVA were used to assess the effects of ETS, BC and the interaction between ETS and BC on the variables. ETS presented smaller cardiac output (0.087 +/- 0.001 vs. 0.105 +/- 0.004 l/min; p = 0.007), higher left ventricular diastolic diameter (19.6 +/- 0.5 vs. 18.0 +/- 0.5 mm/kg; p = 0.024), higher left ventricular (2.02 +/- 0.05 vs. 1.70 +/- 0.03 g/kg; p < 0.001) and atrium (0.24 +/- 0.01 vs. 0.19 +/- 0.01 g/kg; p = 0.003) weight, adjusted to body weight of animals, and higher values of hepatic lipid hydroperoxide (5.32 +/- 0.1 vs. 4.84 +/- 0.1 nmol/g tissue; p = 0.031) than Air. However, considering those variables, there were no differences between Air and BC + ETS (0.099 +/- 0.004 l/min; 19.0 +/- 0.5 mm/kg; 1.83 +/- 0.04 g/kg; 0.19 +/- 0.01 g/kg; 4.88 +/- 0.1 nmol/g tissue, respectively; p > 0.05). Ultrastructural alterations were found in ETS: disorganization or loss of myofilaments, plasmatic membrane infolding, sarcoplasm reticulum dilatation, polymorphic mitochondria with swelling and decreased cristae. In BC + ETS, most fibers showed normal morphological aspects. | Although right-sided diverticulitis is perceived to have a higher incidence among Asians and infrequently requires surgical management in comparison with sigmoid diverticulitis, it is unknown whether differences in outcomes are due to ethnic disparity or disease pathophysiology. The aim of this study was to determine the surgical outcomes for Asian and non-Asian patients with diverticulitis who underwent colectomy. Patients identifiable by ethnicity in the Nationwide Inpatient Sample with diverticulitis and colectomy between 2004 and 2010 were included. Univariate comparisons were made between Asian and non-Asian patients by using t tests for continuous variables and χ tests for categorical variables. Propensity score matching analysis was performed to compare Asian patients with otherwise similar non-Asian patients. Included were 58,142 non-Asian and 335 Asian patients with diverticulitis who underwent a colectomy. The primary outcomes were in-hospital mortality, hospital length of stay, and total costs. Asian patients were younger (56.1 vs. 59.2 years, p < 0.0001), were more likely to undergo a right colectomy (22.7% vs. 4.1%, p < 0.0001), and were more likely to have emergent/urgent surgery than the non-Asian patients (67.1% vs. 49.8%, p < 0.0001). Without controlling for patient/disease factors, there were statistically significant differences in mortality (non-Asian 2.2% vs. Asian 4.2%; p = 0.014), length of stay (non-Asian 8.9 vs. Asian 9.8 days; p = 0.0166), and costs (non-Asian $18,783 vs. Asian $21,901; p = 0.001). Propensity score matching comparing 333 non-Asian patients with 333 similar Asian patients showed that, whereas differences in cost and length of stay became insignificant, the difference in mortality remained statistically significant. |
Does oral administration of cytosolic PLA2 inhibitor arachidonyl trifluoromethyl ketone ameliorate cauda equina compression injury in rats? | Phospholipase A2 (PLA2)-derived proinflammatory lipid mediators such as prostaglandin E2 (PGE2), leukotrienes B4 (LTB4), lysophosphatidylcholine (LPC), and free fatty acids (FFA) are implicated in spinal cord injury (SCI) pathologies. Reducing the levels of these injurious bioactive lipid mediators is reported to ameliorate SCI. However, the specific role of the group IVA isoform of PLA2 cytosolic PLA2 (cPLA2) in lumbar spinal canal stenosis (LSS) due to cauda equina compression (CEC) injury is not clear. In this study, we investigated the role of cPLA2 in a rat model of CEC using a non-toxic cPLA2-preferential inhibitor, arachidonyl trifluoromethyl ketone (ATK). LSS was induced in adult female rats by CEC procedure using silicone blocks within the epidural spaces of L4 to L6 vertebrae. cPLA2 inhibitor ATK (7.5 mg/kg) was administered by oral gavage at 2 h following the CEC. cPLA2-derived injurious lipid mediators and the expression/activity of cPLA2, 5-lipoxygenase (5-LOX), and cyclooxygenase-2 (COX-2) were assessed. ATK-treated (CEC + ATK) were compared with vehicle-treated (CEC + VEH) animals in terms of myelin levels, pain threshold, and motor function. ATK treatment of CEC animals reduced the phosphorylation of cPLA2 (pcPLA2) determined by Western blot, improved locomotor function evaluated by rotarod task, and reduced pain threshold evaluated by mechanical hyperalgesia method. Levels of FFA and LPC, along with PGE2 and LTB4, were reduced in CEC + ATK compared with CEC + VEH group. However, ATK treatment reduced neither the activity/expression of 5-LOX nor the expression of COX-2 in CEC + VEH animals. Increased cPLA2 activity in the spinal cord from CEC + VEH animals correlated well with decreased spinal cord as well as cauda equina fiber myelin levels, which were restored after ATK treatment. | To assess how ascites and alpha-fetoprotein (AFP) added to the Barcelona Clinic Liver Cancer (BCLC) staging predict hepatocellular carcinoma survival. The presence of underlying cirrhosis, ascites and encephalopathy, Child-Turcotte-Pugh (CTP) score, the number of nodules, and the maximum diameter of the largest nodule were determined at diagnosis for 1060 patients with hepatocellular carcinoma at a tertiary referral center for liver disease in Egypt. Demographic information, etiology of liver disease, and biochemical data (including serum bilirubin, albumin, international normalized ratio, alanine and aspartate aminotransferases, and AFP) were evaluated. Staging of the tumor was determined at the time of diagnosis using the BCLC staging system; 496 patients were stage A and 564 patients were stage B. Patients with mild ascites on initial ultrasound, computed tomography, or clinical examination, and who had a CTP score ≤ 9 were included in this analysis. All patients received therapy according to the recommended treatment based on the BCLC stage, and were monitored from the time of diagnosis to the date of death or date of data collection. The effect of the presence of ascites and AFP level on survival was analyzed. At the time the data were censored, 123/496 (24.8%) and 218/564 (38.6%) patients with BCLC stages A and B, respectively, had died. Overall mean survival of the BCLC A and B patients during a three-year follow-up period was 31 mo [95% confidence interval (95%CI): 29.7-32.3] and 22.7 mo (95%CI: 20.7-24.8), respectively. The presence of ascites, multiple focal lesions, large tumor size, AFP level and CTP score were independent predictors of survival for the included patients on multivariate analysis (P < 0.001). Among stage A patients, 18% had ascites, 33% had AFP ≥ 200 ng/mL, and 8% had both. Their median survival in the presence of ascites was shorter if AFP was ≥ 200 ng/mL (19 mo vs 24 mo), and in the absence of ascites, patients with AFP ≥ 200 ng/mL had a shorter survival (28 mo vs 39 mo). For stage B patients, survival for the corresponding groups was 12, 18, 19 and 22 mo. The one-, two-, and three-year survival rates for stage A patients without ascites and AFP < 200 ng/mL were 94%, 77%, and 71%, respectively, and for patients with ascites and AFP ≥ 200 ng/mL were 83%, 24%, and 22%, respectively (P < 0.001). Adding ascites and AFP ≥ 200 ng/mL improved the discriminatory ability for predicting prognosis (area under the curve, 0.618 vs 0.579 for BCLC, P < 0.001). |
Do [ Correlation between pathogenesis of myasthenia gravis and thymus mature dendritic cells ]? | To investigate the correlation between onset of myasthenia gravis (MG) and the changes of the number and distribution of thymus mature dendritic cells (mDC). The specimens of thymus were obtained during operation from 39 MG patients who hadn't received immunosuppressive therapy before thymectomy and 19 sex- and age-matched patients who underwent cardiosurgery as controls. Immunohistochemistry with antibody against DC-LAMP, specific surface marker of DC, was used to examine the number and distribution of thymus mDCs. (1) mDCs were restricted in the medulla and cortex-medulla junctional zone of thymus in the control group; while were irregularly distributed in the cortex, medulla, and stroma in the MG group. (2) mDCs presented a roughly uniform distribution in the medulla of thymus in the control group, while clustering distribution was more often in the MG group, especially dense around the germinal center. (3) The relative ratio and numbers of mDCs per average field of vision in the positive areas of the MG group were (10.9% +/- 2.2%) and (50 +/- 9), both significantly higher than those of the control group [(8.5% +/- 1.5%) and (41 +/- 7) respectively, both P < 0.05]. | We developed a lactoferrin conjugate by modifying bovine lactoferrin (bLF) with a 40-kDa branched poly(ethylene glycol) (PEG) molecule (designated 40 k-PEG-bLf), and we evaluated its in vitro activities and pharmacokinetic properties. We prepared 40k-PEG-bLf by amino conjugation with N-hydroxysuccinimide-activated PEG. This conjugate was purified by cation exchange chromatography and its in vitro biological activities, such as iron binding, anti-inflammatory effects, and resistance to proteolytic enzymes were investigated. In vivo pharmacokinetics analyses, were also performed to examine the rate of clearance from the plasma in rats. The 40k-PEG-bLf conjugate was fully active in iron binding and exhibited 97.1 +/- 5.5% (mean +/- S.E., n = 6) of the original anti-inflammatory activity. The in vitro peptic susceptibility of 40 k-PEG-bLf revealed that the proteolytic half-life increased at least 6-fold that of unmodified LF. This PEGylated conjugate demonstrated a plasma half-life that was 8.7-fold longer than that of the unmodified bLF in rats. |
Is lMO2 a novel predictive marker for a better prognosis in pancreatic cancer? | LIM domain only 2 (LMO2) has been identified as a novel oncogene associated with carcinogenesis and better prognosis in several malignant tumors. We investigate the involvement of LMO2 in pancreatic cancer. We evaluated LMO2 expression in cultured cells, bulk tissues, and microdissected cells from pancreatic cancers by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. Of 164 pancreatic cancers, 98 (60%) were positive for LMO2 expression. LMO2 was more frequently detected in high-grade pancreatic intraepithelial neoplasia (PanIN) lesions (PanIN-2 and -3) than in low-grade PanIN lesions (PanIN-1A and -1B; P < .001) and was not detected in normal pancreatic ductal epithelium. The LMO2 messenger RNA levels were significantly higher in invasive ductal carcinoma cells than in normal pancreatic cells as evaluated by quantitative reverse transcription-polymerase chain reaction analyses of microdissected cells (P = .036). We also found higher incidence of LMO2 expression in histologic grade G1/G2 cancers than in grade G3 cancers (P < .001). The median survival time of LMO2-positive patients was significantly longer than that of LMO2-negative patients (P < .001), and multivariate analyses revealed that high LMO2 expression was an independent predictor of longer survival (risk ratio, 0.432, P < .001). Even among patients with a positive operative margin, LMO2-positive patients had a significant survival benefit compared with LMO2-negative patients. We further performed a large cohort study (n = 113) to examine the LMO2 messenger RNA levels in formalin-fixed paraffin-embedded samples and found similar results. | The purpose of this study was to examine the effectiveness of ankle bracing and taping in preventing recurrencess of ankle sprains, specifically in female athletes. Varsity soccer players' medical records over a five-year period were retrospectively reviewed at a Division III women's college. Data were extracted regarding any history of ankle sprain(s), type of intervention used as prophylaxis after the ankle sprain, number of exposures, and any incidence of recurrence. All collegiate varsity soccer players who had suffered a previous sprain to either one or both ankles (38 players) were identified as subjects. Each previously injured ankle (n = 56) was considered as a case for the analysis. Ankles that had a previous sprain received one of four interventions: 1) a canvas, laced ankle brace (n = 19), 2) taping (n = 12), 3) a combination of taping and ankle bracing (n = 8), or 4) no treatment (n = 17). The four intervention groups had a total of 1717 practice exposures and 650 competitive game exposures; exposures did not differ among the 4 groups. Ankle sprain recurrence frequency was 0%, 25%, 25%, and 35% for the braced, taped, combination, and untreated groups, respectively. The recurrence incidence for the braced group was significantly lower than that of the other three groups. The ankle sprain recurrence frequency did not differ among the taped, combination, and no treatment groups. |
Is leukocyte-poor platelet-rich plasma more effective than the conventional therapy with acetaminophen for the treatment of early knee osteoarthritis? | Knee osteoarthritis (OA) is a degenerative and progressive articular cartilage disease. Infiltration of autologous platelet-rich plasma (PRP) has been proposed as a therapeutic alternative due to the content of biologically active cytokines in PRP. We aimed to compare the clinical response of acetaminophen and intra-articular leukocyte-poor PRP (LP-PRP) in early knee OA. A total of 65 patients with clinically and radiographically documented knee OA (grade 1-2) were analyzed. Patients were randomized into two groups: 32 were treated with acetaminophen (500 mg/8 h) over 6 weeks, and 33 received three intra-articular injections of autologous LP-PRP (once every 2 weeks). All patients were evaluated by the Visual Analogue Scale (VAS), the Western Ontario and McMaster Universities (WOMAC) score, and the SF-12 health survey at baseline and 6, 12, and 24 weeks of follow-up. All LP-PRP preparations were analyzed for the platelet, leukocyte, IL-1ra, and TGF-β concentrations. The decrease in the VAS pain level in the LP-PRP group was greater than that in the acetaminophen group (p < 0.05). Patients treated with LP-PRP showed a sustained improvement in knee function at week 24 (p < 0.01). The SF-12 results only indicated an improvement in quality-of-life in the LP-PRP group at 6, 12, and 24 weeks of follow-up (p < 0.01). Both IL-1ra and TGF-β were detected in the LP-PRP samples (313.8 ± 231.6 and 21,183.8 ± 8556.3 pg/mL, respectively). | Aedes aegypti is the main mosquito vector of the four serotypes of dengue virus (DENV). Previous population genetic and vector competence studies have demonstrated substantial genetic structure and major differences in the ability to transmit dengue viruses in Ae. aegypti populations in Mexico. Population genetic studies revealed that the intersection of the Neovolcanic axis (NVA) with the Gulf of Mexico coast in the state of Veracruz acts as a discrete barrier to gene flow among Ae. aegypti populations north and south of the NVA. The mosquito populations north and south of the NVA also differed in their vector competence (VC) for dengue serotype 2 virus (DENV2). The average VC rate for Ae. aegypti mosquitoes from populations from north of the NVA was 0.55; in contrast the average VC rate for mosquitoes from populations from south of the NVA was 0.20. Most of this variation was attributable to a midgut infection and escape barriers. In Ae. aegypti north of the NVA 21.5% failed to develop midgut infections and 30.3% of those with an infected midgut failed to develop a disseminated infection. In contrast, south of the NVA 45.2% failed to develop midgut infections and 62.8% of those with an infected midgut failed to develop a disseminated infection. |
Are chronic obstructive pulmonary disease patients with psychiatric disorders at greater risk of exacerbations? | To assess prospectively the impact of psychiatric disorders on risk for exacerbations. The course of chronic obstructive pulmonary disease (COPD) is punctuated by acute exacerbations. Although anxiety and mood disorders are common in patients with COPD, no studies have assessed prospectively the association between these disorders and exacerbations. Psychiatric disorders were evaluated by a structured psychiatric interview in 110 patients (51% women, age (mean +/- standard deviation) = 66 +/- 8 years) with stable COPD and previous admission for exacerbations recruited from two outpatient clinics. Patients were followed for a mean of 2 years and both inpatient-treated (i.e., treated in the emergency department or hospital) and outpatient-treated (i.e., treated with medication in the patient's own environment) exacerbations were recorded. Independent of covariates, patients with psychiatric disorders exhibited a significantly higher weighted annual rate of exacerbations treated in an outpatient setting after adjustment for covariates (3 versus 2, p = .003) than patients without psychiatric disorders, but no difference in exacerbations treated in the inpatient setting. They were also at a higher risk for any (relative risk (RR) = 1.56, 95% Confidence Interval (CI) = 1.02-2.37) and outpatient (RR = 1.68, 95% CI = 1.08-2.59) exacerbations, but not inpatient exacerbations (RR = 1.36, 95% CI = 0.82-2.25). | The dynamics of intestinal stem cells are crucial for regulation of intestinal function and maintenance. Although crypt stem cells have been identified in the intestine by genetic marking methods, identification of plural crypt stem cells has not yet been achieved as they are visualised in the same colour. Intestinal organoids were transferred into Matrigel® mixed with lentivirus encoding mCherry. The dynamics of mCherry-positive cells was analysed using time-lapse imaging, and the localisation of mCherry-positive cells was analysed using 3D immunofluorescence. We established an original method for the introduction of a transgene into an organoid generated from mouse small intestine that resulted in continuous fluorescence of the mCherry protein in a portion of organoid cells. Three-dimensional analysis using confocal microscopy showed a single mCherry-positive cell in an organoid crypt that had been cultured for >1year, which suggested the presence of long-lived mCherry-positive and -negative stem cells in the same crypt. Moreover, a single mCherry-positive stem cell in a crypt gave rise to both crypt base columnar cells and transit amplifying cells. Each mCherry-positive and -negative cell contributed to the generation of organoids. |
Is diabetes-linked zinc transporter ZnT8 a homodimeric protein expressed by distinct rodent endocrine cell types in the pancreas and other glands? | Zinc is abundant in pancreas, being required by endocrine islet cells for hormone secretion and by exocrine acinar cells as pancreatic juice component. ZnT8 is a member of the SLC30A family of zinc transporters whose overexpression in cultured pancreatic beta cells leads to increased insulin secretion in response to glucose, suggesting a possible role in regulating glycemia. ZnT8 was therefore proposed as a therapeutic target for diabetes, and recent genome-wide association studies identified polymorphisms in the ZNT8 gene conferring increased type 2 diabetes risk. As limited information was available on the biochemical properties of ZnT8 and on its endogenous expression, we have raised a specific polyclonal antibody and immunostained protein extracts, cell lines and tissue sections. We show that ZnT8 forms a very stable dimer that requires biological membranes to properly assemble. We demonstrate localization of murine ZnT8 to the secretory granules in pancreatic beta and alpha islet cells. Moreover, we show that ZnT8 is also expressed in other secretory cell types, namely the cubical epithelium that lines thyroid follicles and the cortex of the adrenal gland, suggesting a more widespread role in endocrine secretion. | the use of steroids is recognized in septic shock. There are reports of their use in burns. It is also known their negative effect in wound healing. to know the effect of steroids in burn healing. two groups of ten rats (wistar) were exposed to metallic cylinder at 95°C for 15 seconds on the back. At the moment of the burn one group received hydrocortisone dose 5 mg/kg. The other group didn't received medication. The scar was removed at the fifth day and the burn injury was covered with queratinocyte culture. The rats were sacrificed at 14th day. The presence of infection and the percentage of new epithelium, fibrosis, inflammatory process, presence of fibroblast and vascular proliferation were evaluated. We compared both groups using χ(2) test. there are no difference between groups in fibrosis, inflammatory process, or fibroblast presence. But there is a difference in vascular proliferation against the first group (steroid group). There were no signs of infection and all of them were epithelized at the 14th day. |
Is detection of pup odors by non-canonical adult vomeronasal neurons expressing an odorant receptor gene influenced by sex and parenting status? | Olfaction is a fundamental sense through which most animals perceive the external world. The olfactory system detects odors via specialized sensory organs such as the main olfactory epithelium and the vomeronasal organ. Sensory neurons in these organs use G-protein coupled receptors to detect chemosensory stimuli. The odorant receptor (OR) family is expressed in sensory neurons of the main olfactory epithelium, while the adult vomeronasal organ is thought to express other types of receptors. Here, we describe Olfr692, a member of the OR gene family identified by next-generation RNA sequencing, which is highly upregulated and non-canonically expressed in the vomeronasal organ. We show that neurons expressing this gene are activated by odors emanating from pups. Surprisingly, activity in Olfr692-positive cells is sexually dimorphic, being very low in females. Our results also show that juvenile odors activate a large number of Olfr692 vomeronasal neurons in virgin males, which is correlated with the display of infanticide behavior. . In contrast, activity substantially decreases in parenting males (fathers), where infanticidal aggressive behavior is not frequently observed. | The study objective was to determine the relative efficacy and safety of a low-molecular-weight heparinoid (Orgaran) compared with aspirin for the prevention of postoperative venous thromboembolism in patients undergoing surgery for fractured hips. A double-blind, randomized, controlled trial was used to study 251 consecutive eligible and consenting patients undergoing surgery for hip fracture in seven participating hospitals. Patients received either fixed-dose Orgaran by subcutaneous injection every 12 hours in a dose of 750 anti-Factor Xa units or aspirin 100 mg orally twice daily; both regimens were started 12 to 24 hours after surgery and continued for 14 days or until discharge, if sooner. All patients had postoperative 125I-fibrinogen leg scanning and impedance plethysmography. If the results of one or both tests were positive, then venography was performed. Otherwise, venography was done at day 14, or sooner if the patient was ready for discharge. Pulmonary embolism in symptomatic patients was diagnosed on the basis of a high probability perfusion/ventilation lung scan, a positive angiogram, or a clinically significant embolism detected at autopsy. Evaluable venograms were obtained in 90 of the 125 patients randomly assigned to receive Orgaran and in 87 of the 126 patients assigned to receive aspirin. Venous thromboembolism was detected in 25 (27.8%) patients in the Orgaran group and in 39 (44.3%) patients in the aspirin group. Thus, there was a relative risk reduction of 37% with Orgaran (P=.028; 95% confidence interval, 3.7% to 59.7%). Six (6.8%) of 88 patients in the Orgaran group and 12 (14.3%) of 84 patients in the aspirin group developed proximal deep vein thrombosis or pulmonary embolism, a relative risk reduction of 52% with Orgaran (P=.137; 95% confidence interval, -30.7% to 84.6%). Hemorrhagic complications occurred in 2 (1.6%) patients given Orgaran and 8 (6.4%) patients given aspirin (P=.10). There was one major bleed in the Orgaran group compared with four in the aspirin group. |
Is atopy in children with systemic onset juvenile idiopathic arthritis ( SoJIA ) associated with a worse outcome? | Atopy and systemic onset juvenile idiopathic arthritis (SoJIA) are two potential outcomes of a dysregulated immune system. Although rare, SoJIA causes 60% of the morbidity of JIA patients which exhibit a wide heterogeneity of prognosis and treatment. Co-morbidities can complicate the responses to therapy. To study the influence of co-existing atopy on the prognosis of SoJIA. Patients diagnosed with SoJIA between Jan 2006 and Sep 2010 were screened, enrolled in this prospective cohort study, and followed for 2 years. Management of SoJIA patients was assessed by ACR Pedi30/50/70 criteria, laboratory variables, and systemic feature score. At disease onset, 61 SoJIA patients (34 male and 27 female) were enrolled and were divided into SoJIA patients with atopy (n = 27) or those without atopy (n = 34). Atopic group at disease onset had significantly higher numbers of affected joints, ferritin levels and IgE serum levels than the non-atopic group. At 3 and 6 months, fewer SoJIA patients with atopy reached the ACR Pedi50 criteria (p < 0.02). During the 2 years of follow-up time, the number of infections and the number of flares were significantly higher in the SoJIA with atopy group (p < 0.01). | Ischemia or hypoxia activates N-methyl-D-aspartate (NMDA) receptors and results in nitric oxide (NO) production. The purpose of this study was to investigate whether an NMDA channel blocker can inhibit NO production during ischemia. Temporary cerebral ischemia was induced by middle cerebral artery ligation while common carotid arteries were clamped bilaterally for 40 minutes in urethane-anesthetized rats. Extracellular NO concentration in the cortex was recorded through Nafion- and porphyrine-coated carbon fiber electrodes. Ketamine, and NMDA channel blocker, was administered (50 mg/kg) intraperitoneally 15 minutes before the cerebral artery ligation. During middle cerebral artery ligation, cortical NO was increased to its peak (18.76+/-3.36 nmol/L) in 7 minutes and then declined. The overflow of NO can be antagonized by pretreatment with ketamine, dizocilpine maleate (MK801), or N(G)-nitro-L-arginine methyl ester (L-NAME). Local application of nitroprusside also induced NO production. However, this effect was not antagonized by ketamine. |
