Statins and risk of treated incident diabetes in a primary care population.
(i) To examine the incidence of new onset treated diabetes in patients treated with different types of statins and (ii) the relationship between the duration and dose of statins and the subsequent development of new onset treated diabetes. A retrospective cohort study was performed using the Irish Health Services Executive Primary Care Reimbursement Services national pharmacy claims database. Individuals who received any medicines were identified from January 2001 to January 2009 (n = 1 235 671). Patients newly treated with statins from 1 January 2002 to 31 December 2007 were identified (n = 239 628). Cases were identified as individuals newly treated with antidiabetic medication (n = 38 503). Adjusted hazards ratios (HR) with 95% confidence intervals (CI) were calculated to examine the association between statins (any vs. none) and time to new onset treated diabetes using Cox proportional hazard regression. The dose and duration response relationship between statins and new onset treated diabetes was examined using restricted spline functions to assess the linearity of the relationship. Statin use was associated with an increased risk of new onset treated diabetes (HR = 1.18, 95% CI 1.15, 1.22). Increased risk of new onset treated diabetes was found with rosuvastatin (HR = 1.41, 95% CI 1.31, 1.52), atorvastatin (HR = 1.23, 95% CI 1.19, 1.27) and simvastatin (HR = 1.15, 95% CI 1.05, 1.25). There were statistically significant overall dose and duration effects for all statins, excepting fluvastatin, which only demonstrated a duration effect. An increased risk of new onset treated diabetes was found in those treated with statins showing significant duration and dose effect. Further study is required to confirm this association.


What is the quality of the reporting of research ethics in publications of nursing home research?
To assess the quality of reporting of research ethics in published clinical research that involves a particularly vulnerable population: nursing home residents. A structured review of publications researched from 1992 to 1996 that involve nursing home residents. The review instrument assessed each publication's compliance with four common standards for research that involves nursing home residents or the cognitively impaired: justification of the use of nursing home residents, Institutional Review Board (IRB) review, nursing home committee review, and informed consent. For each publication, these results were summed into a quality score. The research ethics requirements contained in the journals' instructions for authors that corresponded with each publication were categorized in order to compare whether an association exists between the average quality score for each category and the detail of its research ethics instructions. Forty-five publications were identified. The four quality measures of research ethics showed that (1) all 45 publications reported justification of use of nursing home residents, (2) 36 publications reported that informed consent was obtained or waived, (3) 18 publications reported IRB review, and (4) six publications reported nursing home committee review. Of the 35 publications reporting informed consent was obtained, 16 reported assessing subjects' decisional capacity, and 24 reported whether cognitively impaired subjects were included (19) or excluded (5). The research ethics requirements of each publication's instructions for authors ranked it in one of four categories: (A) None (9); (B) Less than "Uniform Requirements (UR) for Manuscripts Submitted to Biomedical Journals" (7); (C) UR (24); (D) UR plus Additional Instructions (5). A positive association exists between the detail of a research ethics instructions category and the average research ethics quality score for each category (Kruskal-Wallis chi2 = 11.2, P = .01). That is, the more detailed the instructions, the greater the quality score. In publications of research that involves nursing home residents, basic standards of research ethics are not typically reported. However, the positive association between research ethics instructions category and research ethics quality score suggests that a journal's instructions for authors or other features of peer review and editing can affect the quality of reporting research ethics.


P2X1 receptors mediate sympathetic postjunctional Ca2+ transients in mesenteric small arteries.
Brief, spatially localized Ca(2+) transients occur in the smooth muscle adjacent to perivascular nerves of small arteries during neurogenic contractions. We named these "junctional Ca(2+) transients" (jCaTs) and postulated that they arose from Ca(2+) entering smooth muscle cells through P2X(1) receptors activated by neurally released ATP. Nevertheless, the lack of potent, subtype-selective P2X-receptor antagonists made determining the exact molecular identity of the channels difficult. Here we used small, pressurized mesenteric arteries from P2X(1)-receptor-deficient mice (KO) to test the hypothesis that jCaTs arise from Ca(2+) entering the smooth muscle cell via P2X(1) receptors. In wild-type (WT) arteries, confocal microscopy of fluo-4 fluorescence during electrical field stimulation (EFS) of perivascular sympathetic nerves revealed jCaTs in the smooth muscle cells adjacent to the perivascular nerves, similar to those reported previously in rat arteries, and alpha-latrotoxin (2.5 nM) markedly increased the frequency of "spontaneous" jCaTs. In the KO arteries, however, neither EFS nor alpha-latrotoxin elicited any jCaTs. A potent P2X-receptor agonist, alpha,beta-methylene ATP (10.0 microM), elicited strong contractions and increased intracellular Ca(2+) concentration in WT arteries but elicited neither in KO arteries. A biphasic vasoconstriction in response to EFS was observed in WT arteries. In KO arteries, however, the initial rapid, transient component of the biphasic vasoconstriction was absent. The data support the hypothesis that jCaTs represent Ca(2+) that enters the smooth muscle cells through P2X(1) receptors activated by neurally released ATP and that this Ca(2+) is involved in the initial rapid component of the sympathetic neurogenic contraction.


Gastric lesions in patients with Crohn's disease in Korea: a multicenter study.
Gastric pathology and Helicobacter pylori (H. pylori) infection among Asian patients with Crohn's disease (CD) are still unclear. We evaluated gastric histologic features and frequency of H. pylori infection in Korean patients with CD. Among 492 patients with CD receiving upper gastrointestinal (GI) endoscopic evaluation in 19 Korean hospitals, we evaluated the endoscopic findings and gastric histopathologic features of 47 patients for our study. Histopathologic classification was performed using gastric biopsy tissues, and H. pylori infection was determined using the rapid urease test and histology. There were 36 men (76.6%), and the median age of patients at the time of upper GI endoscopy was 23.8 years (range, 14.2-60.5). For CD phenotype, ileocolonic disease was observed in 38 patients (80.9%), and non-stricturing, non-penetrating disease in 31 patients (66.0%). Twenty-eight patients (59.6%) complained of upper GI symptoms. Erosive gastritis was the most common gross gastric feature (66.0%). Histopathologically, H. pylori-negative chronic active gastritis (38.3%) was the most frequent finding. H. pylori testing was positive in 11 patients (23.4%), and gastric noncaseating granulomata were detected in 4 patients (8.5%). Gastric noncaseating granuloma showed a statistically significant association with perianal abscess/fistula (P=0.0496). H. pylori-negative chronic active gastritis appears to be frequent among Korean patients with CD. The frequency of H. pylori infection was comparable with previous studies. An association with perianal complications suggests a prognostic value for gastric noncaseating granuloma in patients with CD.


A low-molecular-weight heparinoid compared with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. A randomized, double-blind study.
To compare the relative safety and efficacy of a low-molecular-weight heparinoid (ORG 10172) with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. Double-blind randomized trial. Seven Canadian university-affiliated hospitals. Eighty-seven patients with acute ischemic stroke resulting in lower-limb paresis. Patients received either low-molecular-weight heparinoid, 750 anti-factor Xa units twice daily, or unfractionated heparin, 5000 units subcutaneously twice daily. Treatment was continued for 14 days or until hospital discharge if sooner. Deep vein thrombosis was diagnosed using 125I-labeled fibrinogen leg scanning and impedance plethysmography. Venography was indicated if either test was positive. Overt hemorrhage, major or minor, was assessed clinically. Venous thrombosis occurred in four patients (9%) given low-molecular-weight heparinoid and in 13 patients (31%) given heparin (relative risk reduction, 71%; 95% CI, 16% to 93%. The corresponding rates for proximal vein thrombosis were 4% and 12%, respectively (relative risk reduction, 63%; P greater than 0.2). The incidence of hemorrhage was 2% in both groups. Low-molecular-weight heparinoid, given in a fixed dose of 750 anti-factor Xa units subcutaneously twice daily, is more effective than subcutaneous low-dose heparin for the prevention of deep vein thrombosis in patients with acute ischemic stroke.


Real-time functional magnetic resonance imaging neurofeedback for treatment of Parkinson's disease.
Self-regulation of brain activity in humans based on real-time feedback of functional magnetic resonance imaging (fMRI) signal is emerging as a potentially powerful, new technique. Here, we assessed whether patients with Parkinson's disease (PD) are able to alter local brain activity to improve motor function. Five patients learned to increase activity in the supplementary motor complex over two fMRI sessions using motor imagery. They attained as much activation in this target brain region as during a localizer procedure with overt movements. Concomitantly, they showed an improvement in motor speed (finger tapping) and clinical ratings of motor symptoms (37% improvement of the motor scale of the Unified Parkinson's Disease Rating Scale). Activation during neurofeedback was also observed in other cortical motor areas and the basal ganglia, including the subthalamic nucleus and globus pallidus, which are connected to the supplementary motor area (SMA) and crucial nodes in the pathophysiology of PD. A PD control group of five patients, matched for clinical severity and medication, underwent the same procedure but did not receive feedback about their SMA activity. This group attained no control of SMA activation and showed no motor improvement. These findings demonstrate that self-modulation of cortico-subcortical motor circuits can be achieved by PD patients through neurofeedback and may result in clinical benefits that are not attainable by motor imagery alone.


Influence of endothelial dysfunction on telomere length in subjects with metabolic syndrome: LIPGENE study.
Previous evidences support that increased oxidative stress (OxS) may play an important role in metabolic syndrome (MetS) and both are closely linked to vascular dysfunction. This study determined whether there is a relationship between endothelial function and relative telomere length (RTL) in MetS subjects. In this cross-sectional study from the LIPGENE cohort, a total of 88 subjects (36 men and 52 women) were divided into four groups by quartiles of telomere length. We measured ischemic reactive hyperemia (IRH), total nitrite (NO) and protein carbonyl (PC) plasma levels, F2-isoprostanes urinary levels, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) plasma activities. IRH and NO plasma levels were higher in subjects with longer RTL (quartiles 3 and 4), while PC plasma levels, F2-isoprostanes urinary levels, and GPx and SOD plasma activities were lower in quartile 4 subjects (longest RTL). Additionally, MetS subjects with longer RTL had greater homeostatic model assessment-β level and lower triglycerides plasma levels. Our results suggest that endothelial dysfunction, associated with high levels of OxS, could be entailed in an increment of telomere attrition. Thus, further support of the molecular and cellular mechanisms involved in vascular dysfunction may contribute to the development of strategies to decelerate vascular aging or prevent cardiovascular disease.


From the worm to the pill, the parasitic worm product ES-62 raises new horizons in the treatment of rheumatoid arthritis.
Evidence from human studies suggests that parasitic worm infection can protect humans against rheumatoid arthritis (RA) and this idea is strengthened by data generated in model systems. Although therapeutic use of parasitic worms is currently being explored, there are obvious benefits in pursuing drug development through identification and isolation of the 'active ingredients'. ES-62 is a secreted glycoprotein of the filarial nematode Acanthocheilonema viteae, which we have found to protect against the development of collagen-induced arthritis (CIA) in mice. ES-62 activity is dependent on the inflammatory phenotype of the local environment and protection arises via inhibition of Th17- and γδT cell-dependent IL-17 production. At the same time, NK and NK T cell IL-17 production is left intact, and such selectivity suggests that ES-62 might make a particularly attractive therapeutic for RA. However, as a potentially immunogenic protein, ES-62 is unsuitable for development as a drug. Nevertheless, ES-62 activity is dependent on covalently attached phosphorylcholine (PC) residues and we have therefore produced a library of PC-based drug-like ES-62 small-molecule analogues (SMAs) as an alternative therapeutic strategy. Screening this library, we have found an ES-62 SMA that mirrors ES-62 in protecting against CIA and by the same IL-17-dependent mechanism of action.


Supplemental antioxidants do not ameliorate colitis development in HLA-B27 transgenic rats despite extremely low glutathione levels in colonic mucosa.
Oxidative stress is presumed to play an important role in inflammatory bowel disease (IBD). Accordingly, antioxidant supplementation might be protective. Dietary calcium inhibited colitis development in HLA-B27 transgenic rats, an animal model mimicking IBD. As antioxidants might act at mucosa level and calcium predominantly in the gut lumen, we hypothesize that the combination has additive protective effects on colitis development. HLA-B27 rats were fed a control diet or the same diet supplemented with the antioxidants glutathione, vitamin C, and vitamin E, or supplemented with both antioxidants and calcium. Oxidative stress in colonic mucosa, colonic inflammation, intestinal permeability, and diarrhea were quantified. Intestinal permeability, diarrhea, myeloperoxidase, and interleukin-1β levels were significantly lower in rats fed both antioxidants and calcium compared to rats supplemented with antioxidants only. No beneficial effects were observed in rats fed the diet supplemented with antioxidants only. Strikingly, despite extremely low colonic mucosal glutathione levels in HLA-B27 rats, there was no oxidative stress-related damage. Subsequent analyses showed no defect in expression of glutathione synthesis genes. Additional experiments, comparing young and older HLA-B27 rats, showed that glutathione levels and also reactive oxygen species production decreased with progression of intestinal inflammation. Antioxidant supplementation was ineffective in HLA-B27 rats despite low mucosal glutathione levels, because colitis development did not coincide with oxidative stress in this model. This indicates that the neutrophilic respiratory burst, and thus innate immune defense, is compromised in HLA-B27 rats. As supplementation with both calcium and antioxidants attenuated colitis development, we speculate that this protective effect is attributed to calcium only.