Is exercise-induced mitral regurgitation a predictor of morbid events in subjects with mitral valve prolapse? | This study attempted to determine whether a subset of patients with mitral valve prolapse and no mitral regurgitation at rest will develop mitral regurgitation during exercise and have a higher than anticipated risk of morbid cardiovascular events. Mitral regurgitation in patients with mitral valve prolapse identifies a subset of patients at higher risk for morbid events. However, mitral regurgitation in patients with mitral valve prolapse may be intermittent and could go unrecognized. A provocative test to unmask mitral regurgitation in these patients would be useful. Ninety-four adult patients with mitral valve prolapse and no mitral regurgitation at rest were studied during supine bicycle ergometry using color flow Doppler echocardiography in the apical four-chamber and long-axis views. Patients were prospectively followed up for morbid events. Thirty (32%) of 94 patients had exercise-induced mitral regurgitation. Prospective follow-up (mean 38 months) showed more morbid events in the group with than without mitral regurgitation and included, respectively, syncope (43% vs. 5%, p < 0.0001), congestive heart failure (17% vs. 0%, p < 0.005) and progressive mitral regurgitation requiring mitral valve replacement surgery (10% vs. 0%, p < 0.05). Cerebral embolic events, endocarditis or sudden death were rare and not different between groups. | We have performed TNF-alpha gene transfection in a mouse mammary cancer line and found significant antitumor effects. We hypothesize that the antitumor effects observed in this model are mediated by ICAM-1 and by the recruitment of CD4+ and CD8+ T cells. In vivo (Balb/c mice) tumor growth inhibition, treatment of established tumor and the effects of ICAM-1 and CD4+ and CD8+ T cells were evaluated. Gene transfection with highly efficient vectors resulted in secretion of large amounts of TNF-alpha (ELISA). In vivo antitumor effects were tested. The number of cells required to generate palpable tumor 7-10 days after subcutaneous injection was determined (1 x 10(6)). The same number of transfected cells were injected subcutaneously and compared to nontransfected controls. Tumors were measured blindly and size was analyzed on day 30 by the Wilcoxon rank sum test. Mean tumor size after injection of transfected cells is compared to that of controls. Control tumors reached the maximum allowable size by day 30 (4 cm(2)). On day 30 EMT6-TNF-alpha tumors were 0.48 cm(2) (p < 0.05). The effect of repeat injection (challenge was also tested. Animals were injected with transfected cells or wild-type control on day -6 and challenged with the same number of wild-type tumor cells on day 0. Significant immune protection against subsequent challenge was seen after first time injection with EMT6-TNF-alpha but not after first time EMT6 wild-type injection (1.62 vs. 4 cm(2)). Treatment of 6-day-old tumor was also evaluated. On day 30, mean tumor size in animals treated with EMT6-TNF-alpha was 0.9 cm(2) compared to 4 cm(2) for controls. In all experiments, CD8+ T cell depletion and CD4+ T cell depletion caused a reversal of TNF-alpha-induced inhibitory effects. In addition, in vivo antibody blocking of ICAM-1 in tumor growth experiments reversed antitumor effects (control 4 cm(2), TNF-alpha 0.2 cm(2) and ICAM-1 blocking 3.14 cm(2)). Using flow cytometry, MHC class I and II and ICAM-1 adhesion molecule expression of transfected tumor was tested. ICAM-I expression was significantly upregulated. MHC class II antigen expression was also increased. TNF-alpha-transfected human breast cancer was also evaluated. Three cell lines and fresh tumor were transfected to express TNF-alpha. In vitro analysis revealed ICAM-1 upregulation following transfection. Histologic analysis and immunohistochemical staining revealed TNF-alpha and ICAM-1 in transfected tumors and not in wild-type tumors. |
Is rubella virus associated with fuchs heterochromic iridocyclitis? | To determine whether rubella virus (RV) is involved in the pathogenesis of Fuchs heterochromic iridocyclitis (FHI). Retrospective patient-controlled study. Intraocular immunoglobulin G production against RV, herpes simplex virus (HSV), varicella zoster virus (VZV), and Toxoplasma gondii was determined in the aqueous humor of 14 patients with FHI, 13 control subjects with herpetic uveitis anterior, and 19 control subjects with ocular toxoplasmosis by calculation of the Goldmann-Witmer coefficient (GWC). All patients and control subjects were seropositive for RV. Intraocular antibody production (GWC >3) against RV was found in 13 of 14 patients (93%) with FHI. Intraocular antibody production against HSV, VZV, or T gondii was not detected. None of the control subjects with herpetic uveitis anterior or with toxoplasma chorioretinitis had a positive GWC for rubella virus (P < .0001, Fisher exact test). | Tobacco use among persons with Type II diabetes exponentially increases negative health consequences and mortality rates. It is especially troubling that diabetic persons who smoke have a greater difficulty with tobacco cessation as compared to non-diabetic smokers. Diabetes is a metabolic syndrome that consists of insulin resistance due to disruptions in insulin signaling. We have previously shown that insulin depletion enhances the motivational effects of nicotine. The present study expands our previous work by examining whether insulin resistance, produced by a high-fat diet (HFD) regimen, enhances the rewarding effects of nicotine, as measured by the conditioned place preference (CPP) paradigm. Rats were placed on either a regular diet (RD) or a HFD for 5 weeks, after which they were assessed for insulin resistance via blood glucose measurements after an insulin challenge. Rats then underwent a nicotine CPP study. The findings revealed that HFD produced insulin resistant and non-insulin resistant animals. Interestingly, the magnitude of nicotine CPP was larger in insulin resistant rats versus RD rats. Nicotine CPP was absent in non-insulin resistant animals. A similar increase in body weight was observed in insulin resistant and non-insulin resistant rats as compared to RD rats. These findings suggest that neither the increased body weight nor the HFD per se in the insulin resistant rats contributed to the enhanced nicotine reward. |
Is computer-based symptom assessment feasible in patients with advanced cancer : results from an international multicenter study , the EPCRC-CSA? | Symptom assessment by computers is only effective if it provides valid results and is perceived as useful for clinical use by the end users: patients and health care providers. To identify factors associated with discontinuation, time expenditure, and patient preferences of the computerized symptom assessment used in an international multicenter data collection project: the European Palliative Care Research Collaborative-Computerized Symptom Assessment. Cancer patients with incurable metastatic or locally advanced disease were recruited from 17 centers in eight countries, providing 1017 records for analyses. Observer-based registrations and patient-reported measures on pain, depression, and physical function were entered on touch screen laptop computers. The entire assessment was completed by 94.9% (n = 965), with median age 63 years (range 18-91 years) and median Karnofsky Performance Status (KPS) score of 70 (range 20-100). Predictive factors for noncompletion were higher age, lower KPS, and more pain (P ≤ 0.012). Time expenditure among completers increased with higher age, male gender, Norwegian nationality, number of comorbidities, and lower physical functioning (P ≤ 0.007) but was inversely related to pain levels and tiredness (P ≤ 0.03). Need for assistance was predicted by higher age, nationality other than Norwegian, lower KPS, and lower educational level (P < 0.001). More than 50% of patients preferred computerized assessment to a paper and pencil version. | Mice deficient in apolipoprotein E (apoE(-/-)) develop atherosclerosis. The possible linkage between expression of adhesion molecules/cofactors and atherosclerosis was probed at the level of mRNA and protein expression. The hypothesis of a linkage between changes of adhesion molecules/cofactors and atherosclerosis was tested further by suppression of aortic lesion formation in apoE(-/-) mice by expression of very low levels of transgenic apolipoprotein E. We show that at 8.5 months of age, the apoE(-/-) mice display elevated expression of mRNA for LFA-1, MAC-1, VCAM-1, ICAM-1, and for CD44, as well as MCP-1, cathepsin B, and COX-2 (but not that for eNOS) in atherosclerotic aortic arches. At earlier age, (10-13 week old) apoE(-/-) mice already display elevated expression of mRNA of CD44, LFA-1, MAC-1, VCAM-1, ICAM-1, cathepsin, and of COX-2 in lesioned aortic arches. Expressing very low levels of transgenic apolipoprotein E suppresses both aortic lesions and the expression of mRNA of LFA-1, VCAM-1, MCP-1, cathepsin B, and of ICAM-1 in ApoE(-/-) mice. We tested at the level of protein, the observations obtained for mRNA expression. CD11a (a component of LFA-1), VCAM-1 and cathepsin B expression was found to be elevated in apoE(-/-) aortas at 8-9 months; low level expression of transgenic apolipoprotein E rectifies these changes. |
Is uVA1 phototherapy effective in darker skin : a review of 101 patients of Fitzpatrick skin types I-V? | Studies suggest ultraviolet (UV) A1 phototherapy is efficacious and safe in treating a variety of skin disorders. However, most reports evaluating the benefits of UVA1 phototherapy have been from Europe, focusing on a predominantly Caucasian population. Darker skin types have been evaluated only sparingly; none the less, it is widely held that these patients respond poorly to UVA1 phototherapy due to increased pigmentation. We aim to compare efficacy (clinical improvement scores) of UVA1 phototherapy among Fitzpatrick skin types. A retrospective analysis of 101 patients receiving UVA1 treatment at the University of Texas Southwestern Medical Center in Dallas, TX was performed. Data on Fitzpatrick skin type and cumulative UVA1 doses were collected. Clinical improvement scores based on body surface area, erythema, induration, sclerosis, pigmentation, and symptoms of pain or pruritus were obtained. In the population studied, with morphoea and scleroderma being the most frequent diagnoses, improvement scores from UVA1 phototherapy and mean cumulative UVA1 doses were not significantly different among the Fitzpatrick skin types evaluated. Furthermore, little or no correlation was found between improvement score and skin type. | The neuropeptides leptin and ghrelin are involved in the appetite regulating network consisting of distinct orexigenic (ghrelin) and anorexigenic (leptin) circuitries. Recently, it has been shown that elevated leptin levels are associated with alcohol craving in patients suffering from alcoholism. Therefore, the aim of the present pilot study was to determine whether the gut-derived peptide ghrelin which increases hunger and food intake is altered and associated with alcohol craving in alcoholic patients Two types of alcoholic inpatients, group A (active drinker, acutely intoxicated, n=97) and group B (early abstainer, who had stopped drinking 24-72 hrs before, n=21) were consecutively included in a prospective study from the first day of hospitalization. Ghrelin plasma levels and craving data were assessed on days 0, 1, 2 and 7(-10) and compared to those of 24 healthy controls At each time-point ghrelin plasma levels of alcoholic patients were significantly increased compared to healthy subjects. Furthermore, early abstainers showed significantly higher ghrelin levels than active drinkers. In the group of active drinkers ghrelin plasma levels were significantly increased at each time point compared to baseline. No correlations were found between ghrelin levels and craving data measured by the visual analogue scale or the Obsessive Compulsive Drinking Scale |
Is early elevation of plasma von Willebrand factor antigen in pediatric acute lung injury associated with an increased risk of death and prolonged mechanical ventilation? | Von Willebrand factor antigen (vWF-Ag) is a marker of pulmonary and systemic endothelial activation and injury. Adult studies indicate that patients with plasma vWF-Ag levels > or = 450% of control early in the course of acute lung injury (ALI) have an increased risk of death. The objective of this study was to evaluate whether vWF-Ag is elevated in the early phase of ALI in children and whether the magnitude of the increase was predictive of two important outcomes: mortality or duration of mechanical ventilation. Two-center, prospective observational study. Two pediatric intensive care units: one in an academic university setting and one in a major community children's hospital. After appropriate consent, plasma was collected from 48 pediatric patients on day 1 of ALI, 45 patients on day 2 of ALI, and four intubated controls. None. Mean PaO2/FiO2 at the onset of ALI was 140 +/- 70, and mortality rate was 17%. vWF-Ag levels on day 1 of ALI were higher in patients compared with controls (287 +/- 183 vs. 87 +/- 84% of control [mean +/- SD], p < .05). Patients with vWF-Ag levels > or = 450% of control on day 1 of ALI had a markedly greater risk of death (odds ratio, 7.0; confidence interval, 1.31, 37.30; p < .05). Multivariate analysis revealed that elevated vWF-Ag level and either presence of multiple organ system failure or Pediatric Risk of Mortality III score independently predict increased risk of death. vWF-Ag levels on day 2 of ALI were significantly higher in patients who required prolonged mechanical ventilation (316 +/- 173 vs. 191 +/- 89% of control, p < .05). | MicroRNA is a type of endogenous non-coding RNA implicated in various cellular processes, and has been intensely investigated in the field of cancer research for many years. Here, we investigated the functions and mechanisms of miR-124 in prostate cancer, which is a putative tumor suppressor reported in many carcinomas. Using bioinformatics, talin 1 was indicated as a potential target of miR-124. We examined the expression levels of miR-124 and talin 1 in tissue specimens and cell lines. To explore the relationship between miR-124 and talin 1, miR-124 mimics, miR-124 inhibitors, and talin 1 small interfering RNA (siRNA) were transiently transfected into cancer cell lines, followed by analysis using luciferase reporter assays. Next, to investigate the functions of miR-124 in prostate cancer, we performed cell attachment, migration, and invasion assays. A rescue experiment was also conducted to demonstrate whether miR-124 suppressed cell adhesion and motility by targeting talin 1. Finally, we examined the related signaling pathways of miR-124 and talin 1. MiR-124 was down-regulated in prostate cancer specimens and cell lines, while talin 1 was over-expressed in prostate cancer specimens and cell lines. These results showed an inverse correlation of miR-124 and talin 1 expression. Similar to talin 1 siRNA, overexpression of miR-124 by transient transfection of mimics led to a significant decrease in talin 1 levels. Luciferase report assays showed that the seed sequence of the talin 1 3'-untranslated region was a target of miR-124. Functional investigations revealed anti-attachment, anti-migration, and invasion-promoting effects of miR-124 in prostate cancer cells. The rescue experiment confirmed that miR-124 exerted its biological functions by targeting talin 1. Finally, we found that miR-124 and talin 1 impaired cellular adhesion and motility through integrins and the focal adhesion kinase/Akt pathway. |
Do human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells? | In mice, a subpopulation of gut dendritic cells (DCs) expressing CD103 drives the development of regulatory T (T(reg)) cells. Further, it was recently described that the cross-talk between human intestinal epithelial cells (IECs) and DCs helps in maintaining gut immune homeostasis via the induction of non-inflammatory DCs. In this study, an analysis was carried out to determine whether IECs could promote the differentiation of CD103+ tolerogenic DCs, and the function of primary CD103+ DCs isolated from human mesenteric lymph nodes (MLNs) was evaluated. Monocyte-derived DCs (MoDCs) and circulating CD1c+ DCs were conditioned or not with supernatants from Caco-2 cells or IECs isolated from healthy donors or donors with Crohn's disease and analysed for their ability to induce T(reg) cell differentiation. In some cases, transforming growth factor beta (TGFbeta), retinoic acid (RA) or thymic stromal lymphopoietin (TSLP) were neutralised before conditioning. CD103+ and CD103- DCs were sorted by fluorescence-activated cell sorting (FACS) from MLNs and used in T(reg) cell differentiation experiments. It was found that human IECs promoted the differentiation of tolerogenic DCs able to drive the development of adaptive Foxp3+ T(reg) cells. This control was lost in patients with Crohn's disease and paralleled a reduced expression of tolerogenic factors by primary IECs. MoDCs differentiated with RA or IEC supernatant upregulated the expression of CD103. Consistently, human primary CD103+ DCs isolated from MLNs were endowed with the ability to drive T(reg) cell differentiation. This subset of DCs expressed CCR7 and probably represents a lamina propria-derived migratory population. | In patients with ischaemic left ventricular dysfunction, multivessel disease and dominance of necrotic myocardium, perioperative mortality due to coronary artery bypass grafting is still a rather unclear issue. The aim of this study was to analyse the impact of different imaging variables in predicting perioperative mortality. We selected a group of 259 patients who had preoperatively been defined as 'high-risk patients' and who showed a mostly necrotic myocardium as detected by thallium-201 myocardial scintigraphy. Mean ejection fraction was 0.26 +/- 0.07. In a 16-segment model, the mean number of scintigraphic necrotic myocardial segments was 5.07 +/- 1.09, echocardiographic end-diastolic diameter was 29.41 +/- 2.38 mm/m2 and wall motion score index was 2.29 +/- 0.19. Perioperative mortality increased along with the increase in the number of necrotic segments: 5/105 (5%), 4/63 (6%), 8/52 (15%) and 8/39 (20%) patients with four, five, six and seven necrotic segments, respectively. The analysis of additional variables in survived vs. deceased patients demonstrated a significant difference in echocardiographic end-diastolic diameter (27 +/- 8 vs. 31.9 +/- 1.9 mm/m2, P < 0.001) and in wall motion score index (2.2 +/- 0.1 vs. 2.4 +/- 0.2, P < 0.001). |
Does histamine H ( 3 ) receptor-mediated signaling protect mice from cerebral malaria? | Histamine is a biogenic amine that has been shown to contribute to several pathological conditions, such as allergic conditions, experimental encephalomyelitis, and malaria. In humans, as well as in murine models of malaria, increased plasma levels of histamine are associated with severity of infection. We reported recently that histamine plays a critical role in the pathogenesis of experimental cerebral malaria (CM) in mice infected with Plasmodium berghei ANKA. Histamine exerts its biological effects through four different receptors designated H1R, H2R, H3R, and H4R. In the present work, we explored the role of histamine signaling via the histamine H3 receptor (H3R) in the pathogenesis of murine CM. We observed that the lack of H3R expression (H3R(-/-) mice) accelerates the onset of CM and this was correlated with enhanced brain pathology and earlier and more pronounced loss of blood brain barrier integrity than in wild type mice. Additionally tele-methylhistamine, the major histamine metabolite in the brain, that was initially present at a higher level in the brain of H3R(-/-) mice was depleted more quickly post-infection in H3R(-/-) mice as compared to wild-type counterparts. | To investigate a possible difference between true ovarian volume and ovarian volume estimated with two-dimensional (2D) transvaginal ultrasound. Prospective clinical and laboratory study. University hospital research laboratory. Premenopausal girls and women from three Danish national fertility centers (A: n = 42; B: n = 6; C: n = 18), who had one entire ovary removed for cryopreservation of ovarian cortex. Transvaginal 2D ultrasound measurement of ovarian volume before oophorectomy. True ovarian volume was obtained by weighing the ovary. Ovarian volume estimated by weight and ultrasound. Ovarian tissue density was 1.00 g/mL. Mean ovarian volume by ultrasound vs. weight in the three groups was as follows: A: 6.3 mL vs. 7.8 mL; B: 5.4 mL vs. 6.8 mL; and C: 2.8 mL vs. 6.1 ml. Ovarian volume obtained by ultrasound was at least 27% smaller than the true ovarian volume. |
Does a luciferase immunoprecipitation systems assay enhance the sensitivity and specificity of diagnosis of Strongyloides stercoralis infection? | We investigated whether luciferase immunoprecipitation systems (LIPS) can be the basis for a more rapid, specific, and standardized assay for the diagnosis of Strongyloides stercoralis infection. A LIPS assay was developed based on immunoglobulin (Ig) G or IgG4 antibody to a recombinant Strongyloides antigen (NIE) and was compared with an NIE enzyme-linked immunosorbent assay (ELISA). A second antigen, S. stercoralis immunoreactive antigen (SsIR), was tested alone and in combination with NIE. The assays were tested using serum samples from patients with parasitologically proven S. stercoralis or filarial infections and from healthy, uninfected control subjects. The NIE LIPS assay based on IgG antibody easily differentiated between S. stercoralis-infected and uninfected patients (P< .0001) and demonstrated improved specificity compared with the NIE ELISA (100% vs. 95%). Serum from filaria-infected patients did not cross-react when tested with the NIE LIPS assay. When SsIR was used in combination with NIE in the LIPS format, sensitivity and specificity improved to 100%, with a 7-fold difference between positive and negative values. No advantage was found in using a LIPS assay based on IgG4. At posttreatment follow-up, a significant decline in antibody titers was detected using the NIE ELISA (P< .0017) and the NIE LIPS assay (P< .0001). | The Dickkopf (DKK) family comprises a set of proteins that function as regulators of Wnt/beta-catenin signaling and has a crucial role in development. Recent studies have revealed the involvement of this family in tumorigenesis, however their role in tumorigenesis is still remained unclear. We found increased expression of DKK2 but decreased expression of DKK1 in Ewing family tumor (EFT) cells. We showed that EFT-specific EWS/ETS fusion proteins enhance the DKK2 promoter activity, but not DKK1 promoter activity, via ets binding sites (EBSs) in the 5' upstream region. EWS/ETS-mediated transactivation of the promoter was suppressed by the deletion and mutation of EBSs located upstream of the DKK2 gene. Interestingly, the inducible expression of EWS/ETS resulted in the strong induction of DKK2 expression and inhibition of DKK1 expression in human primary mesenchymal progenitor cells that are thought to be a candidate of cell origin of EFT. In addition, using an EFT cell line SK-ES1 cells, we also demonstrated that the expression of DKK1 and DKK2 is mutually exclusive, and the ectopic expression of DKK1, but not DKK2, resulted in the suppression of tumor growth in immuno-deficient mice. |
Is hydrogen Inhalation Superior to Mild Hypothermia in Improving Cardiac Function and Neurological Outcome in an Asphyxial Cardiac Arrest Model of Rats? | Non-shockable rhythms represent an increasing proportion of reported cases of out-of-hospital cardiac arrest but with an associated poor prognosis. In the present study, we investigated the effects of hydrogen inhalation on cardiac and neurological function after cardiopulmonary resuscitation and compared the therapeutic benefit with hypothermia in an asphyxial rat model of cardiac arrest. Cardiopulmonary resuscitation was initiated after 5 min of untreated asphyxial cardiac arrest. Animals were randomly assigned to three experimental groups immediately after successful resuscitation: ventilation with 2% hydrogen/98% oxygen under normothermia (H2 inhalation), ventilation with 2% nitrogen/98% oxygen under normothermia (Control), and ventilation with 2% nitrogen/98% oxygen under hypothermia (TH). Mixed gas inhalation continued for 1 h while hypothermia continued for 2 h. Animals were observed up to 96 h for assessment of survival and neurologic recovery. No statistical differences in baseline measurements were observed among groups and all the animals were successfully resuscitated. Serum cardiac troponin T and S100B measured during earlier post-resuscitation period were markedly reduced in both H2 inhalation and hypothermic groups. However, significantly better left ventricular ejection fraction, cardiac work, and neurological deficit score were observed in the H2 inhalation group. Ninety-six hours survival rate was significantly higher in the H2 inhalation group (75.0%), either compared with TH (45.8%) or compared with Control (33.3%). But there was no statistical difference between TH and Control. | Rheumatoid factor (RF) is prototypic for rheumatoid arthritis (RA) and serves diagnostic and prognostic purposes. RF is associated with joint destruction, but the role of disease activity as a potential mediator of these effects has not been clearly elucidated yet. To investigate if higher radiographic progression (Sharp score, ΔTSS) in RF+ patients is dependent or independent of disease activity. The authors performed a cross-sectional multivariate analysis at baseline and a matched cohort study in patients from five RA clinical trials. The authors pooled methotrexate treatment arms and compared ΔTSS in RF+ and RF- patients before and after matching for other associated variables. Among 686 patients, 124 were RF- and 562 RF+, 343 having high (>160 U/ml) RF. ΔTSS was 1.03±5.83, 3.23±8.10 and 3.58±8.18 (p<0.0001), respectively, and similarly for erosions and joint space narrowing (JSN). After matching for other prognostically important variables, ΔTSS still was lower among 61 RF- versus 61 RF high+ patients (0.52±2.47 vs 3.09±8.28; p=0.028), mainly related to differences in erosion score (0.31±1.88 vs 2.07±5.62; p=0.035), but not JSN (0.21±1.26 vs 1.02±3.31; p=0.162). |
Does immunological profiling in chronic rhinosinusitis with nasal polyps reveal distinct VEGF and GM-CSF signatures during symptomatic exacerbations? | The mechanisms and immune pathways associated with chronic rhinosinusitis (CRS) are not fully understood. Immunological changes during acute exacerbation of CRS may provide valuable clues to the pathogenesis and perpetuation of the disease. To characterize local and systemic immune responses associated with acute worsening of sinonasal symptoms during exacerbation in CRS with nasal polyps (CRSwNP) compared to controls. This was a non-interventional prospective study of individuals with CRSwNP and normal controls. Subjects underwent a baseline visit with collection of nasal secretions, nasal washes, and serum specimens. Within 3 days of acute worsening of sinonasal symptoms, subjects underwent a study visit, followed by a post-visit 2 weeks later. The sinonasal outcome test-22 (SNOT-22) scores and immunological parameters in the specimens were analysed using a novel, unsupervised learning method and by conventional univariate analysis. Both CRSwNP patients and control subjects showed a significant increase in SNOT-22 scores during acute exacerbation. Increased nasal levels of IL-6, IL-5, and eosinophil major basic protein were observed in CRSwNP patients. A network analysis of serum specimens revealed changes in a set of immunological parameters, which are distinctly associated with CRSwNP but not with controls. In particular, systemic increases in VEGF and GM-CSF levels were notable and were validated by a conventional analysis. | Transcatheter aortic valve implantation (TAVI) without predilatation has fewer procedural steps and thereby potentially fewer complications. This has been demonstrated for the antegrade transapical access; however, whether TAVI can be safely performed without predilatation using the retrograde transfemoral route is unknown. We postulated that TAVI is feasible with a balloon-expandable device without predilatation using the retrograde transfemoral route. Twenty-six consecutive patients with stenosis of the native aortic valve (AV) undergoing transfemoral TAVI with the Edwards SAPIEN XT prosthesis without predilatation were enrolled in this retrospective study and compared with 30 patients treated previously with predilatation. The procedure was successfully performed in all 26 patients, irrespective of the AV area and the extent of AV calcification. At baseline mean AV area, mean AV gradient, and median left ventricular ejection fraction were 0.7 ± 0.2 cm(2) , 36.0 ± 17.3 mm Hg, and 55.0% (interquartile range [IQR], 35.0-60.0], respectively; prior to discharge these values were 1.7 ± 0.3 (P < 0.001), 9.8 ± 6.1 mm Hg (P < 0.001), and 57.5% (IQR, 38.7-60.0) (P = not significant). Postdilatation was required in 3 patients due to aortic regurgitation > 2°; this was reduced by the procedure to < 2° in all cases. Radiation dose and amount of contrast dye were significantly reduced in comparison with the predilatation group. No periprocedural neurological adverse events occurred. Mortality at 30 days was 0%. |