Immune checkpoint inhibitors: therapeutic advances in melanoma.
In recent years, new strategies for treating melanoma have been introduced, improving the outlook for this challenging disease. One of the most important advances has been the development of immunotherapy. The better understanding of the role of the immunological system in tumor control has paved the way for strategies to enhance the immune response against cancer cells. Monoclonal antibodies (mAbs) against the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have demonstrated high activity in melanoma and other tumors. Ipilimumab, an anti CTLA-4 antibody, was the first drug of this class that was approved. Although the response rate with ipilimumab is low (less than 20% of patients have objective responses), 20% of patients have long survival, with similar results in the first and second line settings. Nivolumab and pembrolizumab, both anti PD-1 inhibitors, have been approved for the treatment of melanoma, with response rates of 40% and a demonstrated survival advantage in phase III trials. This has marked a new era in the treatment of metastatic melanoma and much research is now ongoing with other drugs targeting checkpoint inhibitors. In addition, the agonist of activating molecules on T cells and their combinations are being investigated. Herein we review the clinical development of checkpoint inhibitors and their approval for treatment of metastatic melanoma.


Steric stabilization of nanoparticles with grafted low molecular weight ligands in highly concentrated brines including divalent ions.
Whereas numerous studies of stabilization of nanoparticles (NPs) in electrolytes have examined biological fluids, the interest has grown recently in media with much higher ionic strengths including seawater and brines relevant to environmental science and subsurface oil and gas reservoirs. Given that electrostatic repulsion is limited at extremely high ionic strengths due to charge screening, we have identified ligands that are well solvated in concentrated brine containing divalent cations and thus provide steric stabilization of silica nanoparticles. Specifically, the hydrodynamic diameter of silica nanoparticles with grafted low molecular weight ligands, a diol ether, [3-(2,3-dihydroxypropoxy)propyl]-trimethoxysilane, and a zwitterionic sulfobetaine, 3-([dimethyl(3-trimethoxysilyl)propyl]ammonio)propane-1-sulfonate, is shown with dynamic light scattering to remain essentially constant, indicating lack of aggregation, at room temperature and up to 80 °C for over 30 days. An extended DLVO model signifies that steric stabilization is strongly dominant against van der Waals attraction for ∼10 nm particles given that these ligands are well solvated even in highly concentrated brine. In contrast, polyethylene glycol oligomers do not provide steric stabilization at elevated temperatures, even at conditions where the ligands are soluble, indicating complicating factors including bridging of the ether oxygens by divalent cations.


Cardioprotective effects of empagliflozin after ischemia and reperfusion in rats.
The Sodium Glucose Co-Transporter-2 inhibitor, empagliflozin (EMPA), reduces mortality and hospitalisation for heart failure following myocardial infarction irrespective of diabetes status. While the findings suggest an inherent cardioprotective capacity, the mechanism remains unknown. We studied infarct size (IS) ex-vivo in isolated hearts exposed to global IR injury and in-vivo in rats subjected to regional myocardial ischemia reperfusion (IR) injury, in whom we followed left ventricular dysfunction for 28 days. We compared rats that were given EMPA orally for 7 days before, EMPA 1.5 h before IR injury and at onset of reperfusion and continued orally during the follow-up period. We used echocardiography, high resolution respirometry, microdialysis and plasma levels of β-hydroxybutyrate to assess myocardial performance, mitochondrial respiration and intermediary metabolism, respectively. Pretreatment with EMPA for 7 days reduced IS in-vivo (65 ± 7% vs. 46 ± 8%, p < 0.0001 while administration 1.5 h before IR, at onset of reperfusion or ex-vivo did not. EMPA alleviated LV dysfunction irrespective of the reduction in IS. EMPA improved mitochondrial respiration and modulated myocardial interstitial metabolism while the concentration of β-hydroxybutyric acid was only transiently increased without any association with IS reduction. EMPA reduces infarct size and yields cardioprotection in non-diabetic rats with ischemic LV dysfunction by an indirect, delayed intrinsic mechanism that also improves systolic function beyond infarct size reduction. The mechanism involves enhanced mitochondrial respiratory capacity and modulated myocardial metabolism but not hyperketonemia.


Pregnancy Outcomes in Women With a History of Previable, Preterm Prelabor Rupture of Membranes.
To characterize subsequent pregnancy outcomes among women with a history of previable, preterm prelabor rupture of membranes (PROM) and assess factors associated with recurrent preterm birth. This was a retrospective cohort study of women cared for with a history of one or more singleton pregnancy complicated by preterm PROM at less than 24 weeks of gestation between 2002 and 2013 who were cared for in two tertiary care health systems by a single group of maternal-fetal medicine specialists. Women were identified using International Classification of Diseases, 9th Revision codes and obstetric databases. Those with iatrogenic preterm PROM and those whose index preterm PROM at less than 24 weeks of gestation was preceded by advanced cervical dilation were excluded. All women with one or more pregnancies reaching the second trimester after an index previable, preterm PROM pregnancy were included. The primary outcome was recurrent preterm birth at less than 37 weeks of gestation. Data were analyzed by χ, Fisher exact, t test, Wilcoxon rank-sum, and logistic regression. Two hundred ninety-four women had one or more pregnancies complicated by previable, preterm PROM. One hundred eight of 294 (37%) had one or more subsequent pregnancies in our health care systems and 50 of 108 (46%) had two or more. In the pregnancy immediately after the index delivery, the risk of prematurity was high: 50 (46%) delivered at less than 37 weeks of gestation, 31 (30%) at less than 34 weeks of gestation, 25 (23%) at less than 28 weeks of gestation, and 18 (17%) before 24 weeks of gestation. Fewer than half (n=49 [45%]) of women received preterm birth prophylaxis (progesterone or cerclage) in a subsequent pregnancy; rates of recurrent preterm birth were similar among women who received preterm birth prophylaxis compared with those who did not. In regression models, the only factor significantly associated with recurrent preterm birth at less than 37 weeks of gestation was a history of preterm birth preceding previable, preterm PROM delivery (adjusted odds ratio 3.23, 95% confidence interval 1.32-7.93). Patients with a history of previable, preterm PROM are at high risk of recurrent preterm birth.