Does modification of the Lund-Kennedy endoscopic scoring system improve its reliability and correlation with patient-reported outcome measures? | To compare three existing endoscopic scoring systems and a newly proposed modified scoring system for the assessment of patients with chronic rhinosinusitis (CRS). Blinded, prospective cohort study. CRS patients completed two patient-reported outcome measures (PROMs)-the visual analogue scale (VAS) symptom score and the Sino-Nasal Outcome Test-22 (SNOT-22)-and then underwent a standardized, recorded sinonasal endoscopy. Videos were scored by three blinded rhinologists using three scoring systems: the Lund-Kennedy (LK) endoscopic score; the Discharge, Inflammation, Polyp (DIP) score; and the Perioperative Sinonasal Endoscopic score. The videos were further scored using a modified Lund-Kennedy (MLK) endoscopic scoring system, which retains the LK subscores of polyps, edema, and discharge but eliminates the scoring of scarring and crusting. The systems were compared for test-retest and inter-rater reliability as well as for their correlation with PROMs. One hundred two CRS patients were enrolled. The MLK system showed the highest inter-rater and test-retest reliability of all scoring systems. All systems except for the DIP correlated with total VAS scores. The MLK was the only system that correlated with the symptom subscore of the SNOT-22 in both unoperated and postoperative patients. | Active cancer-associated fibroblasts (CAFs) or myofibroblasts play important roles not only in the development and progression of breast carcinomas, but also in their prognosis and treatment. Therefore, targeting these cells through suppressing their supportive procarcinogenic paracrine effects is mandatory for improving the current therapies that are mainly targeting tumor cells. To this end, we investigated the effect of the natural and pharmacologically safe molecule, caffeine, on CAF cells and their various procarcinogenic effects. We have shown here that caffeine up-regulates the tumor suppressor proteins p16, p21, p53 and Cav-1, and reduces the expression/secretion of various cytokines (IL-6, TGF-β, SDF-1 and MMP-2), and down-regulates α-SMA. Furthermore, caffeine suppressed the migratory/invasiveness abilities of CAF cells through PTEN-dependent Akt/Erk1/2 inactivation. Moreover, caffeine reduced the paracrine pro-invasion/-migration effects of CAF cells on breast cancer cells. These results indicate that caffeine can inactivate breast stromal myofibroblasts. This has been confirmed by showing that caffeine also suppresses the paracrine pro-angiogenic effect of CAF cells through down-regulating HIF-1αand its downstream effector VEGF-A. Interestingly, these effects were sustained in absence of caffeine. |
Is cardiac injury after subarachnoid hemorrhage independent of the type of aneurysm therapy? | Subarachnoid hemorrhage (SAH) is associated with cardiac injury and dysfunction. Whether aneurysm clipping versus coiling has a differential effect on the risk of troponin release and left ventricular (LV) dysfunction after SAH is unknown. It is hypothesized that aneurysm treatment does not affect the risk of developing cardiac injury and dysfunction. The study included 172 consecutive SAH patients who underwent clipping (n = 109) or coiling (n = 63) aneurysm therapy. Hemodynamic data were collected, cardiac troponin I was measured, and echocardiography was performed on the 1st, 3rd, and 6th days after enrollment. A cardiac troponin I measurement of more than 1.0 microg/L was considered abnormal. For each echocardiographic examination, a blinded observer measured LV ejection fraction (abnormal if <50%) and quantified LV regional wall motion abnormalities. The incidence of cardiac outcomes in the treatment groups was compared using odds ratios (ORs). The coiled patients were older than the clipped patients (mean age, 59 +/- 13 yr versus 53 +/- 12 yr; t test, P < 0.001) and were more likely to have posterior aneurysms (33% versus 18%; chi(2) test, P = 0.019). There were no significant between-group differences in the risk of cardiac troponin I release (coil 21% versus clip 19%; OR = 0.89, P = 0.789), regional wall motion abnormalities (33% versus 28%; OR = 0.76, P = 0.422), or LV ejection fraction lower than 50% (16% versus 17%; OR = 1.06, P = 0.892). No patient died of cardiac causes (heart failure, myocardial infarction, or arrhythmia). | Vitamin D and the vitamin D receptor (VDR) appear to be important immunological regulators of inflammatory bowel diseases (IBD). Defective autophagy has also been implicated in IBD, where interestingly, polymorphisms of genes such as ATG16L1 have been associated with increased risk. Although vitamin D, the microbiome and autophagy are all involved in pathogenesis of IBD, it remains unclear whether these processes are related or function independently. We investigated the effects and mechanisms of intestinal epithelial VDR in healthy and inflamed states using cell culture models, a conditional VDR knockout mouse model (VDR(ΔIEC)), colitis models and human samples. Absence of intestinal epithelial VDR affects microbial assemblage and increases susceptibility to dextran sulfate sodium-induced colitis. Intestinal epithelial VDR downregulates expressions of ATG16L1 and lysozyme, and impairs antimicrobial function of Paneth cells. Gain and loss-of-function assays showed that VDR levels regulate ATG16L1 and lysozyme at the transcriptional and translational levels. Moreover, low levels of intestinal epithelial VDR correlated with reduced ATG16L1 and representation by intestinal Bacteroides in patients with IBD. Administration of the butyrate (a fermentation product of gut microbes) increases intestinal VDR expression and suppresses inflammation in a colitis model. |
Does interferon regulatory factor 3 protect against adverse neo-intima formation? | Vascular smooth muscle cell (VSMC) proliferation is central to the pathophysiology of neo-intima formation. Interferon regulatory factor 3 (IRF3) inhibits the growth of cancer cells and fibroblasts. However, the role of IRF3 in vascular neo-intima formation is unknown. We evaluated the protective role of IRF3 against neo-intima formation in mice and the underlying mechanisms. IRF3 expression was down-regulated in VSMCs after carotid wire injury in vivo, and in SMCs after platelet-derived growth factor (PDGF)-BB challenge in vitro. Global knockout of IRF3 (IRF3-KO) led to accelerated neo-intima formation and proliferation of VSMCs, whereas the opposite was seen in SMC-specific IRF3 transgenic mice. Mechanistically, we identified IRF3 as a novel regulator of peroxisome proliferator-activated receptor γ (PPARγ), a negative regulator of SMC proliferation after vascular injury. Binding of IRF3 to the AB domain of PPARγ in the nucleus of SMCs facilitated PPARγ transactivation, resulting in decreased proliferation cell nuclear antigen expression and suppressed proliferation. Overexpression of wild-type, but not truncated, IRF3 with a mutated IRF association domain (IAD) retained the ability to exert anti-proliferative effect. | To test the hypothesis that the genetic susceptibility to non-insulin dependent diabetes mellitus is the same as that to insulin dependent disease and to see whether glucose intolerance is associated with specific HLA haplotypes. Population based study of men in 1989 first tested for glucose tolerance in 1984. HLA haplotypes, including HLA-A, C, B, DR, and DQ, were defined serologically. HLA haplotype data from a population based Finnish study of childhood diabetes were used for predicting non-insulin dependent diabetes and impaired glucose tolerance. Two communities in Finland. Representative cohort of Finnish men aged 70-89, comprising 98 men with non-insulin dependent diabetes mellitus and a randomly selected group of 74 men, who served as controls, who were tested for glucose tolerance twice within five years. Non-insulin dependent diabetes, impaired glucose tolerance, blood glucose concentration. Diabetes associated HLA haplotypes were present in 94% (85/90) of diabetic subjects, 79% (27/34) of subjects with impaired glucose tolerance, and only 13% (3/23) of non-diabetic subjects. In this group of elderly men sensitivity of the diabetes associated HLA haplotypes for non-insulin dependent diabetes and impaired glucose tolerance was 90%, specificity 87%, and predictive power 97%. Mean fasting blood glucose concentration was only just significantly higher in men with diabetes associated haplotypes than in men with no such haplotypes, but there was a substantial difference in blood glucose values two hours after glucose loading (10.4 and 6.4 mmol/l in men with diabetes associated HLA haplotypes and men with no such haplotypes, respectively (p < 0.0001)). |
Does fatigue correlate with the decrease in parasympathetic sinus modulation induced by a cognitive challenge? | It is known that enhancement of sympathetic nerve activity based on a decrease in parasympathetic nerve activity is associated with fatigue induced by mental tasks lasting more than 30 min. However, to measure autonomic nerve function and assess fatigue levels in both clinical and industrial settings, shorter experimental durations and more sensitive measurement methods are needed. The aim of the present study was to establish an improved method for inducing fatigue and evaluating the association between it and autonomic nerve activity. Twenty-eight healthy female college students participated in the study. We used a kana pick-out test (KPT) as a brief verbal cognitive task and recorded electrocardiography (ECG) to measure autonomic nerve activity. The experimental design consisted of a 16-min period of ECG: A pre-task resting state with eyes open for 3 min and eyes closed for 3 min, the 4-min KPT, and a post-task resting state with eyes open for 3 min and eyes closed for 3 min. Baseline fatigue sensation, measured by a visual analogue scale before the experiment, was associated with the decrease in parasympathetic sinus modulation, as indicated the by ratio of low-frequency component power (LF) to high-frequency component power (HF), during the KPT. The LF/HF ratio during the post-KPT rest with eyes open tended to be greater than the ratio during the KPT and correlated with fatigue sensation. Fatigue sensation was correlated negatively with log-transformed HF, which is an index of parasympathetic sinus modulation, during the post-KPT rest with eyes open. | The T790M mutation of epithelial growth factor receptor (EGFR) is a major cause of the acquired resistance to EGFR tyrosine kinase inhibitor (EGFR-TKIs) treatment for lung cancer patients. The Hippo pathway effector, TAZ, has emerged as a key player in organ growth and tumorigenesis, including lung cancer. In this study, we have discovered high TAZ expression in non-small cell lung cancer (NSCLC) cells harboring dual mutation and TAZ depletion sensitized their response to EGFR-TKIs. Mechanistically, knockdown of TAZ in T790M-induced resistant cells leaded to reduced anchorage-independent growth in vitro, tumor formation and resistance to gefitinib in vivo, correlated with epithelial-mesenchymal transition (EMT) and suppressed migration and invasion. Furthermore, we confirmed CTGF and AXL, novel EMT markers and potential therapeutic targets for overcoming EGFR inhibitor resistance, as directly transcriptional targets of TAZ. |
Do aquaporin-4 autoantibodies increase vasogenic edema formation and infarct size in a rat stroke model? | Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system, which is characterized by autoantibodies directed against the water channel aquaporin-4 (AQP4). As one of the main water regulators in the central nervous system, APQ4 is supposed to be involved in the dynamics of brain edema. Cerebral edema seriously affects clinical outcome after ischemic stroke; we therefore aimed to investigate whether NMO-antibodies may exert the same functional effects as an AQP4-inhibitor in-vivo in acute ischemic stroke. Sixteen male Wistar rats were randomized into two groups twice receiving either purified NMO-IgG or immune globulin from healthy controls, 24 hours and 30 minutes before middle cerebral artery occlusion (MCAO) was performed. T2-weighted MRI was carried out 24 hours after MCAO. MRI-examination showed a significant increase of infarct size in relation to the cerebral hemisphere volume with NMO-IgG treated animals (27.1% ± 11.1% vs. 14.3% ± 7.2%; p < 0.05) when corrected for the space-occupying effect of vasogenic edema formation and similar results without edema correction (34.4% ± 16.4% vs. 17.5% ± 9.3%; p < 0.05). Furthermore, T2-RT revealed a significant increase in cortical brain water content of the treatment group (19.5 ms ± 9.7 ms vs. 9.2 ms ± 5.2 ms; p < 0.05). | Changes in bile acid (BA) pool, such as the reappearance of typically foetal-type molecular species with a 'flat' structure at the steroid ring, occur during hepatocarcinogenesis, both in humans and rodents. Moreover flat-BAs also appear during rat liver regeneration. These changes can be detected in urine. The aim of the present study was to investigate whether flat-BAs also reappear during human liver regeneration, and whether this change correlates with the magnitude of liver resection. Patients undergoing partial hepatectomy were divided in two groups: major hepatectomy group (> 50% of hepatic tissue resection, n = 17) and minor hepatectomy group (< 50%, n = 13). BAs were extracted from serum and urine (collected over 24 h) and analysed by gas chromatography-mass spectrometry. Samples were obtained before surgery (day 0) and on the third and seventh days after hepatectomy. In serum, total BAs significantly increased on day seven after hepatectomy, but only a moderate increase in flat-BA concentrations was observed. By contrast, urinary excretion of total as well as flat-BAs significantly increased at day three and day seven after hepatectomy. Moreover, the amount of flat-BAs excreted in urine during the first week after partial hepatectomy correlated with the magnitude of the resection. |
Are e-cadherin regulators differentially expressed in the epithelium and stroma of keratocystic odontogenic tumors? | The epithelial-mesenchymal transition (EMT) is the process where cells lose their epithelial features and acquire properties of typical mesenchymal cells. The dissociation of tumor cells due to changes in cell-cell adhesion is one of the key principles of tumor invasion and EMT. Thus, the knowledge of the molecular features of EMT in keratocyst odontogenic tumor (KOT) can provide useful markers to aid in the diagnosis and prognosis and perhaps contribute to an alternative therapeutic approach as it shows an aggressive clinical behavior and high recurrence rates. This study aimed to evaluate the EMT in KOT by the immunoexpression of E-cadherin, N-cadherin, Snail, and Slug and comparing to radicular cysts and dental follicles. Thirty-two KOTs, 15 radicular cysts, and 08 dental follicles were used for immunohistochemistry, evaluating the extent, intensity, labeling pattern, cellular compartment in the epithelium and stroma, and the presence of inflammation. E-cadherin was preserved in most cases of keratocystic odontogenic tumor. N-cadherin was increased in the tumor epithelium, a result that was positively correlated with the heterogeneous and nuclear immunoexpression of Slug in the epithelium; Slug also correlated with high Snail immunoexpression. N-cadherin was positively correlated with Slug in the stroma of keratocystic odontogenic tumors. | A third of the world's population does not engage in recommended levels of physical activity (PA), leading to substantial health and economic burdens. The healthcare sector offers a variety of resources that can help counsel, refer and deliver PA promotion programmes for purposes of primordial, primary, secondary and tertiary prevention. Substantial evidence already exists in support of multipronged PA counselling, prescription and referral strategies, in particular those linking healthcare and community-based resources. The Exercise is Medicine (EIM) initiative was introduced in 2007 to advance the implementation of evidence-based strategies to elevate the status of PA in healthcare. In this article, we describe the evolution and global expansion of the EIM initiative, its components, their implementation, an evaluation framework and future initiative activities. Until now, EIM has a presence in 39 countries with EIM Regional Centers established in North America, Latin America, Europe, Africa, Southeast Asia, China and Australasia. The EIM Global Health Initiative is transitioning from its initial phase of infrastructure and awareness building to a phase of programme implementation, with an emphasis in low-to-middle income countries, where 80% of deaths due to non-communicable diseases already occur, but where a large gap in research and implementation of PA strategies exists. |
Do erythrocyte concentrations of metabolites or cumulative doses of 6-mercaptopurine and methotrexate predict liver changes in children treated for acute lymphoblastic leukemia? | During therapy consisting of 6MP and MTX, metabolites accumulate in the erythrocytes. The erythrocyte levels of metabolites reflect the intensity of therapy. Whether they are associated with hepatotoxicity manifested as histological liver changes is not known. We studied the association of the metabolites and cumulative doses of 6MP and MTX with histological liver disease. Serial measurements of E-TGN, E-MTX, and ALT during maintenance therapy were performed and cumulative doses of 6MP and MTX were calculated as g/m2 in 16 children with ALL. Each subject underwent a percutaneous liver biopsy at the end of therapy to screen for histological liver disease. No differences in E-TGN, E-MTX, or cumulative doses of 6MP or MTX were detected in the children with ALL with liver fibrosis compared to those without fibrosis, or in the children with less liver fatty change compared to those with more fatty change. Serum median ALT levels correlated significantly positively with cumulative doses of 6MP during therapy (rS = 0.527, P = 0.036), but not with cumulative doses of MTX, or E-TGN, or E-MTX. | Complement activation is considered a major mechanism in innate immunity. Although it is mainly involved in initiating inflammation, recent data reported its involvement in other processes such as tissue regeneration. In the dental pulp, complement C5a fragment has been shown to be involved in the recruitment of dental pulp stem cells (DPSCs). This study sought to investigate the possible role of C3a, another complement fragment, in the early steps of dentin-pulp regeneration. Expression of C3a receptor (C3aR) was investigated by immunofluorescence and reverse transcriptase polymerase chain reaction on cultured pulp fibroblasts, STRO-1-sorted DPSCs, as well as on human tooth sections in vivo. The effect of C3a on proliferation of both DPSCs and pulp fibroblasts was investigated by MTT assay. Cell migration under a C3a gradient was investigated by using microfluidic chemotaxis chambers. C3aR was expressed in vivo as well as in cultured pulp fibroblasts co-expressing fibroblast surface protein and in DPSCs co-expressing STRO-1. Addition of recombinant C3a induced a significant proliferation of both cell types. When subjected to a C3a gradient, DPSCs were mobilized but not specifically recruited, whereas pulp fibroblasts were specifically recruited following a C3a gradient. |
Does rheumatoid factor determine structural progression of rheumatoid arthritis dependent and independent of disease activity? | Rheumatoid factor (RF) is prototypic for rheumatoid arthritis (RA) and serves diagnostic and prognostic purposes. RF is associated with joint destruction, but the role of disease activity as a potential mediator of these effects has not been clearly elucidated yet. To investigate if higher radiographic progression (Sharp score, ΔTSS) in RF+ patients is dependent or independent of disease activity. The authors performed a cross-sectional multivariate analysis at baseline and a matched cohort study in patients from five RA clinical trials. The authors pooled methotrexate treatment arms and compared ΔTSS in RF+ and RF- patients before and after matching for other associated variables. Among 686 patients, 124 were RF- and 562 RF+, 343 having high (>160 U/ml) RF. ΔTSS was 1.03±5.83, 3.23±8.10 and 3.58±8.18 (p<0.0001), respectively, and similarly for erosions and joint space narrowing (JSN). After matching for other prognostically important variables, ΔTSS still was lower among 61 RF- versus 61 RF high+ patients (0.52±2.47 vs 3.09±8.28; p=0.028), mainly related to differences in erosion score (0.31±1.88 vs 2.07±5.62; p=0.035), but not JSN (0.21±1.26 vs 1.02±3.31; p=0.162). | Arginine vasopressin is a vasoactive drug commonly used in distributive shock states including mixed shock with a cardiac component. However, the direct effect of arginine vasopressin on the function of the ischemia/reperfusion injured heart has not been clearly elucidated. We measured left ventricular ejection fraction using trans-thoracic echocardiography in C57B6 mice, both in normal controls and following ischemia/reperfusion injury induced by a one hour ligation of the left anterior descending coronary artery. Mice were treated with one of normal saline, dobutamine (8.33 microg/kg/min), or arginine vasopressin (0.00057 Units/kg/min, equivalent to 0.04 Units/min in a 70 kg human) delivered by an intraperitoneal micro-osmotic pump. Arterial blood pressure was measured using a micromanometer catheter. In addition, mortality was recorded and cardiac tissues processed for RNA and protein. Baseline left ventricular ejection fraction was 65.6% (60 to 72). In normal control mice, there was no difference in left ventricular ejection fraction according to infusion group. Following ischemia/reperfusion injury, AVP treatment significantly reduced day 1 left ventricular ejection fraction 46.2% (34.4 to 52.0), both in comparison with baseline and day 1 saline treated controls 56.9% (42.4 to 60.2). There were no significant differences in preload (left ventricular end diastolic volume), afterload (blood pressure) or heart rate to account for the effect of AVP on left ventricular ejection fraction. The seven-day mortality rate was highest in the arginine vasopressin group. Following ischemia/reperfusion injury, we found no change in cardiac V1 Receptor expression but a 40% decrease in Oxytocin Receptor expression. |
Are silent infarcts in patients with ischemic stroke related to age and size of the left atrium? | Possible specific risk factors for silent infarcts remain unknown. The aim of this study was to investigate whether risk factors for silent infarcts differ from those for symptomatic infarcts in stroke patients. Silent infarcts were defined as asymptomatic infarcts detected on computed tomographic scan in patients free of history of stroke and unrelated to the symptoms and signs of the index stroke. Of 595 consecutive patients with stroke or transient ischemic attacks, 116 (19%) had at least one silent infarct on the first computed tomographic scan performed within 24 hours after onset. They were compared with the 479 remaining patients for cerebrovascular risk factors and for presumed mechanism of stroke by means of the odds ratio method. A discriminant analysis was then performed in the subgroup of 216 patients with ischemic stroke who underwent an exhaustive cardiac and vascular workup. One hundred forty-one silent infarcts (99% confidence interval [CI], 29% to 41%) and 265 symptomatic infarcts (99% CI, 59% to 71%) were subcortical infarcts smaller than 15 mm. Univariate analysis showed that patients with silent infarcts were more likely to be older than 65 years (odds ratio [99% CI], 1.11 to 3.49) and to have left atrial enlargement on echocardiogram (odds ratio [99% CI], 1.02 to 26.70) and leukoaraiosis (odds ratio [99% CI], 1.39 to 4.21). Discriminant analysis found only two independent risk factors for silent infarcts: left atrial enlargement (P = .007) and age older than 65 years (P = .03); leukoaraiosis was not found to be an independent risk factor (P = .86). | Although short- and long-term results have been described in previous reports of 2-stage hepatectomy, growth activity in metastases resected at the first versus second hepatectomy has not been compared. We analyzed growth activity of liver metastases from colorectal cancers resected at first and second hepatectomy by real-time reverse-transcription polymerase chain reaction and immunohistochemistry in 21 patients undergoing 2-stage hepatectomy to justify the 2-stage approach. Of 24 patients planned to undergo 2-stage hepatectomy for colorectal liver metastases, 21 had completion of both stages. Although maximum tumor size and serum carcinoembryonic antigen before and after the first procedure did not differ, volume of the future liver remnant increased after the first procedure. Ki67 and proliferating cell nuclear antigen positivity rates were comparable between initially and subsequently resected tumors (P = .09 and P = .83, respectively). Expression of mRNA (relative to glyceraldehyde-3-phosphate dehydrogenase mRNA) in initially versus subsequently resected tumors for cyclin D1 (4.27 ± 1.29 vs 6.52 ± 2.23; P = .90), cyclin E1 (24.18 ± 16.81 vs 10.53 ± 2.28; P = .60), hepatocyte growth factor (3.16 ± 1.42 vs 0.58 ± 0.15; P = .11), basic fibroblast growth factor (5.42 ± 1.54 vs 5.92 ± 3.33; P = .13), epidermal growth factor (19.56 ± 14.76 vs 9.07 ± 4.54; P = .74), and transforming growth factor-α (2.63 ± 1.02 vs 2.07 ± 1.15; P = .29) showed no differences between the 2 time points. |
Does scopolamine induce impairments in the recognition of human facial expressions of anger and disgust? | Recent psychopharmacological studies lend support to the notion of partially dissociable neuronal systems dedicated to processing specific emotions. For example, GABA-ergic enhancement after an acute dose of the benzodiazepine, diazepam, produces specific impairments in anger and fear recognition. However, it is unclear if these impairments are a general property of benzodiazepines and other drugs that produce a similar profile of neurocognitive impairment to benzodiazepines, such as the anticholinergic, scopolamine. We investigated the effects of scopolamine and the benzodiazepine, lorazepam, on emotion-recognition accuracy. A double-blind independent group design was used with 48 healthy volunteers to compare the effects of scopolamine and lorazepam with an inactive placebo on a commonly used emotion-recognition task. Control measures included an episodic memory task and subjective mood ratings. Anger and disgust recognition accuracy was impaired after scopolamine. In contrast, lorazepam produced no impairment in emotion-recognition despite producing similar levels of sedation and anterograde amnesia to scopolamine. | It is well established that angiogenesis is a complex and coordinated multistep process. However, there remains a lack of information about the genes that regulate individual stages of vessel formation. Here, we aimed to define the role of human interferon-induced transmembrane protein 1 (IFITM1) during blood vessel formation. We identified IFITM1 in a microarray screen for genes differentially regulated by endothelial cells (ECs) during an in vitro angiogenesis assay and found that IFITM1 expression was strongly induced as ECs sprouted and formed lumens. We showed by immunohistochemistry that human IFITM1 was expressed by stable blood vessels in multiple organs. siRNA-mediated knockdown of IFITM1 expression spared EC sprouting but completely disrupted lumen formation, in both in vitro and in an in vivo xeno-transplant model. ECs lacking IFITM1 underwent early stages of lumenogenesis (ie, intracellular vacuole formation) but failed to mature or expand lumens. Coimmunoprecipitation studies confirmed occludin as an IFITM1 binding partner in ECs, and immunocytochemistry showed a lack of occludin at endothelial tight junctions in the absence of IFITM1. Finally, time-lapse video microscopy revealed that IFITM1 is required for the formation of stable cell-cell contacts during endothelial lumen formation. |