Primary porcine Kupffer cell phagocytosis of human platelets involves the CD18 receptor.
Hepatic failure has been treated successfully with clinical extracorporeal perfusions of porcine livers. However, dog-to-pig and pig-to-baboon liver xenotransplant models have resulted in severe bleeding secondary to liver xenograft-induced thrombocytopenia. Kupffer cells (KC) are abundant phagocytic cells in the liver. KC express the CD11b/CD18 receptor, which has been implicated in chilled platelet binding and phagocytosis through interaction with platelet surface proteins and carbohydrates. We sought to identify the role of KC CD18 in liver xenograft-induced thrombocytopenia. Primary pig KC were characterized by flow cytometry, immunoblots, and quantitative polymerase chain reaction. Pig KC were used in inhibition assays with fluorescently labeled human platelets. The CD18 receptor was targeted for siRNA knockdown. Domestic and α1,3-galactosyltransferase double knockout porcine KC cultures were approximately 92% positive for CD18 as detected by quantitative polymerase chain reaction and flow cytometry. Use of CD18 blocking antibodies resulted in reduction of human platelet binding and phagocytosis. Additionally, asialofetuin, not fetuin, inhibited platelet phagocytosis suggesting the involvement of an oligosaccharide-binding site. Furthermore, reduced CD18 expression by siRNA resulted in decreased human platelet binding. Our data suggest that primary pig KC bind and phagocytose human platelets with involvement of CD18. Further understanding and modification of CD18 expression in pigs may result in a liver xenograft with reduced thrombocytopenic effects, which could be used as a bridge to allogeneic liver transplantation.


Persisting Reductions in Cannabis, Opioid, and Stimulant Misuse After Naturalistic Psychedelic Use: An Online Survey.
Observational data and preliminary studies suggest serotonin 2A agonist psychedelics may hold potential in treating a variety of substance use disorders (SUDs), including opioid use disorder (OUD). The study aim was to describe and analyze self-reported cases in which naturalistic psychedelic use was followed by cessation or reduction in other substance use. An anonymous online survey of individuals reporting cessation or reduction in cannabis, opioid, or stimulant use following psychedelic use in non-clinical settings. Four hundred forty-four respondents, mostly in the USA (67%) completed the survey. Participants reported 4.5 years of problematic substance use on average before the psychedelic experience to which they attributed a reduction in drug consumption, with 79% meeting retrospective criteria for severe SUD. Most reported taking a moderate or high dose of LSD (43%) or psilocybin-containing mushrooms (29%), followed by significant reduction in drug consumption. Before the psychedelic experience 96% met SUD criteria, whereas only 27% met SUD criteria afterward. Participants rated their psychedelic experience as highly meaningful and insightful, with 28% endorsing psychedelic-associated changes in life priorities or values as facilitating reduced substance misuse. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with greater reduction in drug consumption. While these cross-sectional and self-report methods cannot determine whether psychedelics caused changes in drug use, results suggest the potential that psychedelics cause reductions in problematic substance use, and support additional clinical research on psychedelic-assisted treatment for SUD.


Biochemical Characterization of Putative Adenylate Dimethylallyltransferase and Cytokinin Dehydrogenase from Nostoc sp. PCC 7120.
Cytokinins, a class of phytohormones, are adenine derivatives common to many different organisms. In plants, these play a crucial role as regulators of plant development and the reaction to abiotic and biotic stress. Key enzymes in the cytokinin synthesis and degradation in modern land plants are the isopentyl transferases and the cytokinin dehydrogenases, respectively. Their encoding genes have been probably introduced into the plant lineage during the primary endosymbiosis. To shed light on the evolution of these proteins, the genes homologous to plant adenylate isopentenyl transferase and cytokinin dehydrogenase were amplified from the genomic DNA of cyanobacterium Nostoc sp. PCC 7120 and expressed in Escherichia coli. The putative isopentenyl transferase was shown to be functional in a biochemical assay. In contrast, no enzymatic activity was detected for the putative cytokinin dehydrogenase, even though the principal domains necessary for its function are present. Several mutant variants, in which conserved amino acids in land plant cytokinin dehydrogenases had been restored, were inactive. A combination of experimental data with phylogenetic analysis indicates that adenylate-type isopentenyl transferases might have evolved several times independently. While the Nostoc genome contains a gene coding for protein with characteristics of cytokinin dehydrogenase, the organism is not able to break down cytokinins in the way shown for land plants.


The effects of balneotherapy on fibromyalgia patients.
Fibromyalgia syndrome (FMS) is a very common rheumatological diagnosis. There are various treatment modalities. This study was planned to investigate the effects of balneotherapy in the treatment of FMS. A total of 42 primary fibromyalgia patients diagnosed according to American College of Rheumatology criteria were included in the study. Their ages ranged between 30 and 55 years. Patients were randomly assigned to two groups. None of them had had a cardiovascular disease before. Group 1 n=22) received 20-min bathing, once a day and five times per week. Patients participated in the study for 3 weeks (total of 15 sessions). Group 2 (n=20) was accepted as the control group. Patients were evaluated by the number of tender points, Visual Analogue Scale for pain, Beck's Depression Index for depression, and Fibromyalgia Impact Questionnaire for functional capacity. Measurements were assessed initially, after the therapy, and at the end of the 6th month. In group 1, there were statistically significant differences in numbers of tender points, Visual Analogue scores, Beck's Depression Index, and Fibromyalgia Impact Questionnaire scores after the therapy program (P<0.001). Also, 6 months later in group 1, there was still an improvement in the number of tender points (P<0.001), Visual Analogue scores, and Fibromyalgia Impact Questionnaire (P<0.005). But there was not a statistical difference in Beck's Depression Index scores compared to the control group (P>0.05). Patients with FMS mostly complain about pain, anxiety, and the difficulty in daily living activities. This study shows that balneotherapy is effective and may be an alternative method in treating fibromyalgia patients.


An improved double-beam infrared microspectrometer.
The conversion of single-beam monochromators to double-beam microspectrometers is described. The principal advantage of the present system over others used is a great improvement in the long-term stability of the electronics; other advantages include simplicity, compactness, and complete freedom from beats due to mains frequency pickup. The system has been designed for use, in conjunction with a polarizer, for the examination of fibers, small crystals, and small areas of oriented biological macromolecules as well as for microsamples.