Is stomatin-like protein 2 expression associated with clinical survival in patients with cervical cancer? | To investigate the prognostic role of stomatin-like protein 2 (STOML2) in cervical cancer. The expression of STOML2 in 8 pairs of cervical cancer and adjacent normal cervical tissues were detected by Real-time PCR. Immunohistochemistry was performed to evaluation of STOML2 expression in 94 paraffin-embedded cervical cancer samples. The correlation between STOML2 expression and cervical cancer progression and prognosis was analyzed statistically. STOML2 expression was upregulated in cervical cancer tissues compared with adjacent normal cervical tissues. Of the 94 cervical cancer cases, high STOML2 expression was detected in 54 cases (57.4%). STOML2 expression was significantly related to tumor stage (P = 0.013) and tumor size (P = 0.025). Moreover, patients with high expression of STOML2 had a significant shorter overall survival and recurrent free survival time compared with those with low STOML2 expression in cervical cancer (P = 0.001 and P = 0.017, respectively). Multivariate analysis revealed that STOML2 was an independent prognostic factor (P = 0.022) for the overall survival in cervical cancer. | Concentrations of the orexigenic peptide ghrelin is affected by a number of hormones, which also affect circulating levels of free fatty acids (FFAs). The present study was therefore designed to determine the direct effect of FFAs on circulating ghrelin. Eight lean, healthy men were examined for 8 h on four occasions using variable infusion rates (0, 3, 6 and 12 microl/kg per min) of intralipid to create different plasma FFA concentrations. Constant levels of insulin and GH were obtained by administration of acipimox (250 mg) and somatostatin (300 microg/h). At the end of each study day a hyperinsulinaemic-euglycaemic clamp was performed. Four distinct levels of FFAs were obtained at the end of the lipid infusion period (FFA(LIPID): 0.03 +/- 0.00 vs: 0.49 +/- 0.04, 0.92 +/- 0.08 and 2.09 +/- 0.38 mmol/l; ANOVA P < 0.0001) and during hyperinsulinaemia (FFA(LIPID+INSULIN): 0.02 +/- 0.00 vs: 0.34 +/- 0.03, 0.68 +/- 0.09 and 1.78 +/- 0.32 mmol/l; ANOVA P < 0.0001). Whereas, somatostatin infusion alone reduced ghrelin concentration by approximately 67%, concomitant administration of increasing amounts of intralipid reduced circulating ghrelin by a further 14, 19 and 19% respectively (change in ghrelin: 0.52 +/- 0.05 vs: 0.62 +/- 0.06, 0.72 +/- 0.09 and 0.71 +/- 0.05 microg/l; ANOVA P = 0.04). No further reduction in ghrelin concentration was observed during hyperinsulinaemia. |
Do [ Protective effects of N-acetylcysteine on cochlear damage occur in guinea pigs exposed to irradiation ]? | To explore the protective effects of N-acetylcysteine (NAC) on cochlear damage occurring in irradiated guinea pigs. Seventy-two guinea pigs were randomly divided into 4 groups (n = 18 each). Control group received neither NAC nor irradiation, irradiation group received total cranium irradiation of 70 Gy, irradiation & saline group cranium irradiation of 70 Gy and saline solution through a round window and NAC group cranium irradiation of 70 Gy and NAC through a round window. The right ear received radiation. The animals were sacrificed at Day 14 post-irradiation. The specimens were dehydrated, embeded in paraffin and serially cut into 5-µm slices. Sections were stained with immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). The cochlear basal membranes were observed for malondialdehyde (MDA) and superoxide dismutase (SOD) with scanning electron microscope. The cilium of hair cells had no clear loss and apoptotic number of spiral ganglion cells decreased in NAC group. The average optical density value of Caspase 3 in spiral ganglion in NAC group significantly decreased versus the irradiation group (0.08 ± 0.02 vs 0.10 ± 0.01, P < 0.01). The level of MDA of NAC group also decreased versus the irradiation group (0.33 ± 0.05 vs 0.84 ± 0.13, P < 0.05). The level of SOD in the NAC group increased versus the irradiation group (10.7 ± 3.0 vs 8.7 ± 1.3, P < 0.05). The ratio of apoptotic cell in SGC in the NAC group at Day 14 (7.8% ± 1.8%) decreased versus the irradiation group (32.0% ± 8.7%) at Day 14. | Hemoglobin (Hgb) and creatinine clearance (CrCl) are readily-available, routinely-obtained laboratory parameters that predict acute coronary syndrome outcomes. We sought to develop a laboratory index (LI) to predict early mortality in ST-elevation myocardial infarction (STEMI) and determine the additional risk stratification offered by adding the LI to the TIMI Risk Score (TRS) for STEMI. The association between Hgb and CrCl values obtained at hospitalization and 30-day mortality was evaluated in 14,373 STEMI patients undergoing fibrinolysis in Intravenous NPA for the Treatment of Infarcting Myocardium Early II-Thrombolysis In Myocardial Infarction-17 (InTIME II-TIMI 17). Logistic regression models determined the optimal combination of laboratory variables into a LI. Prognostic utility of the LI was validated in 18,427 STEMI patients from Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)-TIMI 25. In InTIME II, Hgb levels <15.0 g/dL and CrCl <100 mL/min were significantly and independently associated with increased risk of death (OR(adj) 1.22, 95% CI 1.15-1.29 for each 1 g/dL decrease in Hgb, P < .001, and OR(adj) 1.23, 95% CI 1.17-1.29 for each 10 mL/min decrease in CrCl, P < .001, respectively). In multivariable analysis, the optimal weighting of Hgb and CrCl to form an LI to predict mortality was (15-Hgb) + (100-CrCl)/8. The LI revealed a 10-fold increase in death across prespecified groups (P < .001). The LI offered additional risk stratification across all TRS groups and improved the discriminatory ability of the TRS (c-statistic from 0.755 to 0.789, P < .001). External validation in ExTRACT showed similar enhancement of the prognostic capacity of the TRS (c-statistic from 0.747 to 0.777, P < .001). |
Does optimization of low pre-operative hemoglobin reduce transfusion requirement in patients undergoing transurethral resection of prostate? | To identify factors that influence peri-operative hemorrhage in view of reducing the need for transfusions in patients undergoing trans uretheral resection of prostate (TURP). All patients undergoing TURP between January 1997 and December 1999 were identified using ICD 9CM coding and indexing system. Overall 430 patients were identified, however, 384 charts were included and reviewed for demographics, pre and intra-operative data and post-operative morbidity. Patients were divided into two groups on the basis of presence of significant hemorrhage. Overall 384 patients were analyzed. Nineteen patients had hemorrhage--group I whereas 365 had no significant hemorrhage--group II. Mean age and co-morbidities in the two groups were similar. However, in group I, 58% presented with urinary retention compared to 33% in group II. In group I, factors that reached statistical significance include; operative time (p<0.05), mean resected tissue weight (p<0.02), and patient presentation (urinary retention) (p<0.032). There was no significant difference in the two groups with respect to type of anesthesia (regional versus general) and histology of the resected tissue. Patients with mean pre-operative hemoglobin of 10.6 % had a 37% transfusion rate. | House dust mites (HDM) have been shown to be important sources of indoor allergens associated with asthma and other allergic conditions. While exogenous proteases from allergens have a direct proinflammatory role in the respiratory tract, the precise mechanisms underlying the release of cytokines from the respiratory epithelium are unclear. The present study examines that extracellular signal-regulated kinase (ERK) activated downstream of the Ca(2+)-sensitive tyrosine kinase plays an important role in the efficient activation of the HDM-induced IL-8 signaling pathway. We examined the effect of HDM, and the role of the Ca(2+)/calmodulin system and mitogen-activated protein kinases, on IL-8 expression in human lung epithelial cells. In H292 cells, HDM induced IL-8 release in a time- and/or dose-dependent manner. This IL-8 release was abolished by treatment with intracellular Ca(2+) chelator (BAPTA-AM), but not by EGTA or nifedipine. Calmodulin inhibitor (calmidazolium) and tyrosine kinase inhibitor (genistein) almost completely blocked IL-8 release by HDM. PD98,059, an ERK pathway inhibitor, completely abolished HDM-induced IL-8 release. Moreover, PD98,059, BAPTA-AM, calmidazolium and genistein suppressed the HDM-induced ERK phosphorylation. |
Is third trimester nonrecurrent fetal loss associated with factor V Leiden and prothrombin gene mutations? | To determine the role of factor V Leiden and prothrombin gene mutation in the pathogenesis of unexplained second and third trimester nonrecurrent fetal loss. One hundred and fourteen women with unexplained nonrecurrent late fetal loss made up the study group, and 106 normal pregnant women with a history of delivery of at least one healthy fetus and no history of late fetal loss made up the control group. The study group was further divided into two subgroups: second (n = 36) and third (n = 78) trimester fetal loss. All women were tested for factor V Leiden and G20210A prothrombin gene mutations. Twenty-one (18.4%) of the women in the study group and seven (6.6%) of the women in the control group were heterozygous carriers of factor V Leiden mutation (OR = 3.19). Eleven (9.6%) of the women in the study group and three (2.8%) of the women in the control group were heterozygous carriers of prothrombin gene mutation (OR = 3.66). In assessing with regard to trimesters, 18 (23%) factor V Leiden and 10 (12.8%) prothrombin gene mutations were present in the group of third trimester fetal loss (OR = 4.24 and OR = 5.04, respectively). Three (8.3%) factor V Leiden and one (2.7%) prothrombin gene mutation were detected in women with second trimester fetal loss (OR = 1.28 and OR = 0.40, respectively). | The nucleus accumbens shell is a key brain area mediating the reinforcing effects of ethanol (EtOH). Previously, it has been shown that the density of μ-opioid receptors in the nucleus accumbens shell is higher in alcohol-preferring Alko Alcohol (AA) rats than in alcohol-avoiding Alko Non-Alcohol rats. In addition, EtOH releases opioid peptides in the nucleus accumbens and opioid receptor antagonists are able to modify EtOH intake, all suggesting an opioidergic mechanism in the control of EtOH consumption. As the exact mechanisms of opioidergic involvement remains to be elucidated, the aim of this study was to clarify the role of accumbal μ- and κ-opioid receptors in controlling EtOH intake in alcohol-preferring AA rats. Microinfusions of the μ-opioid receptor antagonist CTOP (0.3 and 1 μg/site), μ-opioid receptor agonist DAMGO (0.03 and 0.1 μg/site), nonselective opioid receptor agonist morphine (30 μg/site), and κ-opioid receptor agonist U50488H (0.3 and 1 μg/site) were administered via bilateral guide cannulas into the nucleus accumbens shell of AA rats that voluntarily consumed 10% EtOH solution in an intermittent, time-restricted (90-minute) 2-bottle choice access paradigm. CTOP (1 μg/site) significantly increased EtOH intake. Conversely, DAMGO resulted in a decreasing trend in EtOH intake. Neither morphine nor U50488H had any effect on EtOH intake in the used paradigm. |
Does fetal thymus size in human pregnancies reveal inverse association with regulatory T cell frequencies in cord blood? | To determine fetal thymus growth and its relationship with fetal weight and cord blood T-regulatory cells in a prospective study. Assessment of fetal immune organs by ultrasound could provide a screening approach to identify fetuses at risk of impaired postnatal immunity. Thymus size was measured with four ultrasound techniques. The approaches with lowest coefficient of variation (thymus transverse diameter, 3 vessel edge) were used to longitudinally assess fetal and thymus growth in 137 cases at four time points between a gestational age (GA) of 13 and 37 weeks. Cord blood at birth was analyzed by flow-cytometry to evaluate the frequency of regulatory T (Treg) cells. | We describe a three-year experience with patients with dementia. clinical, cognitive and functional evaluation was performed by a multidisciplinary team for persons above 60 years. Mortality was assessed after three years. Mini-Mental State Examination (MMSE) (n=2,074) was 15.7 (8.4). Male patients MMSE (n=758) was 15.6 (8.3) and female's (n=1315) was 15.8 (8.3). Instrumental Activities of Daily Living Scale (n=2023) was 16.5 (7.6); females (n=1277) was 16.9 (7.2) and males (n=745) was 15.7(8.2). From these patients, 12.6% (n=209) died within three years. Baseline cognition of patients still alive was higher (p<0.001) than MMSE of those who died [MMSE=16.3 (8.1) vs. 10.6 (7.6)]. Mortality rate decreased 6% (IR=0.94) for each additional point on MMSE. Higher functional status decreases the mortality rate approximately 11% (IR=0.89) independently of age, gender, and education. |
Do serial montreal cognitive assessments demonstrate reversible cognitive impairment in patients with acute transient ischemic attack and minor stroke? | Cognitive changes after ischemic stroke are often overlooked, particularly acutely and in patients with mild or transient deficits. We assessed patients with transient ischemic attack (TIA)/minor stroke with serial cognitive screening tests. We tested the hypothesis that mild acute deficits are transient and improve after TIA/minor stroke. Patients with acute TIA/minor ischemic stroke, without a history of cognitive impairment, presenting with a National Institute of Health Stroke Scale score ≤3 were assessed <72 hours of onset. Patients were administered the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) at days 1, 7, 30, and 90. Cognitive impairment was defined as MoCA <26 and MMSE ≤26. One hundred patients with a median (interquartile range) National Institute of Health Stroke Scale score of 1 (2) and median age of 68 (20) years were included. Baseline median MoCA score (26 [4]) was lower than the MMSE (29 [2]; P<0.0001). Cognitive impairment was detected in 54 of 100 patients (54%) with MoCA and 16 of 100 (16%; P=0.001) with MMSE. MoCA scores improved at day 7 (27 [5]), day 30 (28 [2]), and day 90 (28 [2]; P<0.0001). Resolution of cognitive deficits was because of resolution of recall deficits. | To investigate the risk of adhesions after laparoscopic myomectomy (LM). To establish the percentage of adhesions, their kind, situation and magnitude. For the period form June 2011 to November 2013 totally 81 patients were operated by LM. In the study only patients with intramural leymyomas bigger than 5 sm were included. For this period 14 patients had second-look because of the need of another operation--LS or Ceasarean section. 22 myoma incisions were checked. We established 35.7% adhesions per patient. After LM adnexas were engaged in 14.2%. |
Do patients with persistent pain after breast cancer surgery show both delayed and enhanced cortical stimulus processing? | Women who undergo breast cancer surgery have a high risk of developing persistent pain. We investigated brain processing of painful stimuli using electroencephalograms (EEG) to identify event-related potentials (ERPs) in patients with persistent pain after breast cancer treatment. Nineteen patients (eight women with persistent pain, eleven without persistent pain), who were surgically treated more than 1 year previously for breast cancer (mastectomy, lumpectomy, and axillary lymph node dissection) and/or had chemoradiotherapy, were recruited and compared with eleven healthy female volunteers. A block of 20 painful electrical stimuli was applied to the calf, somatopically remote from the initially injured or painful area. Simultaneously an EEG was recorded, and a visual analog scale (VAS) pain rating obtained. In comparison with healthy volunteers, breast cancer treatment without persistent pain is associated with accelerated stimulus processing (reduced P260 latency) and shows a tendency to be less intense (lower P260 amplitude). In comparison to patients without persistent pain, persistent pain after breast cancer treatment is associated with stimulus processing that is both delayed (ie, increased latency of the ERP positivity between 250-310 ms [P260]), and enhanced (ie, enhanced P260 amplitude). | Impairments of intestinal barrier function are discussed as risk factors for the development and progression of non-alcoholic fatty liver disease (NAFLD). Studies suggest an association between arginine/citrulline homeostasis and the development of liver damages. Here, the effect of an oral L-citrulline (Cit) supplement on the development of a Western-style diet (WSD)-induced NAFLD was determined in mice. Female 6- to 8-week-old C57BL/6J mice were either pair-fed a liquid Western-style or control diet (C) ± 2.5 g/kg bodyweight Cit for 6 weeks (C + Cit or WSD + Cit). Indices of liver damage, glucose metabolism, intestinal barrier function and NO synthesis were measured. While bodyweight gain was similar between groups, markers of glucose metabolism like fasting blood glucose and HOMA index and markers of liver damage like hepatic triglyceride levels, number of neutrophils and plasminogen activator inhibitor-1 protein levels were significantly lower in WSD + Cit-fed mice when compared to WSD-fed mice only. Protein levels of the tight junction proteins occludin and zonula occludens-1 in duodenum were significantly lower in mice fed a WSD when compared to those fed a WSD + Cit (-~70 and -~60 %, respectively, P < 0.05), whereas portal endotoxin levels, concentration of 3-nitrotyrosine protein adducts in duodenum and toll-like receptor-4 mRNA expression in livers of WSD + Cit-fed mice were markedly lower than in WSD-fed mice (-~43 %, P = 0.056; -~80 and -~48 %, respectively, P < 0.05). |
Is a G1103R mutation in CRB1 co-inherited with high hyperopia and Leber congenital amaurosis? | To identify the genetic basis of recessive inheritance of high hyperopia and Leber congenital amaurosis (LCA) in a family of Middle Eastern origin. The patients were examined using standard ophthalmic techniques. DNA samples were obtained and genetic linkage was carried out using polymorphic markers flanking the known genes and loci for LCA. Exons were amplified and sequenced. All four members of this family affected by LCA showed high to extreme hyperopia, with average spherical refractive errors ranging from +5.00 to +10.00. Linkage was obtained to 1q31.3 with a maximal LOD score of 5.20 and a mutation found in exon 9 of the CRB1 gene, causing a G1103R substitution at a highly conserved site in the protein. CRB1 is a vertebrate homolog of the Drosophila crumbs gene, which is required for photoreceptor morphogenesis, and has been associated with either retinitis pigmentosa (RP) or LCA. This sequence variant has previously been reported as a compound heterozygote in one sporadic LCA patient. | Visceral and subcutaneous adipose tissue may contribute differentially to the septic inflammatory response. Accordingly, we tested the hypothesis that the ratio of visceral to subcutaneous adipose tissue is associated with altered sepsis outcome. A retrospective analysis from a cohort of sepsis patients admitted between 2004 and 2009. A mixed medical-surgical ICU at St. Paul's Hospital in Vancouver, Canada. Patients older than 16 years old who had sepsis and underwent abdominal CT scan (n = 257) for clinical reasons. None. We measured the visceral adipose tissue and subcutaneous adipose tissue areas and calculated the visceral adipose tissue-to-subcutaneous adipose tissue ratio. Visceral adipose tissue/subcutaneous adipose tissue was not correlated with body mass index (r = -0.015, p = NS) and therefore provides additional unique information independent of body mass index. Sepsis patients with higher visceral adipose tissue/subcutaneous adipose tissue had greater 90-day mortality than patients with lower visceral adipose tissue/subcutaneous adipose tissue (log-rank test, linear-by linear association p < 0.005). After adjustment for significant covariates using Cox regression, increased visceral adipose tissue/subcutaneous adipose tissue quartile was significantly associated with increased 90-day mortality with hazard ratios of 2.01 (95% CI, 1.01-3.99) for the third visceral adipose tissue/subcutaneous adipose tissue quartile compared with the first quartile and 2.32 (95% CI, 1.15-4.69) for the highest visceral adipose tissue/subcutaneous adipose tissue quartile when compared with the first quartile. Increased mortality for patients with higher visceral adipose tissue/subcutaneous adipose tissue was found for both patients with body mass index less than 25 kg/m (p = 0.004) and for body mass index greater than or equal to 25 kg/m (p = 0.023). Furthermore, we found significantly greater need for mechanical ventilation, renal replacement therapy, and ICU stay in patients in the highest visceral adipose tissue/subcutaneous adipose tissue quartile. The ratio of proinflammatory (interleukin-8) to anti-inflammatory (interleukin-10) plasma cytokine levels was greater in patients with higher visceral adipose tissue/subcutaneous adipose tissue than in those with lower visceral adipose tissue/subcutaneous adipose tissue (p = 0.043). |
Do long-term lung cancer survivors have permanently decreased quality of life after surgery? | Retrospective evaluation of the long-term health-related quality of life (HRQoL) among survivors after non-small-cell lung cancer (NSCLC) surgery. A total of 586 patients underwent surgery for NSCLC in Helsinki University Central Hospital between January 2000 and June 2009. Two validated quality-of-life questionnaires, the 15D and the EORTC QLQ-C30 with its lung cancer-specific module, QLQ-LC13, were sent to the 276 patients alive in June 2011. Response rate was 83.3%. Results of the 15D were compared with those of an age- and gender-standardized general population. Median follow-up was 5 years. Compared with a general population, our patients had a significantly lower 15D total score, representing their total HRQoL and scores for dimensions of mobility, breathing, usual activities, depression, distress, and vitality. The patients, however, scored significantly higher on vision, hearing, and mental function. | To establish a single-tube single-run multiplex PCR technique that can detect single or mixed samples with four species of Plasmodium. Folding primers were designed based on the fast nested PCR. The reaction component concentrations were optimized and the primers were selected based on the annealing temperature. The established single-tube single-run folding-primer multiplex PCR (FP-PCR) was tested for its sensitivity and specificity to detect single-species and mixed samples with P. vivax, P. falciparum, P. ovale (including P. ovale wallikeri) and/or P. malariae. In all the seven experimental repeats, FP-PCR successfully detected single-species infection for all the four species, with the detection limit reaching or close to 1 parasite/µl blood. For mixed infections with 2-4 species at different densities with the highest being 100 times of the lowest, FP-PCR identified all the species in each combination in 57 out of 84 tests. Further, in 10 dried blood samples on filter paper from healthy subjects, no FP-PCR amplification was found, except weak formation of dimers. |
Do cOAGULATION FACTORS LEVEL IN FRESH FROZEN PLASMA IN RWANDA? | Objectives: To determine the level of coagulation factors and inherited inhibitors in Fresh Frozen Plasma (FFP) and to evaluate Prothrombin Time and activated partial thrombin time in fresh frozen plasma. Cross-sectional study. Jomo Kenyatta University of Agriculture and Technology in Medical Laboratory Sciences. Eighteen blood bags collected from voluntary blood donors. Coagulation factors and inhibitors levels, Prothrombin Time (PT) and Activated Partial thrombin Time (APTT) remained within the reference range requested by quality assurance regulations after three months of storage. APTT and PT show an increase from baseline to one month then remain constant up to three months, while, Fibrinogen, Factor II, Factor V, Factor VII, Factor X, Von Willbrand Factor, Protein C and Antithrombin decreased from baseline up to three months and then Factor VIII, Factor IX, Factor XI, Factor XII and Protein S, remained constant from baseline up to one month and decreased up to three months. | We have previously shown that endogenously active purinergic P2X7 receptors (P2X7Rs) in satellite glial cells of dorsal root ganglia (DRGs) stimulate ATP release. The ATP activates P2Y1Rs located in the enwrapped neuronal somata, resulting in down-regulation of P2X3Rs. This P2X7R-P2Y1-P2X3R inhibitory control significantly reduces P2X3R-mediated nociceptive responses. The underlying mechanism by which the activation of P2Y1Rs inhibits the expression of P2X3Rs remains unexplored. Examining the effect of the activation of p38 mitogen-activated protein kinase on the expression of P2X3Rs in DRGs, we found that the p38 activator, anisomycin (Anis), reduced the expression of P2X3Rs. Blocking the activity of SGCs by the glial Krebs cycle inhibitor, fluorocitrate, did not change the effect of Anis. These results suggest that neuronal p38 plays a major role in the inhibition of P2X3R expression. Western blotting analyses showed that inhibiting P2Y1Rs by MRS2179 (MRS) or blocking P2X7Rs by either oxATP or A740003 reduced pp38 and increased P2X3R expression in DRGs. These results are further supported by the immunohistochemical study showing that P2X7R and P2Y1R antagonists reduce the percentage of pp38-positive neurons. These observations suggest that activation of P2X7Rs and P2Y1Rs promotes p38 activity to exert inhibitory control on P2X3R expression. Since activation of p38 by Anis in the presence of either A740003 or MRS could overcome the block of P2X7R-P2Y1R inhibitory control, p38 in DRG neurons is downstream of P2Y1Rs. In addition, inhibition of p38 by SB202190 was found to prevent the P2X7R and P2Y1R block of P2X3R expression and increase P2X3R-mediated nociceptive flinch behaviors. |
Does distribution of Dengue Virus type 1 and 4 in Blood Components from Infected Blood Donors from Puerto Rico? | Dengue is a mosquito-borne viral disease caused by the four dengue viruses (DENV-1 to 4) that can also be transmitted by blood transfusion and organ transplantation. The distribution of DENV in the components of blood from infected donors is poorly understood. We used an in-house TaqMan qRT-PCR assay to test residual samples of plasma, cellular components of whole blood (CCWB), serum and clot specimens from the same collection from blood donors who were DENV-RNA-reactive in a parallel blood safety study. To assess whether DENV RNA detected by TaqMan was associated with infectious virus, DENV infectivity in available samples was determined by culture in mosquito cells. DENV RNA was detected by TaqMan in all tested blood components, albeit more consistently in the cellular components; 78.8% of CCWB, 73.3% of clots, 86.7% of sera and 41.8% of plasma samples. DENV-1 was detected in 48 plasma and 97 CCWB samples while DENV-4 was detected in 21 plasma and 31 CCWB samples. In mosquito cell cultures, 29/111 (26.1%) plasma and 32/97 (32.7%) CCWB samples were infectious. A subset of samples from 29 donors was separately analyzed to compare DENV viral loads in the available blood components. DENV viral loads did not differ significantly between components and ranged from 3-8 log10 PCR-detectable units/ml. | Sacral nerve stimulation is proposed as a treatment for slow-transit constipation. However, in our randomized controlled trial we found no therapeutic benefit over sham stimulation. These patients have now been followed-up over a long-term period. The purpose of this study was to assess the long-term efficacy of sacral nerve stimulation in patients with scintigraphically confirmed slow-transit constipation. This study was designed for long-term follow-up of patients after completion of a randomized controlled trial. It was conducted at an academic tertiary public hospital in Sydney. Adults with slow-transit constipation were included. At the 1- and 2-year postrandomized controlled trial, the primary treatment outcome measure was the proportion of patients who reported a feeling of complete evacuation on >2 days per week for ≥2 of 3 weeks during stool diary assessment. Secondary outcome was demonstration of improved colonic transit at 1 year. Fifty-three patients entered long-term follow-up, and 1 patient died. Patient dissatisfaction or serious adverse events resulted in 44 patients withdrawing from the study because of treatment failure by the end of the second year. At 1 and 2 years, 10 (OR = 18.8% (95% CI, 8.3% to 29.3%)) and 3 patients (OR = 5.7% (95% CI, -0.5% to 11.9%)) met the primary outcome measure. Colonic isotope retention at 72 hours did not differ between baseline (OR = 75.6% (95% CI, 65.7%-85.6%)) and 1-year follow-up (OR = 61.7% (95% CI, 47.8%-75.6%)). |
Is aortic valve calcification mediated by a differential response of aortic valve interstitial cells to inflammation? | Although calcific aortic stenosis is common, calcification of the other three heart valves is not. The aortic valve interstitial cell (VIC) has been implicated in the pathogenesis of aortic stenosis. Proinflammatory stimulation of aortic VICs induces an osteogenic and inflammatory phenotypic change. We hypothesized that the VICs of the other heart valves do not undergo these changes. Using isolated human VICs from normal aortic, mitral, pulmonary, and tricuspid valves, our purpose was to compare the osteogenic response to proinflammatory stimulation via toll-like receptor 4 (TLR-4). Aortic, pulmonic, mitral, and tricuspid (n=4 for each valve type) VICs were isolated from hearts valves explanted from patients undergoing cardiac transplantation. Cells were cultured and grown to confluence in passage 2-6 before treatment with Lipopolysaccharide (LPS) (100-200 ng/mL) for 24 or 48 h. Cells were characterized by immunofluorescent staining. TLR-4 expression was analyzed (immunoblotting, flow cytometry). Bone morphogenetic protein 2 and intercellular adhesion molecule 1 production were determined (immunoblotting). Monocyte chemoattractant protein 1 levels were determined by enzyme-linked immunosorbent assay. Statistics were by Mann-Whitney U test. TLR-4 stimulation induced bone morphogenetic protein 2 production only in aortic VICs (P<0.05). Intra-cellular adhesion molecule 1 production and monocyte chemoattractant protein 1 secretion increased in a similar fashion among TLR-4-stimulated VICs from all four valves. | Age-related cognitive decline might involve selective deterioration of specific brain systems. We studied the relationship between age and cognition by comparing cognitive function of older and younger high functioning men. A cross-sectional study comparing neuropsychological test battery performance of younger (18-60 years) and older (61-85 years) men. Older men showed impaired psychomotor speed, working memory, attention, declarative verbal memory and executive functions. Impairment in executive function was prominent and not explained by psychomotor slowing, impaired working memory or attention. Regression models showed a non-linear relationship between age and executive function with a change of slopes in the mid-50s. The relationship of age with verbal memory was linear. |
Does vasopressin raise cardiac enzymes following cardiac surgery : a randomized double-blind clinical trial? | The aim of this study was to investigate the relationship between intraoperative vasopressin infusion and postoperative cardiac enzymes. A prospective, double-blind, randomized, controlled study. A single tertiary cardiac center. One hundred consecutive patients undergoing cardiac surgery with or without cardiopulmonary bypass. The study was approved by the Institutional Review Board, and patients provided informed consent to participate. Patients were randomized by computer into 2 equal groups: Vasopressin or control. The blinded study included vasopressin administered at a dose of 1.8 U/h or 1.8 mL/h of normal saline, along with catecholamines. The drug was administered continually during surgery while patients needed catecholamines. The intervention was discontinued upon admission to the intensive care unit when information regarding the true character of the drug was reported to the doctor in charge of patients in the intensive care unit by one of the investigators. Primary outcomes were CK-MB and troponin T levels measured at 0, 6, and 12 hours postoperatively. Of the 100 patients, 8 were excluded; the remaining 92 were randomized to either the vasopressin (n = 47) or control (n = 45) group. There were no significant differences in demographic data between the groups. Postoperatively at 0, 6, and 12 hours, there were no differences in CK-MB (U/l) (37.5 ± 57.9 v 32.0 ± 21.5, 29.4 ± 41.1 v 24.4 ± 23.1, and 21.4 ± 21.3 v. 21.8 ± 32.4, respectively) and troponin T (752.4 ± 638.2 v 762.7 ± 557.1, 753.8 ± 507.3 v 777.6 ± 515.0, and 774.6 ± 572.6 v 698.7 ± 540.2, respectively) values. | Living near community recreation centers (CRC) is associated with increases in adolescent and adult physical activity, but the efficacy of efforts to increase use among Latino parents and young children is unknown. We hypothesized that Latino parent-child dyads with exposure to a CRC through culturally tailored programming would be more likely to use the facility for physical activity a year after programming ended than dyads living in the same geographic area who were not exposed to the programming. Self-identified Latino parent-child dyads who had participated in a randomized controlled trial (RCT) of a culturally tailored healthy lifestyle program and completed a 12-month follow-up assessment constituted the "exposed" group (n = 66). The "unexposed" group included 62 parent-child dyads living in the same zip codes as the exposed group, all within a 5-mile radius of the CRC. Participants completed in-person structured interviews. Approximately two-thirds of exposed parents reported more than monthly use of the CRC for themselves a year after programming ended, compared to one-third of unexposed Latino families with the same geographic access (χ(2) = 11.26, p < 0.01). Parents in the exposed group were four times more likely than the unexposed group to use the CRC with their children on a monthly basis (odds ratio = 4.18, p < 0.01). |
Is direct observation a valid criterion for estimating physical activity and sedentary behavior? | Physical activity and sedentary behavior measurement tools need to be validated in free-living settings. Direct observation (DO) may be an appropriate criterion for these studies. However, it is not known if trained observers can correctly judge the absolute intensity of free-living activities. To compare DO estimates of total MET-hours and time in activity intensity categories to a criterion measure from indirect calorimetry (IC). Fifteen participants were directly observed on three separate days for two hours each day. During this time participants wore an Oxycon Mobile indirect calorimeter and performed any activity of their choice within the reception area of the wireless metabolic equipment. Participants were provided with a desk for sedentary activities (writing, reading, computer use) and had access to exercise equipment (treadmill, bike). DO accurately and precisely estimated MET-hours [% bias (95% CI) = -12.7% (-16.4, -7.3), ICC = 0.98], time in low intensity activity [% bias (95% CI) = 2.1% (1.1, 3.2), ICC = 1.00] and time in moderate to vigorous intensity activity [% bias (95% CI) -4.9% (-7.4, -2.5), ICC = 1.00]. | Human umbilical cord vein endothelial cells (HUVECs) are commonly chosen over freshly isolated endothelial cells from glioblastomas (GECs) due to accessibility and costs. To test their suitability for in vitro studies, we comprehensively compared the transcriptomes and responses to major angiogenic cytokines of HUVECs (n=2) and GECs (n=5). Purity of GEC cultures was confirmed by uptake of acetylated low-density protein and immunostaining. Unsupervised analysis revealed a distinct grouping. We identified 854 differentially expressed genes. Pathway and gene ontology enrichment analyses pointed to clear differences in angiogenesis and leukocyte transmigration. Comparing the expression of cell adhesion molecules in five major angiogenic cytokines revealed that HUVECs in contrast to GECs did not exhibit a previously described down-regulation of cell adhesion molecules upon incubation with transforming growth factor betas, but rather with basic fibroblast growth factor. |
Are findings in the distal colorectum associated with proximal advanced serrated lesions? | Serrated lesions are an important contributor to colorectal cancer (CRC), notably in the proximal colon. Findings in the distal colorectum are markers of advanced proximal adenomatous neoplasia. However, it is not known whether they affect the odds of advanced proximal serrated lesions. We performed a retrospective cross-sectional study of data from 1910 patients (59.3 ± 8.0 years, 53.8% female) who underwent an average-risk screening colonoscopy from August 2005 through April 2012 at Indiana University Hospital and an associated ambulatory surgery center. Colonoscopies were performed by an endoscopist with high rates of detection of adenomas and serrated polyps. Tissue samples of all serrated polyps (hyperplastic, sessile serrated adenoma/polyp [SSA/P], or traditional serrated adenoma) proximal to the sigmoid colon and serrated polyps >5 mm in the rectum or sigmoid colon were reviewed by a gastrointestinal pathologist and reclassified on the basis of World Health Organization criteria. Advanced serrated lesion (ASL) was defined as SSA/P with cytologic dysplasia, SSA/P ≥10 mm, or traditional serrated adenoma. Advanced conventional adenomatous neoplasia (ACN) was defined as tubular adenoma ≥10 mm, villous histology, high-grade dysplasia, or cancer. The prevalence of proximal ASL and ACN was calculated on the basis of distal colorectal findings. Multivariable logistic regression analysis was performed to determine the age-adjusted and sex-adjusted odds of advanced proximal adenomatous and serrated lesions. Secondary analyses were performed to examine the effect of variable ASL definitions. Fifty-two patients (2.7%) had proximal ASL, and 99 (5.2%) had proximal ACN. Of the 52 patients with proximal ASL, 27 (52%) had no distal polyps. Of the 99 patients with proximal ACN, 40 (40%) had no distal polyps. Age and type of distal adenomas were significantly associated with proximal ACN. There were no significant associations between distal polyp type and proximal ASL. In secondary analyses, distal SSA/Ps (P = .008) but not distal hyperplastic polyps or conventional adenomas were associated with any proximal SSA/P. | Isolation of adult animals represents a form of psychsocial stress that produces sympatho-adrenomedullar activation. The aim of this work was to investigate the changes in gene expression and protein levels of catecholamine biosynthetic enzymes: tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in the adrenal medulla of naive control and chronically (12 weeks) socially isolated adult Wistar rat males and the response of these animals to additional immobilization stress (2 h). TH, DBH and PNMT mRNA levels were quantified by quantitative real-time RT-PCR (qRT-PCR). TH, DBH and PNMT immunoproteins were assayed by Western Blot. In chronically isolated rats, gene expression levels of catecholamine biosynthetic enzymes in the adrenal medulla were decreased, but only TH mRNA was significantly decreased. However, protein levels of TH, DBH and PNMT of these animals were elevated by 55%, 20% and 18%, respectively, in relation to the corresponding control. Naive control and chronically socially isolated rats exposed to additional 2-h-immobilization showed increased gene expression of the examined enzymes, the increase being greater in socially isolated rats as compared to the controls. Additional immobilization of naive controls did not affect TH, DBH and PNMT protein levels. In contrast, this stress produced increased TH, DBH and PNMT protein levels in long-term socially isolated rats. |
Is the alpha4bbeta7-integrin dynamically expressed on murine eosinophils and involved in eosinophil trafficking to the intestine? | Of the numerous adhesion molecules expressed by eosinophils, the alpha4-integrin has been identified as critically involved in eosinophil trafficking in the lung. Most studies have focused on the role of the alpha4beta1-adhesion complex, but eosinophils also express the alpha4beta7-integrin complex. To investigate the role of alpha4beta7, by assessing its membrane expression on eosinophils from different compartments using allergen-challenged mice and IL-4/IL-5 bi-transgenic mice. In addition, we aim to determine the impact of beta7-integrin deficiency on eosinophil recruitment to the lungs and intestine in specific experimental allergic models. Evaluation of alpha4beta7 expression on bronchoalveolar lavage fluid (BALF) and lung tissue eosinophils revealed a down-regulation of this integrin as eosinophils migrate through the lungs. Indeed eosinophils isolated from the BALF and lung of allergic mice had low expression of the alpha4beta7-complex. While expression of the alpha4-chain remained unchanged, a significant decrease in beta7-surface expression was observed. Intestinal eosinophils, isolated from Peyer's patches, also displayed a down-regulation of the alpha4beta7-integrin, albeit only modest. In contrast, circulating eosinophils, isolated from the blood and spleen, expressed high levels of the alpha4beta7-integrin. However, eosinophil trafficking into the lungs of beta7-integrin-deficient mice was not significantly impaired in response to respiratory allergen challenges. In contrast, beta7-deficient mice had impaired eosinophil recruitment to the intestine. | Radiation therapy, alone or in combination with chemotherapy, is effective for patients with locally advanced and recurrent pancreatic cancer. Ionizing radiation induces cell cycle arrest and cell apoptosis through enhancement several signals such as p53, p21(Waf1/Cip1), and caspase. However, the therapeutic efficacy is attenuated by radiation-induced activation of NF-κB. Nafamostat mesilate, a synthetic serine protease inhibitor, inhibits NF-κB activation in pancreatic cancer. Therefore, we hypothesized that nafamostat mesilate inhibited radiation-induced activation of NF-κB and improves therapeutic outcome. In combination group, NF-κB activation was significantly inhibited in comparison with that of radiation group. Nafamostat mesilate obviously down-regulated the expression levels of Mdm2 compared with control cells or irradiated cells. Consequently, p53 expression was stabilized inversely in correlation with Mdm2 protein expression level. The expression levels of p53, p21(Waf1/Cip1), cleaved caspase-3 and -8 were the highest in the combination group. Nafamostat mesilate enhanced ionizing radiation-induced cell apoptosis and G2/M cell cycle arrest. In combination group, cell proliferation and tumor growth were significantly slower than those in other groups. |
Does acidic pH shock induce the expressions of a wide range of stress-response genes? | Environmental signals usually enhance secondary metabolite production in Streptomycetes by initiating complex signal transduction system. It is known that different sigma factors respond to different types of stresses, respectively in Streptomyces strains, which have a number of unique signal transduction mechanisms depending on the types of environmental shock. In this study, we wanted to know how a pH shock would affect the expression of various sigma factors and shock-related proteins in S. coelicolor A3(2). According to the results of transcriptional and proteomic analyses, the major number of sigma factor genes were upregulated by an acidic pH shock. Well-studied sigma factor genes of sigH (heat shock), sigR (oxidative stress), sigB (osmotic shock), and hrdD that play a major role in the secondary metabolism, were all strongly upregulated by the pH shock. A number of heat shock proteins including the DnaK family and chaperones such as GroEL2 were also observed to be upregulated by the pH shock, while their repressor of hspR was strongly downregulated. Oxidative stress-related proteins such as thioredoxin, catalase, superoxide dismutase, peroxidase, and osmotic shock-related protein such as vesicle synthases were also upregulated in overall. | Adipose tissue is closely associated with angiogenesis, but the mechanisms are not fully understood. Some of the adipocyte-derived cytokines are hypothesized to play an important role in angiogenesis. We evaluated tube formation of human umbilical vascular endothelial cells (HUVECs) cultured in type I collagen gel when overlaid with the supernatant of 3T3-L1 cell culture, and expression of tube-forming factor(s) in 3T3-L1 cells with or without pioglitazone. We also studied plasma growth factor levels in patients with type 2 diabetes mellitus treated with pioglitazone. The supernatant of 3T3-L1 cells increased tube formation of HUVECs by 9.03-fold of control. Reverse transcription-polymerase chain reaction showed that hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) mRNA were expressed in 3T3-L1 cells. Western blot analysis also demonstrated HGF and VEGF protein expression. When 3T3-L1 cells were treated with 100 nM small interfering RNAs (siRNAs) for HGF, the HGF mRNA and protein were suppressed. The VEGF mRNA and protein in the cells were also suppressed by siRNA for VEGF. The supernatant of 3T3-L1 cells treated with HGF siRNA suppressed tube formation of HUVECs by 61% compared with the supernatant of cells treated with control siRNA. Addition of VEGF siRNA resulted in no significant changes. The supernatant conditioned with pioglitazone further promoted the tube formation. Pioglitazone enhanced HGF mRNA expression in 3T3-L1 cells. After 12 weeks of pioglitazone treatment, the changes of plasma HGF levels in patients treated with pioglitazone were significantly higher than those in control. |
Is virological failure after 1 year of first-line ART associated with HIV minority drug resistance in rural Cameroon? | The aim of this study was to describe clinical and virological outcomes in therapy-naive HIV-1-positive patients treated in a routine ART programme in rural Cameroon. In a prospective cohort, 300 consecutive patients starting first-line ART were enrolled and followed for 12 months. Among 238 patients with available viral load data at Month 12, logistic regression was used to analyse risk factors for virological failure (≥1000 HIV RNA copies/mL) including clinical, immunological and virological parameters, as well as data on drug adherence. Population sequencing was performed to detect the presence of drug-resistance mutations in patients with virological failure at Month 12; minority drug-resistance mutations at baseline were analysed using next-generation sequencing in these patients and matched controls. At Month 12, 38/238 (16%) patients experienced virological failure (≥1000 HIV RNA copies/mL). Patients with virological failure were younger, had lower CD4 cell counts and were more often WHO stage 3 or 4 at baseline. Sixty-three percent of patients with virological failure developed at least one drug-resistance mutation. The M184V (n = 18) and K103N (n = 10) mutations were most common. At baseline, 6/30 patients (20%) experiencing virological failure and 6/35 (17%) matched controls had evidence of minority drug-resistance mutations using next-generation sequencing (P = 0.77). Lower CD4 count at baseline (OR per 100 cells/mm(3) lower 1.41, 95% CI 1.02-1.96, P = 0.04) and poorer adherence (OR per 1% lower 1.05, 95% CI 1.02-1.08, P < 0.001) were associated with a higher risk of virological failure. Unavailability of ART at the treatment centre was the single most common cause for incomplete adherence. | To address the hypothesis that hydrogen sulfide (H(2)S) is a functionally significant stimulator in the development of glioblastoma (GBM) and explore the mechanism of stimulation. Forty adult Sprague-Dawley (SD) rats were given intracerebral injection of rat C6 glioma cell suspension, and an intraperitoneal injection of sodium hydrosulfide (NaHS), an exogenous H(2)S donor. The 40 rats were randomly divided into 4 groups of 10 rats in each: the control group, NaHS group, C6 glioma group (intracerebral implantation of C6 glioma cells) and C6-NaHS group (intracerebral implantation of C6 glioma cells and intraperitoneal injection of NaHS). Food and water were freely available during all phases of the experiment. Physical symptoms were observed and the tumor size was measured. Histological changes were examined by pathology. Immunohistochemical staining was used to analyze the expression of HIF-1α and integrated optical density (IOD) was used to determine the tumor microvessel density (MVD). The H(2)S content in the brain was measured. The physical symptoms of tumor-bearing rats became more serious after NaHS injection. The H(2)S level in the C6 glioma group was higher than that in the control group [(35.25 ± 1.03) nmol/g vs. (29.12 ± 0.94) nmol/g, P < 0.05], and the highest H(2)S level was found in the C6-NaHS group. The pathological examination showed that the implanted tumors were predominantly spheroid with a distinct border and no capsule could be detected. Neovascular proliferation was also observed. Foci of tumor necrosis, intratumoral hemorrhage, pseudopalisades and tumor cavity were clearly observed. The glioma cells had scant eosinophilic cytoplasm and enlarged hyperchromatic nuclei. All these phenomena were more markedly in the C6-NaHS group compared with that in other three groups. The mean tumor volume was significantly different between the C6 and C6-NaHS rats [(32.0 ± 6.9) mm(3) vs. (67.8 ± 11.9) mm(3), P < 0.001]. Immunohistochemical analysis exhibited that the hypoxia-inducible factor-1alpha (HIF-1α) and CD34 expression were significantly increased after the intraperitoneal injection of NaHS in the C6-NaHS rats (comparing the IOD between C6-NaHS group and C6 group, HIF-1α: 133 962.9 ± 451.4 vs. 38 569.8 ± 408.6, P < 0.001; CD34: 73 368.6 ± 404.8 vs. 14 570.6 ± 748.7, P < 0.001). Moreover, compared with the C6 group, there were higher MVD in the C6-NaHS group [(41.2 ± 7.9)/mm(2) vs. (97.0 ± 10.8)/mm(2), P < 0.001]. |
Does cystamine improve functional recovery via axon remodeling and neuroprotection after stroke in mice? | Stroke is a leading cause of disability. However, there is no pharmacological therapy available for promoting recovery. Although treatment of stroke with cystamine has gained increasing interest, the detailed mechanisms underlying this process remain elusive. Thus, our aim is to examine the effect of cystamine on the function recovery after stroke and investigate further cystamine mechanisms. Adult male C57BL/6J mice were subjected to photothrombotic model of focal stroke or sham operation. Cystamine or saline was administered intraperitoneally at 24 h after stroke. Functional recovery was analyzed using behavioral tests; axon remodeling was analyzed using magnetic resonance diffusion tensor imaging (DTI) and histological assessment. ANA-12, an antagonist of tropomyosin-related kinase B (TrkB), was administrated to examine the mechanisms underlying the neuroprotection mediated by cystamine. Treatment with cystamine resulted in amelioration of impaired function with concomitant enhancement of axonal remodeling. Cystamine treatment significantly increased brain-derived neurotrophic factor (BDNF) levels and phosphorylation of TrkB in brain after stroke. Cystamine significantly enhanced neuronal progenitor cell proliferation, neuronal survival, and plasticity through BDNF/TrkB pathway. | Two out of three patients with Coeliac Disease (CD) in Australia are undiagnosed. This prospective clinical audit aimed to determine how many CD patients would be undiagnosed if duodenal biopsy had only been performed if the mucosa looked abnormal or the patient presented with typical CD symptoms. All eligible patients presenting for upper gastrointestinal endoscopy (OGD) in a regional center from 2004-2009 underwent prospective analysis of presenting symptoms and duodenal biopsy. Clinical presentations were defined as either Major (diarrhea, weight loss, iron deficiency, CD family history or positive celiac antibodies- Ab) or Minor Clinical Indicators (CI) to duodenal biopsy (atypical symptoms). Newly diagnosed CD patients had follow up celiac antibody testing. Thirty-five (1.4%) new cases of CD were identified in the 2,559 patients biopsied at upper endoscopy. Almost a quarter (23%) of cases presented with atypical symptoms. There was an inverse relationship between presentation with Major CI's and increasing age (<16, 16-59 and >60: 100%, 81% and 50% respectively, p = 0.03); 28% of newly diagnosed CD patients were aged over 60 years. Endoscopic appearance was a useful diagnostic tool in only 51% (18/35) of CD patients. Coeliac antibodies were positive in 34/35 CD patients (sensitivity 97%). |