Doxorubicin-provoked increase of mitotic activity and concomitant drain of G0-pool in therapy-resistant BE(2)-C neuroblastoma.
In this study chemotherapy response in neuroblastoma (NB) was assessed for the first time in a transplantation model comprising non-malignant human embryonic microenvironment of pluripotent stem cell teratoma (PSCT) derived from diploid bona fide hESC. Two NB cell lines with known high-risk phenotypes; the multi-resistant BE(2)-C and the drug sensitive IMR-32, were transplanted to the PSCT model and the tumour growth was exposed to single or repeated treatments with doxorubicin, and thereafter evaluated for cell death, apoptosis, and proliferation. Dose dependent cytotoxic effects were observed, this way corroborating the experimental platform for this type of analysis. Notably, analysis of doxorubicin-resilient BE(2)-C growth in the PSCT model revealed an unexpected 1,5-fold increase in Ki67-index (p<0.05), indicating that non-cycling (G0) cells entered the cell cycle following the doxorubicin exposure. Support for this notion was obtained also in vitro. A pharmacologically relevant dose (1μM) resulted in a marked accumulation of Ki67 positive BE(2)-C cells (p<0.0001), as well as a >3-fold increase in active cell cycle (i.e. cells positive staining for PH3 together with incorporation of EdU) (p<0.01). Considering the clinical challenge for treating high-risk NB, the discovery of a therapy-provoked growth-stimulating effect in the multi-resistant and p53-mutated BE(2)-C cell line, but not in the drug-sensitive p53wt IMR-32 cell line, warrants further studies concerning generality and clinical significance of this new observation.


Improvement of insulin resistance after obesity surgery: a comparison of gastric banding and bypass procedures.
Obesity is a major risk factor for the development of type 2 diabetes mellitus (T2DM). Insulin resistance (IR) is considered the pathologic link between T2DM and obesity. The mechanism in improving T2DM after bariatric surgery remains speculative. This trial assessed the effect of duodenal jejunal exclusion on the resolution of IR in gastric banding and gastric bypass procedures. 660 patients with complete biochemical and clinical data at baseline and at 3 years were selected for analysis. There were 197 males and 463 females. The mean age was 31.5 years (18-64) and mean BMI was 41.4 (32-77). There were 544 patients who received laparoscopic gastric bypass, and 116 patients received laparoscopic gastric banding. IR was measured by homeostatic model assessment (HOMA) index (HI), that can be calculated as HI = plasma glucose (mmol/l) x insulin (UI/ml)/22.5. HI was measured before surgery and 1, 3, 6, 12, 24, and 36 months after surgery. Of the 660 individuals, 517 (78.4%) had IR. The mean HI was 7.62 +/- 13.13. The HI was correlated with BMI, waist circumference, insulin resistance, hyperlipidemia, inflammatory indicators, and abnormal liver enzymes. Before surgery, the HI was 7.92 +/- 14.18 for the bypass group and 6.27 +/- 6.47 for the banding group. After surgery, the HI began to lower in both groups, and this reduction was maintained during follow-up. At 36 months after surgery, mean percentage of excess weight loss (%EWL) was 70.5% for the bypass group and 41.9% for the banding group. The HI was 1.00 +/- 0.79 for bypass and 1.51 +/- 1.25 for banding. The bypass patients had a better and faster weight reduction, but the HI was similar between the two groups at the same weight reduction percentage. IR is common in morbidly obese patients. Both gastric banding and gastric bypass are effective for the reverse of IR in these patients. It seems that the effect is related to the absolute weight loss rather than different surgical procedures. There is no duodenal jejunal exclusion effect on IR resolution was observed in this study.


Open-flow microperfusion of subcutaneous adipose tissue for on-line continuous ex vivo measurement of glucose concentration.
To evaluate a novel technique for on-line continuous glucose measurement in subcutaneous adipose tissue, and to investigate its accuracy for detection of hypoglycemia. The method combined an open-flow microperfusion of subcutaneous adipose tissue using a double lumen catheter and an extracorporeal sensor cell. An isotonic ion-free solution was perfused through the inner lumen of the catheter, equilibrated with the subcutaneous tissue fluid, and sampled through the outer lumen. The recovery was continuously monitored as the ratio between the measured sampled fluid conductivity and the subcutaneous tissue fluid conductivity (assumed to have a constant value of 1.28 S/m at 25 degrees C). Glucose concentration was calculated on-line from the measured glucose in the sampled fluid and the measured recovery in healthy volunteers during hyperglycemic glucose loads (n = 8), hypoglycemic hyperinsulinemic clamp (n = 6), and a 24-h monitoring period (n = 7). Subcutaneous glucose concentrations in the fasting state were 94% of the plasma glucose concentrations in arterialized venous samples. According to the error grid analysis, 96.9% of the on-line measured subcutaneous glucose concentrations during hyperglycemia and 96.3% during hypoglycemia were in accurate or acceptable zones. The mean differences between the measured subcutaneous glucose and the actual plasma glucose concentration were -0.06-3.3 mmol/l (hyperglycemia), and -0.6-1.1 mmol/l (hypoglycemia). By combining open-flow microperfusion, glucose sensor, and conductivity measurement, glucose concentration in the subcutaneous adipose tissue can be monitored on-line, extracorporeally, and continuously without any in vivo calibration, and gives accurate measurements during hyper- and hypoglycemia.


Reconsideration of pelvic floor muscle training to prevent and treat incontinence after radical prostatectomy.
Urinary incontinence is common after radical prostatectomy. Pelvic floor muscle training provides a plausible solution. Although early trials provided promising results, systematic reviews have questioned the efficacy of this intervention. A major consideration is that most clinical trials in men have applied principles developed for pelvic floor muscle training for stress urinary incontinence in women, despite differences in anatomy between sexes and differences in the mechanisms for continence/incontinence. Literature regarding continence control in men has been conflicting and often based on erroneous anatomy. New understanding of continence mechanisms in men, including the complex contribution of multiple layers of striated pelvic floor muscles, and detailed consideration of the impact of radical prostatectomy on continence anatomy and physiology, have provided foundations for a new approach to pelvic floor muscle training to prevent and treat incontinence after prostatectomy. An approach to training can be designed to target the pathophysiology of incontinence. This approach relies on principles of motor learning and exercise physiology, in a manner that is tailored to the individual patient. The aims of this review are to consider new understanding of continence control in men, the mechanisms for incontinence after radical prostatectomy, and to review the characteristics of a pelvic floor muscle training program designed to specifically target recovery of continence after prostatectomy.


Infectious and tropical diseases in Oman: a review.
Oman is generally hot and dry, but the Salalah region in southern Dhofar province is relatively cool and rainy during the summer monsoon, and has a distinctive pattern of infection. Important, notifiable infections in Oman include tuberculosis, brucellosis (endemic in Dhofar), acute gastroenteritis, and viral hepatitis: 4.9% of the adults are seropositive for hepatitis B surface antigen and approximately 1.2% for hepatitis C virus. Infection with human immunodeficiency virus is uncommon, and leprosy, rabies, and Crimean-Congo hemorrhagic fever are rare. Between 1990 and 1998, the incidence of malaria, (>70% due to Plasmodium falciparum) decreased from 32,700 to 882 cases. Cutaneous and visceral leishmaniasis (caused by Leishmania tropica and L. infantum, respectively) and Bancroftian filariasis occur sporadically. Intestinal parasitism ranges from 17% to 42% in different populations. A solitary focus of schistosomiasis mansoni in Dhofar has been eradicated. There are major programs for the elimination of tuberculosis, leprosy, and malaria, and to control brucellosis, leishmaniasis, sexually transmitted diseases, trachoma, acute respiratory infection in children, and diarrheal diseases. The Expanded Program on Immunization was introduced in 1981: diphtheria, neonatal tetanus, and probably poliomyelitis have been eliminated.