Is ischemia change in stable coronary artery disease an independent predictor of death and myocardial infarction? | The aim of this study was to evaluate the independent prognostic significance of ischemia change in stable coronary artery disease (CAD). Recent randomized trials in stable CAD have suggested that revascularization does not improve outcomes compared with optimal medical therapy (MT). In contrast, the nuclear substudy of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial found that revascularization led to greater ischemia reduction and suggested that this may be associated with improved unadjusted outcomes. Thus, the effects of MT versus revascularization on ischemia change and its independent prognostic significance requires further investigation. From the Duke Cardiovascular Disease and Nuclear Cardiology Databanks, 1,425 consecutive patients with angiographically documented CAD who underwent 2 serial myocardial perfusion single-photon emission computed tomography scans were identified. Ischemia change was calculated for patients undergoing MT alone, percutaneous coronary intervention, or coronary artery bypass grafting. Patients were followed for a median of 5.8 years after the second myocardial perfusion scan. Cox proportional hazards regression modeling was used to identify factors independently associated with the primary outcome of death or myocardial infarction (MI). Formal risk reclassification analyses were conducted to assess whether the addition of ischemia change to traditional predictors resulted in improved risk classification for death or MI. More MT patients (15.6%) developed ≥5% ischemia worsening compared with those undergoing percutaneous coronary intervention (6.2%) or coronary artery bypass grafting (6.7%) (p < 0.001). After adjustment for established predictors, ≥5% ischemia worsening remained a significant independent predictor of death or MI (hazard ratio: 1.634; p = 0.0019) irrespective of treatment arm. Inclusion of ≥5% ischemia worsening in this model resulted in significant improvement in risk classification (net reclassification improvement: 4.6%, p = 0.0056) and model discrimination (integrated discrimination improvement: 0.0062, p = 0.0057). | Hyaluronic acid receptor is a glycoprotein of the plasmatic membrane, and the CD44 is its representative, expressed in many cell types where it has the task of cell adhesion. the goal of the present experimental study is to investigate the possibility of using immunohistochemistry to identify the distribution of hyaluronic acid along the vocal fold. We resected the normal vocal folds from a normal 23 year-old male black individual. The slides were analyzed by means of a histomorphometric study, comparing the color intensity in the superficial, middle and deep layers of the lamina propria. In the silanized slides we used immunohistochemistry, and evaluated the slides under light microscopy with 40x magnification, and the color changed to brown when there was a reaction with the receptor for hyaluronic acid. Immunohistochemical findings showed the presence of hyaluronic acid receptors in the epithelium covering the vocal fold, being more concentrated in the central region of the vocal fold. |
Does eGF reverse multi-drug resistance via the p-ERK pathway in HepG2/ADM and SMMC7721/ADM hepatocellular carcinoma models? | To investigate signaling pathways for reversal of EGF-mediated multi-drug resistance (MDR) in hepatocellular carcinoma (HCC) models. HCC MDR cell strain HepG2/adriamycin (ADM) and SMMC7721/ADM models were established using a method of exposure to medium with ADM between low and high concentration with gradually increasing concentration. Drug sensitivity and reversal of multi-drug resistance by EGF were determined and the cell cycle distribution and apoptosis were analyzed by flow cytometry. Phosphorylation of ERK1, ERK2, ERK5 and expression of Bim were detected by Western blotting. The results showed that HepG2/ADM and SMMC7721/ADM cells were resistant not only to ADM, but also to multiple anticancer drugs. When used alone, EGF had no anti-tumor activity in HepG2/ADM and SMMC7721/ADM cells in vitro, while it increased the cytotoxicity of ADM. EGF induced cell apoptosis and G0/G1 phase cell cycle arrest in HepG2/ADM And SMMC7721/ADM cells, while enhancing activity of p-ERKs and up-regulated expression of BimEL. | The purpose of this study is to determine whether chiropractic manipulation is associated with any measurable changes in the difference between the arterial blood pressures on the left and right before and after treatment in normotensive subjects. A nonrandomized, matched pair, controlled clinical trial, with the treatment (manipulation) group and control (resting) group matched for age and sex, was performed in chiropractic student clinics in London, UK. The treatment group consisted of 35 new patients presenting to a single student chiropractor between the start of April 2003 and the end of August 2003. The control group consisted of 35 nonpatients matched for sex and age. The intervention was chiropractic manipulation. Preintervention and postintervention systolic and diastolic blood pressures were recorded in both arms through the use of a digital oscillometric sphygmomanometer. A significant difference was found between the pre- and posttreatment blood pressure differences for systolic pressures (P = .01), but no significant difference was found in either set of control data or the treatment diastolic values. A significant difference was also found between the treatment and control group's preintervention systolic differences (P = .002), but not between the groups at any other time. |
Is kRAS mutation present in a small subset of primary urinary bladder adenocarcinomas? | To determine whether KRAS mutations occur in primary bladder adenocarcinoma. Twenty-six cases of primary urinary bladder adenocarcinoma were analysed. DNA was extracted from formalin-fixed, paraffin-embedded tissue and amplified with shifted termination assay technology, which recognizes wild-type or mutant target sequences and selectively extends detection primers with labelled nucleotides. A mutation in KRAS was found in three (11.5%) of 26 primary bladder adenocarcinomas. Two of these three cases exhibited a G13D mutation, whereas the remaining case contained a mutation in G12V. None of the ten cases of urothelial carcinoma with glandular differentiation displayed KRAS mutation. Colonic adenocarcinoma contained a KRAS mutation in 18 (33%) of 55 cases. There was no distinct difference with regard to grade, stage or outcome according to the limited clinicopathological data available. However, the two youngest patients, aged 32 and 39 years, in our study group, with a mean population age of 61 years, were found to have mutations in KRAS. | It has been suggested that weight loss can improve systemic inflammation associated with obesity by decreasing the adipose production of pro-inflammatory cytokines. This suggestion, however, remains controversial. To analyse the effect of weight loss on peripheral inflammatory markers and subcutaneous adipocytokine production. Patients were studied at baseline, at the end of the weight loss period, and after 2 weeks of weight stabilisation. Nineteen morbid obese non-diabetic patients and 20 lean control subjects. During the weight loss period patients followed a 6-week low-calorie diet. Plasma levels of inflammatory markers, maximal in vitro whole-blood cytokine production, subcutaneous adipose tissue expression and content of several cytokines. Obese subjects had higher circulating levels of C reactive protein (CRP), serum amyloid A (SAA), interleukin IL-6, IL-1 and soluble tumor necrosis factor receptors (sTNFR). Weight loss was associated with a significant decrease in CRP, SAA, leucocytes and plasma IL-6. Maximal in vitro cytokine production of IL-1 and sTNFR1 increased during this period. Weight loss did not induce significant changes in the adipose concentrations of IL-6, IL-1 or sTNF-receptors. However, adipose expression of IL-6, IL-1, TNFalpha, membrane cofactor protein-1 and adiponectin increased at the end of the weight loss period. During weight maintenance, circulating inflammatory parameters increased and in some cases returned to baseline. |
Is recovery of fibrinogen concentrate after intraosseous application equivalent to the intravenous route in a porcine model of hemodilution? | Fibrinogen concentrate is increasingly considered as a hemostatic agent for trauma patients experiencing bleeding. Placing a venous access is sometimes challenging during severe hemorrhage. Intraosseous access may be considered instead. Studies of intraosseous infusion of coagulation factor concentrates are limited. We investigated in vivo recovery following intraosseous administration of fibrinogen concentrate and compared the results with intravenous administration. This study was performed on 12 pigs (mean [SD] body weight, 34.1 [2.8] kg). Following controlled blood loss (35 mL/kg) and fluid replacement with balanced crystalloid solution, intraosseous (n = 6) administration of fibrinogen concentrate (80 mg per kilogram of bodyweight) in the proximal tibia was compared with intravenous (n = 6) administration of the same dose (fibrinogen infusion time approximately 5 minutes in both groups). The following laboratory parameters were assessed: blood cell count, prothrombin time index, activated partial thromboplastin time, and plasma fibrinogen concentration (Clauss assay). Coagulation status was also assessed by thromboelastometry. All tested laboratory parameters were comparable between the intraosseous and intravenous groups at baseline, hemodilution, and 30 minutes after fibrinogen concentrate administration. In vivo recovery of fibrinogen was also similar in the two groups (89% [23%] and 91% [22%], respectively). There were no significant between-group differences in any of the thromboelastometric parameters. Histologic examination indicated no adverse effects on the tissue surrounding the intraosseous administration site. | DNA methylation is an important type of epigenetic modification involved in gene regulation. Although strong DNA methylation at promoters is widely recognized to be associated with transcriptional repression, many aspects of DNA methylation remain not fully understood, including the quantitative relationships between DNA methylation and expression levels, and the individual roles of promoter and gene body methylation. Here we present an integrated analysis of whole-genome bisulfite sequencing and RNA sequencing data from human samples and cell lines. We find that while promoter methylation inversely correlates with gene expression as generally observed, the repressive effect is clear only on genes with a very high DNA methylation level. By means of statistical modeling, we find that DNA methylation is indicative of the expression class of a gene in general, but gene body methylation is a better indicator than promoter methylation. These findings are general in that a model constructed from a sample or cell line could accurately fit the unseen data from another. We further find that promoter and gene body methylation have minimal redundancy, and either one is sufficient to signify low expression. Finally, we obtain increased modeling power by integrating histone modification data with the DNA methylation data, showing that neither type of information fully subsumes the other. |
Do low-abundance HIV drug-resistant viral variants in treatment-experienced persons correlate with historical antiretroviral use? | It is largely unknown how frequently low-abundance HIV drug-resistant variants at levels under limit of detection of conventional genotyping (<20% of quasi-species) are present in antiretroviral-experienced persons experiencing virologic failure. Further, the clinical implications of low-abundance drug-resistant variants at time of virologic failure are unknown. Plasma samples from 22 antiretroviral-experienced subjects collected at time of virologic failure (viral load 1380 to 304,000 copies/mL) were obtained from a specimen bank (from 2004-2007). The prevalence and profile of drug-resistant mutations were determined using Sanger sequencing and ultra-deep pyrosequencing. Genotypes were interpreted using Stanford HIV database algorithm. Antiretroviral treatment histories were obtained by chart review and correlated with drug-resistant mutations. Low-abundance drug-resistant mutations were detected in all 22 subjects by deep sequencing and only in 3 subjects by Sanger sequencing. In total they accounted for 90 of 247 mutations (36%) detected by deep sequencing; the majority of these (95%) were not detected by standard genotyping. A mean of 4 additional mutations per subject were detected by deep sequencing (p<0.0001, 95%CI: 2.85-5.53). The additional low-abundance drug-resistant mutations increased a subject's genotypic resistance to one or more antiretrovirals in 17 of 22 subjects (77%). When correlated with subjects' antiretroviral treatment histories, the additional low-abundance drug-resistant mutations correlated with the failing antiretroviral drugs in 21% subjects and correlated with historical antiretroviral use in 79% subjects (OR, 13.73; 95% CI, 2.5-74.3, p = 0.0016). | Intestinal reflexes induced by distention in dogs are facilitated by either simultaneous or previous distentions. The aim of this study was to determine whether these phenomena also modulate the responses to intestinal distention, particularly perception, in humans. Perception and intestinal relaxation were measured in 11 healthy subjects in response to increasing jejunal balloon distentions tested (by stimulus-response trials) alone, as control, and with conditioning distentions applied either simultaneously, immediately (10 seconds) before at the same site, or immediately before and 5 cm distant. In 8 additional subjects, the effect of prolonged (90-minute) conditioning distention was tested. Conditioning had more pronounced effects on perception than on intestinal reflexes. Perception of intestinal distention increased (by 84 +/- 47%; P < 0.05) when a simultaneous distention was applied nearby. By contrast, perception decreased (by 38 +/- 12%; P < 0.05) when a previous distention was applied at the same but not at an adjacent site. Prolonged intestinal distention elicited remarkably stable perception during a 90-minute period. The effects of conditioning were unrelated to intestinal compliance because it remained unchanged. |
Do osteoblasts play key roles in the mechanisms of action of strontium ranelate? | Strontium ranelate reduces fracture risk in postmenopausal women with osteoporosis. Evidence from non-clinical studies and analyses of bone markers in phase III trials indicate that this is due to an increase in osteoblast formation and a decrease of osteoclastic resorption. The aim of this work was to investigate, in human cells, the mechanisms by which strontium ranelate is able to influence the activities of osteoblasts and osteoclasts. Human primary osteoblasts were used to examine effects of strontium ranelate on replication (thymidine incorporation), differentiation (Runx2 and alkaline phosphatase) and cell survival (cell counts and caspase activity). Osteoprotegerin (OPG) was measured by quantitative reverse transcription PCR (qRT-PCR) and elisa and receptor activator of NFkappaB ligand (RANKL) by qRT-PCR and Western blot. As strontium ranelate has been proposed as an agonist of the calcium-sensing receptor (CaSR), the involvement of CaSR in the effects of strontium ranelate on OPG and RANKL expression, and cell replication was examined using siRNA. Strontium ranelate increased mRNA and protein levels of OPG and suppressed those of RANKL. Strontium ranelate also stimulated osteoblast replication and differentiation and increased cell survival under stress. Knocking down CaSR suppressed strontium ranelate-induced stimulation of OPG mRNA, reduction of RANKL mRNA, and increase in replication, indicating the involvement of CaSR in these responses. | Because of greater recognition and improved imaging capabilities, intraductal papillary mucinous neoplasms (IPMNs) are being diagnosed with increasing frequency. IPMNs of the main pancreatic duct cause symptoms and lead to pancreatitis. Side-branch (SB) IPMNs are thought to cause symptoms less frequently, and their association with pancreatitis is not well defined. Our purpose was to ascertain whether an association exists between SB-IPMN and pancreatitis. Single-center, retrospective study. Academic medical center. A total of 305 patients underwent EUS examinations between October 2002 and October 2006 for pancreatic cystic lesions. The main outcome measure was the frequency of acute or chronic pancreatitis that was not procedurally related. Thirty-two patients had SB-IPMNs, and 11 (34%) had pancreatitis. Three patients reported a single episode, and 8 patients reported having recurrent episodes of pancreatitis. Overall, 17 (53%) patients had symptoms possibly attributable to SB-IPMN. Female sex (73% vs 38%) and multiple pancreatic lesions (54% vs 24%) were more commonly seen in those with pancreatitis, but were not statistically significant factors. Larger cyst size or cyst fluid marker levels did not appear associated with pancreatitis occurrence. EUS-FNA demonstrated communication with the pancreatic duct in 94% and thick, mucinous fluid in 84%. |
Are mannose-binding lectin gene polymorphisms associated with disease activity and physical disability in untreated , anti-cyclic citrullinated peptide-positive patients with early rheumatoid arthritis? | To study the association between polymorphisms in the mannose-binding lectin gene (MBL2) and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA). Patients with early RA (n=158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion for MBL2 pooled structural genotypes (O/O, A/O, A/A), regulatory MBL2 promoter polymorphism in position -221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score). Eight patients were homozygous MBL2 defective (O/O), 101 belonged to an intermediate group, and 49 were MBL2 high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p=0.02), and physical disability by HAQ (p=0.01) were associated with high MBL2 expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs. | Induction of heme oxygenase-1 (HO-1) protects the liver against reperfusion injury after hemorrhagic shock. Previous data suggest that the beta(1)-adrenoceptor agonist dobutamine induces HO-1 in hepatocytes. To investigate the functional significance of dobutamine pretreatment for liver function after hemorrhagic shock in vivo. Anesthetized rats received either Ringer's (Vehicle/Shock), 10 microg/kg/min of the beta(1)-adrenoceptor agonist dobutamine (Dob/Shock), or 10 microg/kg/min dobutamine and 500 microg/kg/min of the beta(1)-adrenoceptor antagonist esmolol (Dob/Esmolol/Shock) for 6 h. Hemorrhagic shock was induced thereafter (mean arterial pressure, 35 mm Hg for 90 min). Animals were resuscitated with shed blood and Ringer's. In addition, the HO pathway was blocked after dobutamine pretreatment with 10 micromol/kg tin-mesoporphyrin-IX (Dob/SnMP/Shock) or animals received 100 mg/kg of the carbon monoxide donor dichloromethane (DCM/Shock). Hepatocellular metabolism and liver blood flow were measured by plasma disappearance rate of indocyanine green (PDR(ICG)) as a sensitive marker of liver function. Pretreatment with dobutamine induced HO-1 in pericentral hepatocytes and improved PDR(ICG) (Vehicle/Shock: 11.7 +/- 8.12%/min vs. Dob/Shock: 19.7 +/- 2.46%/min, p = 0.006). Blockade of the HO pathway after preconditioning and the combined pretreatment with dobutamine and esmolol decreased PDR(ICG) (Dob/SnMP/Shock: 12.6 +/- 4.24%/min, p = 0.011; Dob/Esmolol/Shock: 10.2 +/- 4.34%/min, p = 0.008). Pretreatment with a carbon monoxide donor improved PDR(ICG) (DCM/Shock: 18 +/- 3.19%/min, p = 0.022) compared with Vehicle/Shock. |
Does cytotoxic T lymphocyte antigen-4 promoter -658CT gene polymorphism is associate with ulcerative colitis in Chinese patients? | Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a role in the downregulation of T cell activation. The present study aimed to examine an association between the CTLA-4 gene polymorphisms and ulcerative colitis (UC) in the Han Chinese in central China. One hundred seventeen patients with UC and 246 healthy controls were genotyped for CTLA-4 gene -658CT in the promoter and CT61 at the 3' untranslated region using a method of polymerase chain reaction-based restriction fragment length polymorphism and single-strand conformation polymorphism, respectively. The distributions of the genotypes and the allele frequencies of the CTLA-4 gene in UC patients and healthy controls were compared by chi-square test. The frequency of the T/T+C/T genotype at the CTLA-4 gene -658CT in the promoter was significantly higher in UC patients than in healthy controls (26.5% vs 15.4%, chi (2) = 6.287, P = 0.015, OR = 1.973, 95%CI = 1.153-3.375). The frequency of the T allele at the CTLA-4 -658CT was also significantly higher in UC patients than in the controls (13.2% vs 8.1%, chi (2) = 4.707, P = 0.033, OR = 1.726, 95%CI = 1.049-2.838). The frequency of the T/T genotype at the -658 locus was highly associated with extensive colitis in UC patients (P = 0.037, OR = 3.955, 95%CI = 1.068-14.647). The frequency of the T allele at the -658 locus was highly associated with extensive colitis in UC patients (P = 0.0067, OR = 3.05, 95%CI = 1.320-7.048). | To test the hypothesis that B-type natriuretic peptide (BNP) acts as a potent vasculogenic agent by enhancing the number, proliferation, adhesion, and migration of endothelial progenitor cells (EPCs). BNP is a neurohormonal peptide that predicts outcome and used for treatment in chronic heart failure patients. It has been shown to promote angiogenesis in experimental animals. EPCs have been demonstrated to contribute to postnatal angiogenesis and vasculogenesis. The number of EPC colony forming units (CFU) and levels of N-terminal ProBNP were assayed in patients with severe, yet controlled, New York Heart Association (NYHA) II-IV heart failure. The in vitro effects of BNP on early EPC-CFU numbers, proliferation, migration, adhesive, and vascular tube formation capacities were studied using human and murine systems. The effects of in vivo BNP administration on Sca-1/Flk-1 progenitors and on vasculogenesis in the hindlimb ischemia model were then assayed in wild-type mice. A significant correlation was found between circulating N-terminal ProBNP levels and EPC-CFU numbers. We observed a dose-dependent effect of BNP on the numbers of CFU and proliferation capacity of human EPCs as well as on their adhesive, migratory, and tube formation properties, in vitro. Systemic BNP administration to mice led to a significant increase in bone marrow Sca-1/Flk-1 EPCs and improvement in blood flow and capillary density in the ischemic limbs of mice. |
Does intravascular parasympathetic cardiac nerve stimulation prevent ventricular arrhythmias during acute myocardial ischemia? | Although previous animal studies clearly demonstrated antiarrhythmic effects of vagal stimulation during acute myocardial ischemia, highly invasive nature of vagal stimulation limited its clinical use. Recently, intravascular parasympathetic cardiac nerve stimulation (IPS) has emerged as a novel approach to the cardiac autonomic nervous system. We hypothesized that IPS might prevent ventricular arrhythmias during acute myocardial ischemia. The IPS (36 V, 10 Hz) was performed in superior vena cava using an expandable electrode-basket catheter. In 18 open-chest dogs, left anterior descending coronary artery ligation was performed without IPS (control group, n= 6), with IPS (IPS group, n= 6) and with IPS and right atrial pacing at 180/min (IPS+P group, n=6). The ECGs were monitored for 60 min. The incidence and severity of ventricular arrhythmias were analyzed. The IPS significantly decreased the frequency of premature ventricular contractions (control group: 9.1 ± 4.6/min, IPS group: 0.2 ± 0.4 /min, IPS+P group: 10.6 ± 4.2 / min; p<0.05). The frequency of ventricular tachycardia was lower in IPS group (0 ± 0 /min) than in control group (0.15 ± 0.18 /min, p<0.05) and than in IPS+P group (0.17 ± 0.12 /min, p<0.05). The incidence of ventricular fibrillation was lower in IPS group (0%) than in control group (33.3%) and than in IPS+P group (33.3%). | Corticosteroids are a critical component of therapy for acute lymphoblastic leukemia (ALL) but are associated with late effects, such as osteoporosis. Risk factors remain poorly defined. Because CRHR1 polymorphisms have been associated with other corticosteroid effects, our goal was to define whether CRHR1 polymorphisms predict which patients with ALL are likely to develop bone mineral deficits. The mean bone mineral density z scores of 309 long-term survivors of ALL were determined by quantitative computed tomography of the trabecular lumbar spine. We analyzed whether CRHR1 genotypes, adjusted for sex, ALL treatment regimen, and weight, could predict bone density. We found that three single nucleotide polymorphisms (SNPs), all in linkage disequilibrium, were associated with bone density in a sex-specific manner. Bone density was lower in males (P = .001), in nonblack patients (P < .08), in those who were not overweight (P < .001), and in those who received intensive antimetabolites and glucocorticoids (P < .001). After adjustment for these features, the G allele at the rs1876828 SNP was associated with lower z scores (P = .02) in males but tended to have the opposite association in females (P = .09). |
Does atrial electrogram interpretation improve after an innovative education program? | To avoid adverse patient outcomes from inappropriate treatment, it is recommended that an atrial electrogram (AEG) be recorded whenever atrial arrhythmias develop in patients after cardiac surgery. However, AEGs are not commonly performed because nurses lack knowledge about differentiating atrial rhythms on AEGs. To investigate whether completing a novel online evidence-based education program on interpreting AEGs would improve critical care nurses' AEG interpretation. Specialized critical care nurses were taught about obtaining and interpreting atrial rhythms on AEGs using a 42-minute online mini-movie. AEG interpretation was assessed pre and two and eight weeks post-intervention. AEG interpretation increased two weeks post intervention and was retained at eight weeks. Some participants used this newly acquired knowledge to interpret arrhythmias that were not taught during the education program. | To investigate the specific role of Frizzled-related protein (FRZB) and Secreted frizzled-related protein 1 (SFRP1) in the onset and progression of Osteoarthritis (OA) using Frzb(-/-) and Sfrp1(-/-) mice in the destabilization of medial meniscus model (DMM), a slowly progressing model of OA. Secreted frizzled-related proteins (SFRPs) were identified as secreted Wingless-type (Wnt) antagonists. The Wnt signaling cascade is a major regulator in cartilage development, homeostasis and degeneration. The DMM model was surgically induced in eight-week-old male C57/Bl6 Frzb(-/-), Sfrp1(-/-) or wild-type mice by transection of the medial meniscotibial ligament. Cartilage damage in the femoral and tibial articular surfaces was calculated following the Osteoarthritis Research Society International (OARSI) histopathology initiative guidelines. Histomorphometry was used to evaluate the subchondral bone plate thickness. OA severity scores were significantly higher in the tibia of Frzb(-/-) mice as compared to littermates, whereas no interaction was seen between genotype and intervention in Sfrp1(-/-) mice. Moreover, the DMM model resulted in significantly greater subchondral bone changes compared to sham but was not different between Frzb(-/-) mice and littermates. In contrast, the subchondral bone properties in Sfrp1(-/-) mice were significantly different from littermates. |
Do radiographic characteristics fail to predict clinical course after subdural electrode placement? | Subdural arrays of grid and strip electrodes are frequently used in epilepsy patients to localize the seizure focus and determine the location of critical brain functions via stimulation mapping. Postoperatively, the majority of patients with implanted subdural electrodes develop subacute extra-axial collections (EACs). Although conservative management is appropriate in most of these cases, occasionally patients manifest neurological symptoms that may necessitate reoperation for collection evacuation. Currently, there is little information available regarding the range of EAC size and the potential correlation between EAC size and symptom development. To facilitate treatment decision-making in postoperative subdural electrode patients, we reviewed and compared the computed tomographic (CT) features of postelectrode placement EACs in asymptomatic and symptomatic patients. We retrospectively reviewed the medical records and CT scans of 22 consecutive patients who underwent craniotomy for placement of subdural grid and strip electrodes at Columbia University Medical Center. Medical records were reviewed for neurological complications from the time of grid placement until its removal. Each EAC was measured on CT for volume (% of total cranial volume), maximal thickness, and midline shift. One patient was excluded secondary to the development of an intracerebral hemorrhage. Thirteen of 21 patients remained asymptomatic or minimally symptomatic during their hospitalization, with only mild to moderate, intermittent, postoperative headaches. The remaining eight developed symptoms such as persistent and severe headache, transient motor deficit, or speech impairment. Two of these patients underwent reoperation for hematoma evacuation. EACs in asymptomatic patients had a mean volume, maximal thickness, and midline shift of 5.7%, 1.25 cm, and 0.33 cm, respectively. EACs in symptomatic patients had a mean volume, maximal thickness, and midline shift of 7.7%, 1.46 cm, and 0.5 cm, respectively. Differences between maximal thickness and midline shift did not approach statistical significance. Despite this, the difference between the mean volume of symptomatic and asymptomatic EACs was statistically significant (P = 0.04). | Cardiotrophin-1 (CT-1) is a cytokine involved in the growth and survival of cardiac cells via activation of the Janus activated kinase/signal transducer activator of transcription (JAK/STAT). Statins, 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have effects that extend beyond cholesterol reduction and inhibit vascular smooth muscle cell (VSMC) proliferation and cardiac hypertrophy. However, whether stains also can inhibitin vitromyocardial hypertrophy or not still remains elusive. The purpose of this study was to explore the effects of simvastatin on the hypertrophy of cultured rat cardiomyocytes induced by CT-1 and to investigate whether this effect was mediated via JAK-STAT signaling pathway. Primary cardiomyocytes from 2-day-old (P2) rats were cultured, stimulated with CT-1, and treated with various concentration of simvastatin. Incorporation of [(3)H] leucine, reverse transcription-polymerase chain reaction and western blotting techniques were used to investigate cardiacmyocyte size, ANP mRNA and JAK-STAT protein expression. Simvastatin was proved, in a dose-independent manner, to decrease cardiacmyocytes size as well as protein synthesis, and inhibit ANP mRNA synthesis and JAK-STAT protein expression induced by CT-1 in cardiacmyocytes. |
Is hepaticoduodenostomy an alternative to Roux-en-Y hepaticojejunostomy for biliary reconstruction in live donor liver transplantation? | A Roux-en-Y hepaticojejunostomy (HJ) is usually performed during live donor liver transplantation (LDLT) when a duct-to-duct reconstruction is not possible. However, direct anastomosis of the bile duct to the duodenum (hepaticoduodenostomy [HD]) is an alternative technique for biliary repair that has been previously used for conventional biliary surgery and at our center for cadaveric liver transplant. We provide the first evidence that HD is an alternative technique for biliary reconstruction in LDLT. We performed a total of 71 LDLT between 2002 and 2008. An end-to-end anastomosis was used in 30 patients. Forty-one patients had a biliary enteric anastomosis in which seven were reconstructed with an HD. Accessory ducts were fashioned into a common duct or implanted into the duodenum separately. There were no patient deaths or retransplants in a follow-up period that ranged from 90 to 771 days after surgery. One patient was diagnosed with cholangitis that responded to intravenous antibiotics and removal of the stent by endoscopy. | To analyze the effect of antiretroviral therapy, including drugs that have good penetration in cerebrospinal fluid (CSF), on neuropsychologic performance. One hundred sixty-five HIV-1-infected patients exposed to a stable highly active antiretroviral therapy (HAART) regimen were studied. Neuropsychologic examinations were performed for all patients. A total of 50.3% of patients were impaired. In multivariate analysis, older age (for 10-year increase, odds ratio [OR] = 4.8, 95% confidence interval [CI]: 2.2 to 10.4; P< 0.0001) and higher plasma HIV-1 RNA levels (OR = 1.90, 95% CI: 1.1 to 3.2; P = 0.021) at testing were independently associated with an increased probability of impaired neurocognitive performance, whereas higher educational level was a protective factor (OR = 0.76, 95% CI: 0.65 to 0.90; P=0.001). A significant linear correlation was observed between the neuropsychologic z score for 8 tests (NPZ8) score, a quantitative parameter of neurocognitive impairment, and CD4 cell count at neuropsychologic testing (R = 0.273, P = 0.001) and between the NPZ8 score and the patient's age (R = 0.288, P = 0.001). |
Does release of Cathepsin B in Cytosol cause Cell Death in Acute Pancreatitis? | Experimental studies in acute pancreatitis (AP) suggest a strong association of acinar cell injury with cathepsin B-dependent intracellular activation of trypsin. However, the molecular events subsequent to trypsin activation and their role, if any, in cell death is not clear. In this study, we have explored intra-acinar events downstream of trypsin activation that lead to acinar cell death. Acinar cells prepared from the pancreas of rats or mice (wild-type, trypsinogen 7, or cathepsin B-deleted) were stimulated with supramaximal cerulein, and the cytosolic activity of cathepsin B and trypsin was evaluated. Permeabilized acini were used to understand the differential role of cytosolic trypsin vs cytosolic cathepsin B in activation of apoptosis. Cell death was evaluated by measuring specific markers for apoptosis and necrosis. Both in vitro and in vivo studies have suggested that during AP cathepsin B leaks into the cytosol from co-localized organelles, through a mechanism dependent on active trypsin. Cytosolic cathepsin B but not trypsin activates the intrinsic pathway of apoptosis through cleavage of bid and activation of bax. Finally, excessive release of cathepsin B into the cytosol can lead to cell death through necrosis. | The aim of this study was to determine how the treatment needs and outcomes of polysubstance-using patients entering opioid-substitution treatment (OST) may be affected if the patient had a parent with substance-use problems. This prospective observational study examined outcomes of 255 patients (97% male) entering OST at eight clinics in the Veterans Health Administration. Self-reported substance-use outcomes in the first year of treatment were compared between patients with (n = 121) and without (n = 134) a parent with substance-use problems. The association between receipt of practice guideline-recommended elements of care and treatment outcome was examined. Parent history-positive patients had greater drug use at 6 months, but by 12 months they had reduced their drug use to the same extent as parent history-negative patients. Ongoing methadone (Dolophine, Methadose) maintenance was associated with improved outcomes of drug use in parent history-negative patients; however, parent history-positive patients who ended methadone maintenance reduced drug use as much as those who continued treatment. The association between treatment received and outcome differed in these populations. In parent history-negative patients, reduced severity of substance use at 1 year was predicted solely by receiving methadone for a greater number of days. In parent history-positive patients, reduced severity of substance use was predicted by receiving methadone for fewer days, by greater satisfaction with and receipt of counseling services, and by lesser tendency for providers to encourage a reduction in methadone use. |
Do cervical cages placed bilaterally in the facet joints from a posterior approach significantly increase foraminal area? | Foraminal stenosis is a common cause of cervical radiculopathy. Posterior cervical cages can indirectly increase foraminal area and decompress the nerve root. The aim of this study was to assess the influence of bilateral posterior cervical cages on the surface area and shape of the neural foramen. Radiographic analysis was performed on 43 subjects enrolled in a prospective, multi-center study. CT scans were obtained at baseline and 6- and 12-months after cervical fusion using bilateral posterior cervical cages. The following measurements were performed on CT scan: foraminal area (A), theoretical area (TA), height (H), superior diagonal (DSI), inferior diagonal (DIS), and inferior diagonal without implant (DISI). Comparisons were performed using R-ANOVA with a significance of α < 0.05. Foraminal area, height, TA and DISI were significantly greater following placement of the implant. The mean (SD) A increased from 4.01 (1.09) mm(2) before surgery to 4.24 (1.00) mm(2) at 6 months, and 4.18 (1.05) mm(2) at 12 months after surgery (p < 0.0001). Foraminal height (H) increased from mean (SD) 9.20 (1.08) mm at baseline to 9.65 (1.06) mm and 9.55 (1.14) mm at 6- and 12-months post-operatively, respectively (p < 0.0001). The mean DIS did not change significantly. There was a significant decrease in DSI: 6.18 (1.59) mm pre-operatively, 5.95 (1.47) mm and 5.73 (1.46) mm at 6- and 12-months (p < 0.0001). | Immune activation contributes to the persistent state of inflammation associated with metabolic dysfunction in obesity. The specific immune receptors that sense metabolic stress signals and trigger inflammation are nevertheless largely unknown, and little is known on inflammatory and immune gene regulation in obesity. The study includes a cross-sectional and a longitudinal arm. Forty children and adolescents were enrolled: 22 obese subjects and 18 age-matched normal weight controls. Obese subjects participated in an 18-month therapeutic protocol, based on intensive lifestyle modification (dietary regimen, physical activity and behavioral interventions). Expression of genes involved in the inflammasome pathway, plasma concentration of the inflammasome-associated pro-inflammatory cytokines (interleukin (IL)-1β and IL-18) and indexes of microbial translocation (lipopolysaccharide (LPS), soluble CD14 (sCD14) and intestinal fatty acid-binding protein) were analyzed at baseline in obese subjects compared with controls, and after 18 months in obese subjects. Cross-sectional analyses showed that the LPS-induced expression of genes involved in inflammasome (NLRP3, caspase 5 and NAIP), Nod-like receptors (NLRX1 and NOD1), downstream signaling (P2RX7, RAGE, RIPk2, TIRAP and BIRC2) and effector molecules (IFN-γ, IL-12β, IL-1β, CCL2, CCL5, IL-6 and TNFα) was significantly increased in obese subjects at baseline as compared with normal weight controls. The baseline plasma concentration of inflammasome-related cytokines (IL-1β and IL-18) and of microbial translocation markers (LPS and sCD14) was augmented in obese subjects as compared with controls as well. Longitudinal analyses indicated that intensive lifestyle modification resulted in a normalization of parameters in subjects with a significant reduction of BMI after 18 months. |
Is self-reported sleep disturbance associated with Alzheimer 's disease risk in men? | To study the association between self-reported sleep disturbances and dementia risk. Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of β-amyloid (Aβ) peptides 1-40 and 1-42 were measured at ages 70, 77, and 82 years. Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P < .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P < .001). No group differences were found in Aβ levels. | The purpose of this article was to study the influence of the anastomosis angle on the flow fields at end-to-side anastomoses in vivo. Polyurethane grafts of similar internal diameter to that of the abdominal aorta (8 mm) were implanted from the suprarenal to the infrarenal level in 10 pigs. Three angles of standardized distal end-to-side anastomoses (90 degrees, 45 degrees, and 15 degrees) were studied. The anatomic position of the anastomoses was constant, the proximal outflow segment was occluded, and the flow rate through the graft was controlled. Flow visualization was accomplished by a color-flow Doppler ultrasound system. The angulation was reproduced within 10%. Gross hemodynamic parameters were stable, and the similarity parameters were typical for peripheral bypasses (mean Reynold's number is 424 and Womersley's parameter is 5.9). The flow fields were clearly dependent on the anastomosis angle. A zone of recirculation (approximately 5% of the flow area), extending from the toe to one diameter downstream, was found in the 45-degree and 90-degree anastomoses. No flow disturbances were detected at the toe and one diameter downstream with an anastomosis angle of 15 degrees. At the heel different recirculating flow patterns were found in the different anastomoses. |
Are concerns about covert HIV testing associated with delayed presentation of suspected malaria in Ethiopian children : a cross-sectional study? | Early diagnosis is important in preventing mortality from malaria. The hypothesis that guardians' fear of covert human immunodeficiency virus (HIV) testing delays presentation of children with suspected malaria was tested. The study design is a cross-sectional survey. The study population consisted of guardians of children with suspected malaria who presented to health centres in Oromia Region, Ethiopia. Data were collected on attitudes to HIV testing and the duration of children's symptoms using interview administered questionnaires. Some 830 individuals provided data representing a response rate of 99% of eligible participants. Of these, 423 (51%) guardians perceived that HIV testing was routinely done on blood donated for malaria diagnosis, and 353 (43%) were aware of community members who delayed seeking medical advice because of these concerns. Children whose guardians suspected that blood was covertly tested for HIV had longer median delay to presentation for evaluation at health centres compared to those children whose guardians did not hold this belief (three days compared to two days, p < 0.001). Children whose guardians were concerned about covert HIV testing were at a higher odds of a prolonged delay before being seen at a health centre (odds ratio 1.73, 95% confidence intervals: 1.10 to 270 for a delay of ≥ 3 days compared to those seen in ≤ 2 days). | Extracellular matrix (ECM) remodeling is predominantly mediated by fibroblasts using intracellular and extracellular pathways. Although it is well known that extracellular degradation of the ECM by proteases derived from cancer cells facilitates cellular invasion, the intracellular degradation of ECM components by cancer cells has not been clarified. The aim of this study was to characterize collagen internalization, which is the initial step of the intracellular degradation pathway in pancreatic cancer cells, in light of epithelial-mesenchymal transition (EMT). We analyzed the function of collagen internalization in two pancreatic cancer cell lines, SUIT-2 and KP-2, and pancreatic stellate cells (PSCs) using Oregon Green 488-gelatin. PSCs had a strong ability for collagen uptake, and the pancreatic cancer cells also internalized collagen although less efficiently. The collagen internalization abilities of SUIT-2 and KP-2 cells were promoted by EMT induced by human recombinant transforming growth factor β1 (P<0.05). Expression of Endo180, a collagen uptake receptor, was high in mesenchymal pancreatic cancer cell lines, as determined by EMT marker expression (P<0.01). Quantitative RT-PCR and western blot analyses showed that Endo180 expression was also increased by EMT induction in SUIT-2 and KP-2 cells. Endo180 knockdown by RNA interference attenuated the collagen uptake (P<0.01) and invasive abilities (P<0.05) of SUIT-2 and KP-2 cells. |
Is reflux esophagitis in humans mediated by oxygen-derived free radicals? | Oxidative stress in reflux esophagitis was investigated before and after antireflux surgery. Oxidative stress was studied in the distal and proximal esophagus of control patients (without esophagitis, but with other gastrointestinal disorders), of patients with various grades of esophagitis (including Barrett's esophagus), and in patients who had a Nissen fundoplication. Oxidative stress was assessed by chemiluminescence, lipid peroxidation (LP), and by measuring superoxide dismutase (SOD). Chemiluminescence and LP increased with the degree of esophagitis and was highest in patients with Barrett's esophagus; SOD decreased with damage, except in cases of Barrett's esophagus associated with mild esophagitis. Chemiluminescence and LP in reflux patients were higher in the distal than in the proximal esophagus, and SOD was lower, whereas no such difference was found in controls. Findings after Nissen fundoplication were similar to those of controls. | To determine whether increased sequence variation occurs in regions of endogenous HIV-1 targeted by HIV-1-specific CD4 T cells. The presence of increased variation would be suggestive of immune evasion by HIV-1. We performed a cross-sectional study of untreated HIV-1-infected subjects measuring HIV-1-specific interferon (IFN)-gamma-secreting CD4 T-cell responses against epitopes in Gag p17 and p24 and concurrent endogenous plasma HIV-1 RNA epitope sequence variation. CD8- depleted IFNgamma enzyme-linked immunospot assays were used to identify regions of HIV-1 Gag recognized by CD4 T cells. Reverse transcriptase polymerase chain reaction and TA cloning were used to sequence endogenous plasma HIV-1 virus and identify variants. CD4 T-cell epitopes in Gag p17 and p24 were identified in 5 individuals, and concurrent sequence information on endogenous HIV-1 was obtained in 4 of these individuals. Endogenous plasma HIV-1 RNA sequencing revealed no intrapatient amino acid sequence variation through identified epitopes. |
Is human degenerative valve disease associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation? | The goal of this research was to define the cellular mechanisms involved in myxomatous mitral valve disease and calcific aortic valve disease and to redefine the term degenerative valve disease in terms of an active cellular biology. "Degenerative" valvular heart disease is the primary cause of regurgitant and stenotic valvular lesion in the U.S. However, the signaling pathways are not known. We hypothesize that valve degeneration occurs due to an osteoblastic differentiation process mediated by the low-density lipoprotein receptor-related protein 5 (Lrp5) signaling pathway to cause valve thickening. We examined human diseased valves: myxomatous mitral valves (n = 23), calcified tricuspid aortic valves (n = 27), calcified bicuspid aortic valves (n = 23), and control tissue from mitral and aortic valves (n = 40). The valves were examined by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry for signaling markers important in osteoblast differentiation: Sox9 and Cbfa1 (transcription factors for osteoblast differentiation); Lrp5 and Wnt3 (osteoblast differentiation signaling marker), osteopontin and osteocalcin (osteoblast endochrondral bone matrix proteins), and proliferating cell nuclear antigen (a marker of cell proliferation). Cartilage development and bone formation was measured by Alcian blue stain and Alizarin red stain. Computed Scano MicroCT-40 (Bassersdorf, Switzerland) analysis measured calcium burden. Low-density lipoprotein receptor-related protein 5, osteocalcin, and other osteochrondrogenic differentiation markers were increased in the calcified aortic valves by protein and gene expression (p > 0.001). Sox9, Lrp5 receptor, and osteocalcin were increased in myxomatous mitral valves by protein and gene expression (p > 0.001). MicroCT was positive in the calcified aortic valves and negative in the myxomatous mitral valves. | Inflammatory mediators released by nonparenchymal inflammatory cells in the liver have been implicated in the progression of acetaminophen (APAP) hepatotoxicity. Among hepatic nonparenchymal inflammatory cells, we examined the role of the abundant natural killer (NK) cells and NK cells with T-cell receptors (NKT cells) in APAP-induced liver injury. C57BL/6 mice were administered a toxic dose of APAP intraperitoneally to cause liver injury with or without depletion of NK and NKT cells by anti-NK1.1 monoclonal antibody (MAb). Serum alanine transaminase (ALT) levels, liver histology, hepatic leukocyte accumulation, and cytokine/chemokine expression were assessed. Compared with APAP-treated control mice, depletion of both NK and NKT cells by anti-NK1.1 significantly protected mice from APAP-induced liver injury, as evidenced by decreased serum ALT level, improved survival of mice, decreased hepatic necrosis, inhibition of messenger RNA (mRNA) expression for interferon-gamma (IFN-gamma), Fas ligand (FasL), and chemokines including KC (Keratinocyte-derived chemokine); MIP-1 alpha (macrophage inflammatory protein-1 alpha); MCP-1 (monocyte chemoattractant protein-1); IP-10 (interferon-inducible protein); Mig (monokine induced by IFN-gamma) and decreased neutrophil accumulation in the liver. Hepatic NK and NKT cells were identified as the major source of IFN-gamma by intracellular cytokine staining. APAP induced much less liver injury in Fas-deficient (lpr) and FasL-deficient (gld) mice compared with that in wild-type mice. |
Does sIRT6 Overexpression potentiate Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein-Dependent Apoptotic Pathway? | To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC). The expression of SIRT6 in 60 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry. The expression of SIRT6 in 101 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by Western blotting analysis and qPCR. The biologic consequences of overexpression and knockdown of SIRT6 in HCC cell lines were studied in vitro and in vivo SIRT6 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with tumor grade (P = 0.02), tumor size (P = 0.02), vascular invasion (P = 0.004), and shorter survival (P = 0.024). Depletion of SIRT6 from multiple liver cancer cell lines inhibited their growth and induced apoptosis in vitro At the molecular level, we observed that the activation of the BCL2-associated X protein (Bax) signaling pathway, a major pathway that determines cancer cell apoptosis, is regulated by SIRT6 via its deacetylase activity. SIRT6 was recruited to the promoter of Bax, where it deacetylated histone 3 lysine 9 and suppressed its promoter activity. Binding of transcription factors (p53 and E2F-1) to Bax promoter was also generally increased in SIRT6-depleted cells. In mouse xenografts, SIRT6 suppression inhibited tumor growth and induced apoptosis. Finally, there is a negative correlation between SIRT6 and Bax mRNA expressions in human HCC samples. | Cerebral pressure passivity is common in sick premature infants and may predispose to germinal matrix/intraventricular hemorrhage (GM/IVH), a lesion with potentially serious consequences. We studied the association between the magnitude of cerebral pressure passivity and GM/IVH. We enrolled infants <32 weeks' gestational age with indwelling mean arterial pressure (MAP) monitoring and excluded infants with known congenital syndromes or antenatal brain injury. We recorded continuous MAP and cerebral near-infrared spectroscopy hemoglobin difference (HbD) signals at 2 Hz for up to 12 hours/day and up to 5 days. Coherence and transfer function analysis between MAP and HbD signals was performed in 3 frequency bands (0.05-0.25, 0.25-0.5, and 0.5-1.0 Hz). Using MAP-HbD gain and clinical variables (including chorioamnionitis, Apgar scores, gestational age, birth weight, neonatal sepsis, and Score for Neonatal Acute Physiology II), we built a logistic regression model that best predicts cranial ultrasound abnormalities. In 88 infants (median gestational age: 26 weeks [range 23-30 weeks]), early cranial ultrasound showed GM/IVH in 31 (37%) and parenchymal echodensities in 10 (12%) infants; late cranial ultrasound showed parenchymal abnormalities in 19 (30%) infants. Low-frequency MAP-HbD gain (highest quartile mean) was significantly associated with early GM/IVH but not other ultrasound findings. The most parsimonious model associated with early GM/IVH included only gestational age and MAP-HbD gain. |
Does weight loss induced by bariatric surgery restore adipose tissue PNPLA3 expression? | Obesity and its related co-morbidities such as non-alcoholic fatty liver disease (NAFLD) are increasing dramatically worldwide. The genetic variation in Patatin-like phospholipase domain-containing protein 3 (PNPLA3), which is also called adiponutrin (ADPN), in residue 148 (I148M, rs738409) has been associated with NAFLD. However, the regulation and function of PNPLA3 in metabolic diseases remains unclear. Laparoscopic gastric banding (LAGB) of severely obese patients reduces body weight, liver and adipose tissue inflammation. In this study, we investigated whether weight loss induced by LAGB affected PNPLA3 expression in hepatic and adipose tissue. Liver and subcutaneous adipose tissue samples were collected from 28 severely obese patients before and 6 months after LAGB. PNPLA3 expression was assessed by quantitative real-time PCR. To understand whether inflammatory stimuli regulated PNPLA3 expression, we studied the effect of tumour necrosis factor alpha (TNFα) and lipopolysaccharide (LPS) on PNPLA3 expression in human adipocytes and hepatocytes. PNPLA3 was strongly expressed in the liver and clearly detectable in subcutaneous adipose tissue of obese patients. Weight loss induced by LAGB of severely obese patients led to significantly increased adipose, but not hepatic, tissue expression of PNPLA3. Subcutaneous PNPLA3 expression negatively correlated with body-mass-index, fasting glucose and fasting insulin. TNFα potently suppressed PNPLA3 expression in adipocytes but not hepatocytes. | High rates of 23S rDNA mutations implicated in macrolide resistance have been identified in Treponema pallidum samples from syphilis patients in many countries. Nonetheless, some clinicians have been reluctant to abandon azithromycin as a treatment for syphilis, citing the lack of a causal association between these mutations and clinical evidence of drug resistance. Although azithromycin resistance has been demonstrated in vivo for the historical Street 14 strain, no recent T. pallidum isolates have been tested. We used the well-established rabbit model of syphilis to determine the in vivo efficacy of azithromycin against 23S rDNA mutant strains collected in 2004 to 2005 from patients with syphilis in Seattle, Wash. Groups of 9 rabbits were each infected with a strain containing 23S rDNA mutation A2058G (strains UW074B, UW189B, UW391B) or A2059G (strains UW228B, UW254B, and UW330B), or with 1 wild type strain (Chicago, Bal 3, and Mexico A). After documentation of infection, 3 animals per strain were treated with azithromycin, 3 were treated with benzathine penicillin G, and 3 served as untreated control groups. Treatment efficacy was documented by darkfield microscopic evidence of T. pallidum, serological response, and rabbit infectivity test. Azithromycin uniformly failed to cure rabbits infected with strains harboring either 23S rDNA mutation, although benzathine penicillin G was effective. Infections caused by wild type strains were successfully treated by either azithromycin or benzathine penicillin G. |