Italian Version of the Jebsen-Taylor Hand Function Test for the Assessment of Hand Disorders: A Cross-Sectional Study.
Having a test to evaluate hand function is fundamental to occupational therapy practice. To assess the psychometric properties of the Italian version of the Jebsen-Taylor Hand Function Test (JTHFT). Cross-sectional study. Three health care institutions in Rome, Italy. 136 people with injuries, burns, or neurological diseases of the hand. No intervention was provided. We administered the JTHFT, an assessment of fine motor skills during performance of activities of daily living, and compared results with dynamometer readings. The mean ± standard deviation total time required to perform all subtests was 89.47 ± 67.98 s for the dominant hand (DH) and 167.11 ± 257.58 s for the nondominant hand (NDH). Reliability procedures were applied to data from 51 participants; mean intrarater intraclass correlation coefficient (ICC) was .814 for the DH and .981 for the NDH, and mean interrater ICC was .818 for the DH and .821 for the NDH. Pearson's correlation coefficients were significant. Results support the use of the Italian version of the JTHFT as a measure of functional dexterity in people with upper limb disorders. The JTHFT is a valid and reliable assessment tool for nonspecific hand diseases. Italian health professionals can now use the JTHFT with more confidence.


Effects of social exclusion on depressive symptoms: elderly Chinese living alone in Shanghai, China.
Research has identified social exclusion as one of the social determinants of health. There are risks of social exclusion in later life in recent years. However, despite the fact that China has the largest aging population in the world and reports a rapid growth in the proportion of older people living alone, research on the role of social exclusion on depression is limited. This study examined the effects of social exclusion on depressive symptoms in older Chinese who are living alone in China, based on the data from one Shanghai neighbourhood. The data used were obtained between August and October 2008 through face-to-face interviews, using a structured survey questionnaire, from a simple random sample of 228 Chinese 60 and older living alone in a Shanghai community. Depressive symptoms were measured by a 15-item Chinese version Geriatric Depression Scale. Social exclusion was represented by income adequacy, social relations, civic participation, and housing condition. Over 30% of participants reported symptoms of a mild or above mild level of depression. When controlled for the demographics and health variables in hierarchical multiple regression, social exclusion variables, represented by a lower level income adequacy, a less favourable housing condition, and feeling more lonely correlated significantly with more depressive symptoms. Contrary to previous studies on depression in the older adults in China, this study has obtained findings indicating that social exclusion variables are more important than other socio-demographic factors in the context of contemporary China. While two significant social exclusion variables (i.e. income and housing) are related to structural changes in the economic context in China, the intra-personal role of feeling lonely that ties strongly living alone and role of older adults in an increasingly competitive market economy should not be underestimated. To address depression and mental health of older Chinese who live alone, social policies and programs to reduce various forms of social exclusion should be developed. In additional to providing assistance in financial support and housing improvement, services to strengthen the social networks and social relations of these older people are essential.


Preferential decorporation of americium by pulmonary administration of DTPA dry powder after inhalation of aged PuO(2) containing americium in rats.
After inhalation of plutonium oxides containing various percentages of americium in rats, we identified an acellular transient pulmonary compartment, the epithelial lining fluid (ELF), in which a fraction of actinide oxides dissolve prior to absorption and subsequent extrapulmonary deposit. Chelation therapy is usually considered to be poorly efficient after inhalation of actinide oxides. However, in the present study, prompt pulmonary administration of diethylenetraminepentaacetic acid (DTPA) as a dry powder led to a decrease in actinide content in ELF together with a limitation of bone and liver deposits. Because americium is more soluble than plutonium, higher amounts of americium were found in ELF, extrapulmonary tissues and urine. Our results also demonstrated that the higher efficacy of DTPA on americium compared to plutonium in ELF induced a preferential inhibition of extrapulmonary deposit and a greater urinary excretion of americium compared to plutonium. All together, our data justify the use of an early and local DTPA treatment after inhalation of plutonium oxide aerosols in which americium can be in high proportion such as in aged compounds.


Use of a refined drug tracer algorithm to estimate prevalence and incidence of Parkinson's disease in a large israeli population.
Estimating rates of Parkinson's disease (PD) is essential for health services planning and studies of disease determinants. However, few PD registries exist. We aimed to estimate annual prevalence and incidence of PD in a large Israeli population over the past decade using computerized drug purchase data. Based on profiles of anti-parkinsonian drugs, age at first purchase, purchase density, and follow-up time, we developed a refined algorithm for PD assessment (definite, probable or possible) and validated it against clinical diagnoses. We used the prescription database of the second largest Health Maintenance Organization in Israel (covers ~25% of population), for the years 1998-2008. PD rates by age, gender and year were calculated and compared using Poisson models. The algorithm was found to be highly sensitive (96%) for detecting PD cases. We identified 7,134 prevalent cases (67% definite/probable), and 5,288 incident cases (65% definite/probable), with mean age at first purchase 69 ± 13 years. Over the years 2000-2007, PD incidence rate of 33/100,000 was stable, and the prevalence rate increased from 170/100,000 to 256/100,000. For ages 50+, 60+, 70+, median prevalence rates were 1%, 2%, 3%, respectively. Incidence rates also increased with age (RR = 1.76, 95%CI 1.75-1.77, ages 50+, 5-year interval). For ages 50+, rates were higher among men for both prevalence (RR = 1.38, 95%CI 1.37-1.39) and incidence (RR = 1.45, 95%CI 1.42-1.48). In conclusion, our refined algorithm for PD assessment, based on computerized drug purchases data, may be a reliable tool for population-based studies. The findings indicate a burden of PD in Israel higher than previously assumed.


Image scanning ellipsometry for measuring nonuniform film thickness profiles.
A novel technique to measure the two-dimensional (2-D) thickness profile of a nonuniform, thin film, from several nanometers to several micrometers, in a steady state as well as in a transient state has been developed and tested. Image scanning ellipsometry (ISE) is a full-field imaging technique that one can use to study every point on the surface simultaneously with high spatial resolution and thickness sensitivity, i.e., it can measure and map the 2-D film thickness profile. The primary purpose of this paper is to present the basic concept of ISE and a demonstration of its use.


School burnout and cardiovascular functioning in young adult males: a hemodynamic perspective.
This study investigated aortic and brachial hemodynamic functioning that may link school burnout to cardiovascular risk factors. Methodological improvements from previous research were implemented including (1) statistical control of depressive and anxiety symptoms (2) resting, stress-induced and cardiac recovery condition comparisons and (3) use of pulse wave analysis. Forty undergraduate young adult males completed self-report measures of school burnout, trait anxiety and depressive symptoms. Participants then completed a protocol consisting of a 10-min seated rest, 5-min baseline (BASE), 3-min cold pressor test (CPT) and a 3-min recovery period (REC). Indices of brachial and aortic hemodynamics were obtained by means of pulse wave analysis via applanation tonometry. Controlling for anxiety and depressive symptoms, planned contrasts identified no differences in cardiovascular parameters at BASE between participants in burnout and non-burnout groups. However, negative changes in hemodynamic indices occurred in burnout participants at CPT and REC as evidenced by increased aortic and brachial systolic and diastolic blood pressures, increased left ventricular work and increased myocardial oxygen consumption. Findings suggest that school burnout symptoms are associated with cardiac hyperactivity during conditions of cardiac stress and recovery and therefore may be associated with the early manifestations of cardiovascular disease. Future studies are suggested to reveal underlying autonomic mechanisms explaining hemodynamics functioning in individuals with school burnout symptomatology.


Endoscopic transorbital approach to the infratemporal fossa and parapharyngeal space: a cadaveric study.
The infratemporal fossa (ITF) and parapharyngeal space are anatomical regions that can be challenging to access without the use of complex, cosmetically disfiguring approaches. With advances in endoscopic techniques, a new group of surgical approaches to access the intracranial space through the orbit has been recently referred to as transorbital neuroendoscopic surgery (TONES). The objective of this study was to establish a transorbital endoscopic approach utilizing the inferior orbital fissure (IOF) to gain access to the ITF and parapharyngeal space and provide a detailed endoscopic anatomical description of this approach. Four cadaveric heads (8 sides) were dissected using a TONES approach through the IOF to reach the ITF and parapharyngeal space, providing stepwise dissection with detailed anatomical findings and a description of each step. An inferior eyelid approach was made with subperiosteal periorbital dissection to the IOF. The zygomatic and greater wing of the sphenoid were drilled, forming the boundaries of the IOF. The upper head of the lateral pterygoid muscle in the ITF and parapharyngeal space was removed, and 7 distinct planes were described, each with its own anatomical contents. The second part of the maxillary artery was mainly found in plane 1 between the temporalis laterally and the lateral pterygoid muscle in plane 2. The branches of the mandibular nerve (V3) and middle meningeal artery (MMA) were identified in plane 3. Plane 4 was formed by the fascia of the medial pterygoid muscle (MTM) and the tensor veli palatini muscle. The prestyloid segment, found in plane 5, was composed mainly of fat and lymph nodes. The parapharyngeal carotid artery in the poststyloid segment, found in plane 7, was identified after laterally dissecting the styloid diaphragm, found in plane 6. V3 and the origin of the levator and tensor veli palatini muscles serve as landmarks for identification of the parapharyngeal carotid artery. The transorbital endoscopic approach provides excellent access to the ITF and parapharyngeal space compared to previously described complex and morbid transfacial or transcranial approaches. Using the IOF is an important and useful landmark that permits a wide exposure.


Suicidal behavior differs among early and late adolescents treated with antidepressant agents.
To identify circumstances and characteristics of suicidal behavior among early (aged 10-14 years) and late (aged 15-18 years) adolescents from a cohort of youth who were prescribed antidepressant medication. In-depth reviews of all available medical records were performed for 250 randomly chosen confirmed episodes of suicidal behavior identified as part of a large retrospective cohort study of antidepressant users and suicidal behavior. Study data were obtained from Tennessee Medicaid records and death certificates from January 1, 1995, to December 31, 2006. Medical records and autopsy reports for cases identified from electronic data were adjudicated by 2 investigators blinded to exposure status and classified by using a validated scale. Of the 250 cases reviewed, 65.6% were female and 26.4% were aged 10 to 14 years. Medication ingestion was the most frequent method of suicidal behavior for both early and late adolescents; however, early adolescents were significantly more likely to use hanging as a method of suicide. Nearly one-half of the adolescents had previously attempted suicide. Early adolescents were significantly more likely to have a history of sexual abuse and significantly less likely to have a history of substance abuse. Early adolescents were also significantly more likely than older adolescents to have a history of a psychotic disorder and to report hallucinations before the suicide attempt. Suicidal behavior among early and late adolescents prescribed antidepressant medication differed in terms of methods used, previous psychiatric history, and proximal symptoms.


Job strain in relation to ambulatory blood pressure, heart rate, and heart rate variability among female nurses.
This study examined the effects of exposure to job strain on independent predictors of cardiovascular disease (ambulatory blood pressure, heart rate, and heart rate variability). The participants comprised a homogeneous group of 159 healthy female nurses [mean age 35.9 (SD 8.5) years]. The choice of this population minimized variance attributable to gender, socioeconomic status, and work characteristics. Job demands, decision latitude, and social support were measured with the Karasek job content questionnaire, which was administered twice with an average interval of 12.2 months. The nurses' scores for job demands and decision latitude on both occasions were used to define their job-strain category. Ambulatory blood pressure, heart rate, and heart rate variability were assessed on a workday and a day of leisure. No effect on the ambulatory levels of blood pressure, heart rate, or heart rate variability was found for job strain by itself or in interaction with social support. In addition, job strain was not associated with differences in short-term or long-term physiological recovery during sleep after a workday or a day of leisure. High job demand was associated with higher systolic blood pressure at work and with higher diastolic blood pressure at work, but the latter association was found only when decision latitude was concurrently high, rather than low. High job strain among young female nurses is not associated with an unfavorable ambulatory cardiovascular profile. The robust effect of job strain on male health appears to be less apparent for women.


Distinguishing apathy from depression: A review differentiating the behavioral, neuroanatomic, and treatment-related aspects of apathy from depression in neurocognitive disorders.
This narrative review describes the clinical features of apathy and depression in individuals with neurocognitive disorders (NCDs), with the goal of differentiating the two syndromes on the basis of clinical presentation, diagnostic criteria, neuropathological features, and contrasting responses to treatments. Literature was identified using PubMed, with search terms to capture medical conditions of interest; additional references were also included based on our collective experience and knowledge of the literature. Evidence from current literature supports the distinction between the two disorders; apathy and depression occur with varying prevalence in individuals with NCDs, pose different risks of progression to dementia, and have distinct, if overlapping, neurobiological underpinnings. Although apathy is a distinct neuropsychiatric syndrome, distinguishing apathy from depression can be challenging, as both conditions may occur concurrently and share several overlapping features. Apathy is associated with unfavorable outcomes, especially those with neurodegenerative etiologies (e.g., Alzheimer's disease) and is associated with an increased burden for both patients and caregivers. Diagnosing apathy is important not only to serve as the basis for appropriate treatment, but also for the development of novel targeted interventions for this condition. Although there are currently no approved pharmacologic treatments for apathy, the research described in this review supports apathy as a distinct neuropsychiatric condition that warrants specific treatments aimed at alleviating patient disability. Despite differences between these disorders, both apathy and depression pose significant challenges to patients, their families, and caregivers; better diagnostics are needed to develop more tailored treatment and support.