Does surfactant pretreatment decrease long-term damage after ischemia-reperfusion injury of the lung? | Lung ischemia-reperfusion injury (LIRI) is a risk factor for primary acute graft failure following lung transplantation. LIRI hereby contributes to morbidity and mortality after lung transplantation. We have previously shown that surfactant pretreatment ameliorates LIRI up to 1 week after reperfusion. However, the impact of surfactant pretreatment on long-term outcome following LIRI is unknown. Therefore, the objective of this study was to investigate the effect of surfactant pretreatment on long-term outcome following LIRI. Male Sprague-Dawley rats (n=63) were randomized to receive intratracheally administered porcine surfactant (400mg/kg) or no pretreatment. One hour thereafter, animals underwent 120min of warm ischemia by clamping the bronchus, pulmonary artery and vein of the left lung. A third group was sham-operated; a fourth group served as unoperated controls. Animals were killed on day 30 or 90 after surgery. Arterial oxygenation and lung compliance were determined. Broncho-alveolar lavage fluid (BALf) was collected to assess surfactant function and alveolar protein. Leukocyte infiltration was determined by flowcytometry in BALf, lung tissue and thoracic lymph nodes. Lungs of three animals per group were used for histological assessment. Lung compliance was lower on day 30 and day 90 after LIRI than in sham-operated controls (day 30 V(max) 6.1+/-2.1 vs 12.6+/-1.3, day 90 6.9+/-3.0 vs 12.1+/-1.6; C(max) day 30 0.49+/-0.17 vs 1.08+/-0.21, day 90 0.67+/-0.31 vs 1.11+/-0.17). Furthermore, the number of CD45RA(+)-lymphocytes in left lung tissue was decreased on day 90 compared to unoperated animals (230.633+/-96.770 vs 696.347+/-202.909) and the number of macrophages elevated in left BALf on day 90. HE slides of LIRI animals were scored as fibroproliferative with moderate atelectasis. Surfactant pretreatment improved lung compliance (V(max) day 30 11.7+/-1.8, day 90 11.1+/-1.2; C(max) day 30 1.04+/-0.23, day 90 1.16+/-0.21) and normalized the number of CD45RA(+)-lymphocytes (769.555+/-421.016) in left lung tissue. Furthermore lung architecture on HE slides was on return to normal. However, more CD5(+)CD4(+)-lymphocytes on day 30 (754.788+/-97.269 vs 430.409+/-109.909) and more macrophages on day 90 (2.144.000+/-630.633 vs 867.454+/-383.220) were measured in pretreated lung tissue compared to LIRI animals. | Heart type fatty acid binding protein (H-FABP) is a small protein and released into the circulation when myocardial damage has occurred. Previous studies have demonstrated that H-FABP is closely associated with cardiac and some endocrinologic disorders including prediabetes, metabolic syndrome, and acromegaly. Hyperthyroism is a well-known disorder associated with cardiovascular diseases. We aimed to investigate the effect of hyperthyrodism on H-FABP levels. Forty six patients with hyperthyroidism with no known history of coronary artery disease and 40 healthy controls are involved in the study. Serum H-FABP levels are measured using sandwich enzyme-linked immunosorbent assay. There was no significant difference between serum H-FABP levels of patients with hyperthyroidism and controls (871±66 pg/mL, and 816±66 pg/mL, respectively P=0.56). There was no significant correlation between H-FABP, free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels in patients and controls. |
Is heavy snoring a risk factor for case fatality and poor short-term prognosis after a first acute myocardial infarction? | Sleep disordered breathing has been associated with an increased risk for developing coronary heart disease. Data on the effects of sleep disordered breathing on case fatality and prognosis of a myocardial infarction are sparse. The present study aimed to investigate a possible relationship of snoring and case fatality and mortality after an acute myocardial infarction. DESIGN, SETTINGS, PATIENTS, AND MEASUREMENTS: In this study, we enrolled 1660 first acute myocardial infarction cases and examined the effects of self- or relative-reported heavy snoring on case fatality and prognosis. The average follow-up time was 8 years, SD = 262 days. There was a variation in the association between snoring and mortality with time, with a strong association in the first 28 days after infarction but not later during the follow-up. Occasional and regular heavy snorers, when compared to those never having heavy snoring, had a 2.04 (95% confidence interval, 1.50 to 2.79) and 3.30 (95% confidence interval, 2.37 to 4.58) hazard ratio for mortality within the first 28 days after controlling for age, gender, obesity, history of diabetes and hypertension, physical activity, smoking, and education, respectively. There was no association between snoring and new myocardial infarction, stroke, or hospitalization for heart failure during the follow-up. | Intracellular targets sensitive to oxidized damage generated by photodynamic therapy (PDT) utilizing N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-mesochlorin e6 monoethylenediamine (Mce6) conjugates was explored to aid in the design of second generation PDT delivery systems. Low temperature, metabolic inhibitor, and nuclear localization sequences (NLS(FITC)) were used to achieve desired subcellular localization that was evaluated by confocal analysis and subcellular fractionation. Mce6 was bound to HPMA copolymer conjugates via non-degradable dipeptide linkers (P-GG-Mce6, P-NLS(FITC)-GG-Mce6) or lysosomally degradable tetrapeptide spacers (P-GFLG-Mce6, P-NLS(FITC)-GFLG-Mce6). Chemotherapeutic efficacy was assessed by the concentration that inhibited growth by 50% (IC50), cell associated drug concentration (CAD) and confocal microscopy. P-GFLG-Mce6 possessed enhanced chemotherapeutic activ ity compared to P-GG-Mce6 indicating enzymatically released Mce6 was more active than copolymer-bound Mce6. Lysosomes appeared less sensitive to photodamage as observed by a higher IC50. Nuclear-directed HPMA copolymer-Mce6 conjugates (P-NLS(FITC)-GG-Mce6, P-NLS(FITC)-GFLG-Mce6) possessed enhanced chemotherapeutic activity. However, control cationic HPMA copolymer-Mce6 conjugates containing a scrambled NLS (P-scNLS(FITC)-GG-Mce6) or amino groups (P-NH2-GG-Mce6) also displayed increased chemotherapeutic activity. |
Do [ Insulin-like growth factor-II and basic fibroblast growth factor affect periodontal ligament cells expressing osteoprotegerin in vitro ]? | This study was carried out to investigate the effects of insulin-like growth factor-II (IGF-II) and basic fibroblast growth factor (bFGF) on osteoprotegerin (OPG) secretion of periodontal ligament cells (PDLCs). Healthy human premolars extracted for orthodontic reasons from 12-14 years old donators were obtained, and periodontal tissues were collected and cultured to obtain PDL cells. Primary or first passage PDLCs were cloned by means of limited dilutions. PDLCs with osteoblastic phenotypes were characterized as follows: Alkaline phosphatase activity, collagen III production and bone-like nodules formation. IGF-II and bFGF were added into culture media and their effects on PDLCs proliferation and OPG secretion were observed. The OPG concentrations in cell culture supernatants were detected by sandwich ELISA. Living cell numbers were demonstrated by MTT test. The average levels of OPG secretion by a single cell were calculated by dividing OPG concentration with MTT-test result. Both IGF-II and bFGF upregulated the mtt values (P < 0.05), but ICF-II downregulated the opg/mtt values (P < 0.05), whereas bFGF had no significant effect on opg/mtt values (P > 0.05). | We investigated whether aprepitant, a neurokinin-1 antagonist, could decrease chemotherapy-induced nausea and vomiting (CINV) following cisplatin, when a conventional anti-emetic regimen had failed. This was a prospective study (April 2011-April 2012) of patients with lung cancer, treated with cisplatin at the Beijing Cancer Hospital, and initially receiving granisetron, dexamethasone, and metoclopramide as anti-emetics. If patients experienced vomiting of grade ≥2 and required rescue anti-emetic medications during the first cycle, oral aprepitant was added in subsequent cycles (day 1: 125 mg; days 2-3: 80 mg once daily). Acute (day 1) and delayed (days 2-5) nausea and vomiting, use of rescue medications, and occurrence of adverse reactions were monitored after the start of chemotherapy. Twenty-five of 132 patients (18.9 %) were administered aprepitant for secondary prophylaxis against emesis during the second cycle of chemotherapy. The incidences of acute and delayed nausea were 52 and 100 % in the first cycle, but 8 and 72 % in the second cycle. The incidences of acute and delayed vomiting were 20 and 100 % in the first cycle, but 0 and 36 % in the second cycle. No patients required rescue medications or intravenous rehydration during the second cycle. Aprepitant was not associated with additional adverse events. |
Does family accommodation mediate the association between anxiety symptoms in mothers and children? | The link between child anxiety and maternal anxiety has been well established but the factors underlying this association are not well understood. One potential factor is family accommodation, which describes ways in which parents change their behaviour to help a child avoid or alleviate anxiety. Family accommodation has been associated with greater symptom severity, more impairment and poorer treatment outcomes in the child. The aim of this study was to investigate whether maternal accommodation mediates the relation between parent and child anxiety. Mothers of children (N = 85) aged 7-17 years (M = 11.79) completed measures of their own anxiety (State-Trait Anxiety Inventory (STAI)), their child's anxiety (Screen for Child Anxiety Related Disorders (SCARED)), and family accommodation (Family Accommodation Scale Anxiety (FASA)). Structural equation modelling (SEM) was used to test the mediational role of accommodation linking parent and child anxiety. Family accommodation was found to significantly mediate the link between maternal anxiety and child anxiety. | Insulin resistance is correlated with the progress of albuminuria in diabetic patients, and podocytes are crucial for maintaining the normal function of the glomerular filtration barrier. In the present study, we aimed to investigate the high glucose-induced insulin resistance and cell injury in human podocytes and the putative role of autophagy in this process. Human podocytes were cultured in high glucose-supplemented medium and low glucose and high osmotic conditions were used for the controls. Autophagy in the podocytes was regulated using rapamycin or 3-methyladenine stimulation. Next, autophagy markers including LC3B, Beclin-1, and p62 were investigated using western blot and qPCR, and the insulin responsiveness was analyzed based on glucose uptake and by using the phosphorylation of the insulin receptor with Nephrin as a podocyte injury marker. The basal autophagy level decreased under the high glucose conditions, which was accompanied by a decrease in the glucose uptake and phosphorylation of the insulin receptor in the human podocytes. More interestingly, the glucose uptake and the phosphorylation of the insulin receptor were decreased by 3-MA stimulation and increased by rapamycin, illustrating that the responsiveness of insulin was regulated by autophagy. The activation of autophagy by rapamycin also ameliorated cell injury in the human podocytes. |
Is dipM required for peptidoglycan hydrolysis during chloroplast division? | Chloroplasts have evolved from a cyanobacterial endosymbiont and their continuity has been maintained over time by chloroplast division, a process which is performed by the constriction of a ring-like division complex at the division site. The division complex has retained certain components of the cyanobacterial division complex, which function inside the chloroplast. It also contains components developed by the host cell, which function outside of the chloroplast and are believed to generate constrictive force from the cytosolic side, at least in red algae and Viridiplantae. In contrast to the chloroplasts in these lineages, those in glaucophyte algae possess a peptidoglycan layer between the two envelope membranes, as do cyanobacteria. In this study, we show that chloroplast division in the glaucophyte C. paradoxa does not involve any known chloroplast division proteins of the host eukaryotic origin, but rather, peptidoglycan spitting and probably the outer envelope division process rely on peptidoglycan hydrolyzing activity at the division site by the DipM protein, as in cyanobacterial cell division. In addition, we found that DipM is required for normal chloroplast division in the moss Physcomitrella patens. | Implantable cardioverter-defibrillator (ICD) implantation is contraindicated in those with <1-year life expectancy. The aim of this study was to develop a risk prediction score for 1-year mortality in patients with primary prevention ICDs and to determine the incremental improvement in discrimination when serum-based biomarkers are added to traditional clinical variables. We analyzed data from the Prospective Observational Study of Implantable Cardioverter-Defibrillators, a large prospective observational study of patients undergoing primary prevention ICD implantation who were extensively phenotyped for clinical and serum-based biomarkers. We identified variables predicting 1-year mortality and synthesized them into a comprehensive risk scoring construct using backward selection. Of 1189 patients deemed by their treating physicians as having a reasonable 1-year life expectancy, 62 (5.2%) patients died within 1 year of ICD implantation. The risk score, composed of 6 clinical factors (age ≥75 years, New York Heart Association class III/IV, atrial fibrillation, estimated glomerular filtration rate <30 mL/min/1.73 m(2), diabetes, and use of diuretics), had good discrimination (area under the curve 0.77) for 1-year mortality. Addition of 3 biomarkers (tumor necrosis factor α receptor II, pro-brain natriuretic peptide, and cardiac troponin T) further improved model discrimination to 0.82. Patients with 0-1, 2-3, 4-6, or 7-9 risk factors had 1-year mortality rates of 0.8%, 2.7%, 16.1%, and 46.2%, respectively. |
Is volumetric breast density essential for predicting cosmetic outcome at the late stage after breast-conserving surgery? | The critical issue related to breast-conserving therapy (BCT) is that cosmetic outcomes deteriorate with long-term follow-up. There is little research for breast density as a predictor of cosmetic outcomes at the late stage after BCT. To improve the long-term quality of life after BCT of breast cancer patients, the correlation of volumetric breast density (VBD) and cosmetic outcome at the late stage after BCT was evaluated. Breast volume, fibroglandular tissue volume, adipose tissue volume, and VBD were calculated on mammography using image analysis software (Volpara(®)) in 151 patients with BCT. Furthermore, the correlation of breast density and the change of breast volume over time was analyzed on mammography in 99 patients who were followed-up long-term after BCT. On multivariate analysis, VBD was a predictor of cosmetic outcome after BCT with percent breast volume excised (PBVE). Decreased adipose tissue volume and increased fibrosis were more common in patients with VBD < 15%. Furthermore, remnant breast volume continued to decrease over time in low breast density patients during long-term follow-up. 93% of patients with VBD ≥ 15% and PBVE < 10% had a better cosmetic outcome, while 60% of patients with VBD < 15% and PBVE ≥ 10% had a worse cosmetic outcome after BCT. | Enteroendocrine cells, the largest and most diverse population of mammalian endocrine cells, comprise a number of different cell types in the gut mucosa that produce, store, and secrete small molecules, peptides, and/or larger proteins that regulate many aspects of gut physiology. Little is known about less typical endocrine cells in the intestinal mucosa that do not contain secretory granules, such as brush or caveolated cells. We studied a subset of these enteroendocrine cells in duodenum that produce several peptides, including endogenous opioids, and that also express the Trpm5 cation channel. We studied expression patterns of Trpm5 and other molecules by immunohistochemical and enzyme-linked immunosorbent assay analyses of intestinal tissues from transgenic mice that express green fluorescent protein from the Trpm5 promoter, as well as wild-type and Trpm5-null mice. We describe a type of enteroendocrine cell in mouse duodenum that is defined by the presence of Trpm5 and that does not contain typical secretory granules yet expresses endogenous opioids (beta-endorphin and Met-enkephalin) and uroguanylin in apical compartments close to the lumen of the gut. |
Do isoflurane and desflurane impair right ventricular-pulmonary arterial coupling in dogs? | Halogenated anesthetics depress left ventricular function, but their effects on the right ventricle have been less well studied. Therefore, the authors studied the effects of isoflurane and desflurane on pulmonary arterial (PA) and right ventricular (RV) properties at baseline and in hypoxia. Right ventricular and PA pressures were measured by micromanometer catheters, and PA flow was measured by an ultrasonic flow probe. PA mechanics were assessed by flow-pressure relations and by impedance spectra derived from flow and pressure waves. RV contractility was assessed by end-systolic elastance (Ees), RV afterload was assessed by effective PA elastance (Ea), and RV-PA coupling efficiency was assessed by the Ees:Ea ratio. Anesthetized dogs were randomly assigned to increasing concentrations (0.5, 1, and 1.5 times the minimum alveolar concentration) of isoflurane (n = 7) or desflurane (n = 7) in hyperoxia (fraction of inspired oxygen, 0.4) and hypoxia (fraction of inspired oxygen, 0.1). Isoflurane and desflurane had similar effects. During hyperoxia, both anesthetics increased PA resistance and characteristic impedance, increased Ea (isoflurane, from 0.82 to 1.44 mmHg/ml; desflurane, from 0.86 to 1.47 mmHg/ml), decreased Ees (isoflurane, from 1.09 to 0.66 mmHg/ml; desflurane, from 1.10 to 0.72 mmHg/ml), and decreased Ees:Ea (isoflurane, from 1.48 to 0.52; desflurane, from 1.52 to 0.54) in a dose-dependent manner (all P < 0.05). Hypoxia increased PA resistance, did not affect characteristic impedance, increased afterload, and increased contractility. During hypoxia, isoflurane and desflurane had similar ventricular effects as during hyperoxia. | We sought to evaluate the link between long-term tea intake and prevalence of type 2 diabetes mellitus, in a sample of elderly adults. During 2005-2007, 300 men and women from Cyprus, 142 from Mitilini, 100 from Samothraki, 114 from Kefalonia, 131 from Crete, 150 from Corfu and 103 from Zakynthos (aged 65 to 100 years) were enrolled. Dietary habits (including tea consumption) were assessed through a food frequency questionnaire. Among various factors, fasting blood glucose was measured and prevalence of (type 2) diabetes mellitus was estimated. 54% of the participants reported that they consume tea at least once a week (mean intake 1.6 +/- 1.1 cup/day). The majority of the participants (98%) reported green or black tea consumption. The participants reported that they consume tea for at least 30 years of their life. After adjusting for various confounders, tea intake was inversely associated with lower blood glucose levels (b +/- SEM per 1 cup: - 5.9 +/- 2.6 mg/dL, p = 0.02). Moreover, multiple logistic regression revealed that moderate tea consumption (1 - 2 cups/day) was associated with 70% (95% CI 41% to 86%) lower odds of having (type 2) diabetes, irrespective of age, sex, body mass, smoking, physical activity status, dietary habits and other clinical characteristics. |
Do [ A new application of MR tomography of the lung using ultra-short turbo spin echo sequences ]? | Development of an improved MR sequence for examining the lung. T2 weighted ultra-short turbo spin echo sequences were used in five individuals with variations in echo times, delayed triggering and echo intervals. To reduce movement artifacts all examinations were carried out with ECG and respiratory triggering. The sequences giving optimal image quality were then employed in 19 patients having various pulmonary abnormalities. Image resolutions, artifacts, image contrasts and diagnostic value were then judged by two observers and compared with CT. In the first study, a diastole-triggered UTSE sequence with the shortest echo proved optimal (TE = 90 ms, TR = 2-4 s, echo = 9 ms, turbo factor = 19). In the patient series studied, MRT was inferior to CT with regard to resolution and number of artifacts, but better in respect of contrast and diagnostic value. | Recently novel type 2 diabetes risk loci were identified and reported to associate with beta-cell dysfunction. We assessed whether the risk alleles in TCF7L2, CDKAL1, HHEX, SLC30A8, IGF2BP2, CDKN2A/2B, JAZF1, and WFS1 reduce insulin secretion in an additive manner and whether their impact is influenced by insulin sensitivity. We genotyped 1397 nondiabetic subjects for the aforementioned risk alleles and performed risk allele summation. Participants underwent an oral glucose tolerance test and in a subgroup also an iv glucose tolerance test with C-peptide and insulin measurements. In our cohort, only polymorphisms in SLC30A8, HHEX, TCF7L2, and CDKAL1 influenced insulin secretion. So we tested only these polymorphisms and, in a separate analysis, all above-mentioned polymorphisms. We observed a 28% decline in insulin secretion with increment of risk alleles (P <or= 0.0018). Subjects with two to four risk alleles displayed a progressive decline in ss-cell function, which was not further enhanced in carriers of five to seven alleles. After stratification for insulin sensitivity, subjects with low insulin sensitivity revealed a significant decline in insulin secretion with increment of risk alleles (P = 0.0086), whereas this was not seen in subjects with high insulin sensitivity (P = 0.07). The additional study with eight risk alleles provided similar results. |
Is high salt intake associated with a higher risk of cardiovascular events : a 7.2-year evaluation of a cohort of hypertensive patients? | It is controversial whether high salt intake is directly associated with cardiovascular (CV) events and how far this relation is independent of blood pressure (BP). As Portugal has higher salt consumption and higher mortality by stroke than other European countries, we examined whether salt intake could predict the development of stroke and CV events in a hypertensive population. In a longitudinal retrospective study of a cohort of 608 adult treated hypertensive patients 54.1±14.3 years of age, BMI 29.3±8.3 kg/m, 56.3% women and 17.1% diabetics, we evaluate the long-term prognostic significance of urinary sodium (UNa) excretion measured in 24 h valid samples within the first 3 months after admission along with 24 h ambulatory blood pressure monitoring and pulse wave velocity [(PWV), complior)] measurements. The mean follow-up duration was 7.2 years (0.5-11.1 years), during which 122 CV events occurred including 80 strokes and 36 coronary events. In 608 patients (group A=507 without events and group B=101 with events: 69 strokes, 26 coronary events, six others), the mean 24 h UNa was 208±79 mmol/day, corresponding to a salt intake of 12.1±4.6 g/day. Twenty-four hours UNa correlated positively with BMI, PWV and systolic blood pressure (SBP) particularly with night-time SBP. Group B versus A showed higher UNa (260+98 vs. 198+71 mmol/day, P<0.001) and higher PWV, BP office, 24 h, daytime and night-time SBP. Logistic regression analysis identified age, night-time SBP and 24 h UNa+ [HR=1.09 (95% CI, 1.06-1.12, P<0.001)] for each 10 mmol increase of UNa+ as the only independent predictors of CV events. UNa+ above the median (189 mmol sodium/day) predicted CV events with HR=2.99 (95% CI, 1.75-5.13, P<0.001) with worse CV event-free survival rates (log rank statistics of 17.44, P<0.001). | Fluorescence in situ hybridization (FISH) analysis has shown that human embryos display a high level of chromosomal mosaicism at all preimplantation stages. The aim of this study was to investigate the mechanisms involved by the use of two probes for each of three autosomes at different loci and to determine the true level of aneuploid mosaicism by excluding FISH artefacts. Embryos were cultured in two different types of medium: group I were cultured in standard cleavage medium for up to day 5 and group II were cultured from day 3 to day 5 in blastocyst medium. Three rounds of FISH were performed. In round 1, the probes used were 1pTel, 11qTel and 18CEP; in round 2, the probes used were 1satII/III, 11CEP and 18qTel; in round 3, the probes used were 18CEP, XCEP and YCEP. A total of 21 embryos were analysed in each group. The FISH results revealed one uniformly diploid and 20 mosaic embryos for group I, and two uniformly diploid and 19 mosaic embryos for group II. The predominant type of mosaicism was diploid/aneuploid. The use of two different probes per autosome was able to distinguish FISH artefacts affecting 5% of nuclei from true single cell anomalies. |
Do prostaglandin FP agonists alter metalloproteinase gene expression in sclera? | The present study was undertaken to determine whether exposure of the sclera to prostaglandin (PG)F(2alpha) or to the PGF(2alpha) analogue latanoprost acid alters mRNA for matrix metalloproteinases. Fifteen human eye bank eyes were studied. Circular pieces of sclera were either immediately preserved in a stabilization reagent or cultured in low-serum DMEM/F-12 medium. The cultures were treated for 24 hours with medium supplemented with PGF(2a), latanoprost acid, or vehicle. Total RNA was then isolated, and the expression of mRNA for matrix metalloproteinase (MMP)-1, -2, -3, -8, -9, -10, and -12 were determined by real-time PCR. All results were normalized according to the GAPDH mRNA in each sample. Altered mRNA expression after PG treatments also was evaluated with microarrays containing 19 MMP genes and 4 tissue inhibitor of matrix metalloproteinase (TIMP) genes. Real-time PCR results showed that 24 hours of exposure to 100 nM PGF(2alpha) significantly increased mRNA for MMP-1 and -9 (P < 0.06 Wilcoxon test) and that exposure to 100 nM latanoprost acid significantly increased mRNA for MMP-9 (P < 0.06 Wilcoxon test). Array analysis demonstrated increases of MMP-3 and -10 mRNA after exposure to 100 nM latanoprost and further increases after exposure to 200 nM latanoprost. The array results also showed that latanoprost induced dose-dependent increases in the expression of TIMP-1, -2, and -3 mRNA in the scleral cultures. | While the association between cigarette smoking and abdominal fat has been well studied in normal and overweight patients, data regarding the influence of tobacco use in patients with morbid obesity remain scarce. The aim of this study is to evaluate body fat distribution in morbidly obese smokers. We employed a cross-sectional study and grouped severely obese patients (body mass index [BMI] >40 kg/m2 or >35 kg/m2 with comorbidities) according to their smoking habits (smokers or non-smokers). We next compared the anthropometrical measurements and body composition data (measured by electric bioimpedance) of both groups. We analyzed the effect of smoking on body composition variables using univariate and multiple linear regression (MLR); differences are presented as regression coefficients (b) and their respective 95% confidence intervals. We included 536 morbidly obese individuals, 453 (84.5%) non-smokers and 83 (15.5%) smokers. Male smokers had a higher BMI (b=3.28 kg/m2, p=0.036), larger waist circumference (b=6.07 cm, p=0.041) and higher percentage of body fat (b=2.33%, p=0.050) than non-smokers. These differences remained significant even after controlling for confounding factors. For females, the only significant finding in MLR was a greater muscle mass among smokers (b=1.34kg, p=0.028). No associations were found between tobacco load measured in pack-years and anthropometric measures or body composition. |
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