Variation in warfarin thromboprophylaxis after mitral valve repair: does equipoise exist and is a randomized trial warranted?
There are limited data available to inform decision making regarding warfarin thromboprophylaxis early after mitral valve repair. We studied 13,082 patients from The Society of Thoracic Surgeons Adult Cardiac Surgery Database (STS ACSD) who underwent primary mitral valve repair between January 1, 2008, and June 30, 2010. Excluded were those having other major concomitant operations or with an indication/contraindication to warfarin. The predictors of warfarin administration at dismissal were evaluated. In this cohort (median age 58 years; 59% male), warfarin was prescribed at hospital dismissal for 46% (5,963) of patients. Median postoperative length of stay was 5 days overall (6 days warfarin versus 5 days, p < 0.0001). Substantial surgeon and center variation existed, and multivariable analysis identified that warfarin use was more common among patients with postoperative atrial fibrillation (odds ratio [OR] 4.04, 95% confidence interval [CI]: 3.57 to 4.58), postoperative neurologic events (stroke OR 1.72, 95% CI: 1.08 to 2.71; transient ischemic attack/reversible ischemic neurologic deficit OR 6.29, 95% CI: 2.67 to 14.84), and preoperative arrhythmia (OR 2.49, 95% CI: 1.84 to 3.38). Warfarin use was less common among patients having surgery in the more recent era (OR 0.92, 95% CI: 0.89 to 0.96, per half-year increase in date of surgery), those requiring intraoperative transfusion of red blood cells (OR 0.82, 95% CI: 0.71 to 0.96), and patients with advanced heart failure (New York Heart Association functional class IV OR 0.77, 95% CI: 0.59 to 1.00). At present, half of patients are prescribed warfarin after isolated mitral valve repair in North American cardiac surgical practice which may impact the length of hospital stay. Although patient-level predictors of warfarin prescription exist, center- and surgeon-level variations are prominent. There is a pressing need for a randomized trial both to guide therapy and to ascertain the potential for resource conservation.


Benchtop isolation and characterization of functional exosomes by sequential filtration.
Early and minimally invasive detection of malignant events or other pathologies is of utmost importance in the pursuit of improved patient care and outcomes. Recent evidence indicates that exosomes and extracellular vesicles in serum and body fluids can contain nucleic acid, protein, and other biomarkers. Accordingly, there is great interest in applying these clinically as prognostic, predictive, pharmacodynamic, and early detection indicators. Nevertheless, existing exosome isolation methods can be time-consuming, require specialized equipment, and/or present other inefficiencies regarding purity, reproducibility and assay cost. We have developed a straightforward, three-step protocol for exosome isolation of cell culture supernatants or large volumes of biofluid based on sequential steps of dead-end pre-filtration, tangential flow filtration (TFF), and low-pressure track-etched membrane filtration that we introduce here. Our approach yields exosome preparations of high purity and defined size distribution and facilitates depletion of free protein and other low-molecular-weight species, extracellular vesicles larger than 100nm, and cell debris. Samples of exosomes prepared using the approach were verified morphologically by nanoparticle tracking analysis and electron microscopy, and mass spectrometry analyses confirmed the presence of previously reported exosome-associated proteins. In addition to being easy-to-implement, sequential filtration yields exosomes of high purity and, importantly, functional integrity as a result of the relatively low-magnitude manipulation forces employed during isolation. This answers an unmet need for preparation of minimally manipulated exosomes for investigations into exosome function and basic biology. Further, the strategy is amenable to translation for clinical exosome isolations because of its speed, automatability, scalability, and specificity for isolating exosomes from complex biological samples.


Analysis of genetic polymorphisms in acetylcholinesterase as reflected in different populations.
Acetylcholinesterase (AChE) plays a crucial physiological role in termination of impulse transmission at cholinergic synapses through rapid hydrolysis of acetylcholine. In addition, it was implicated in amyloid plaque formation, a hallmark of Alzheimer's disease (AD), and most of the drugs used in AD treatment are AChE inhibitors. Thus ACHE is an obvious candidate gene for pharmacogenetic study of AD treatment. However, AChE is a highly conserved molecule, and only a few naturally occurring genetic polymorphisms have been reported in the human gene. The goals of this study were to make a systematic effort to identify natural single nucleotide polymorphisms (SNPs) in the human ACHE gene, and to reveal their population specific architecture. To this end, the genomic coding sequences for AChE of 96 unrelated control individuals from three distinct ethnic groups, African Americans, Ashkenazi Jews and Israeli Arabs, were analyzed. Thirteen ACHE SNPs were identified, ten of which are newly described, and five of which should produce amino-acid substitutions (Arg34Gln, Gly57Arg, Glu344Gly, His353Asn and Pro592Arg). Population frequencies of 11 of the 13 SNPs were established in four different populations, African Americans, Ashkenazi Jews, Sephardic Jews and Israeli Arabs; 17 haplotypes and 5 ethno-specific alleles were identified, and a cladogram of ACHE haplotypes was constructed. Among the SNPs resulting in an amino-acid substitution, three are within the mature protein, mapping on its external surface; they are thus unlikely to affect its catalytic properties, yet could have antigenic consequences or affect putative protein-protein interactions. Furthermore, the newly identified SNPs open the door to a study of the possible association of AChE with deleterious phenotypes - such as adverse drug responses to AChE inhibitors employed in treatment of AD patients and hypersensitivity to pesticides.


Physiological activities of carbon monoxide-releasing molecules: Ca ira.
In this issue of British Journal of Pharmacology, Megías and colleagues demonstrate how preincubation of human colonic Caco-2 cells with CORM-2, a carbon monoxide releasing molecule (CO-RM), reduces the expression of inducible nitric oxide synthase, interleukin (IL)-6 and IL-8 caused by proinflammatory cytokines. A role for IL-6 in the regulation of metalloproteinase (MMP)-7 expression by CORM-2 is described. However, it is the demonstration that CORM-2 inhibits MMP-7 or matrilysin expression, which is most intriguing as this small MMP has been implicated in carcinogenesis. Thus, CO-RMs appear to now possess chemoprotective properties and, in this particular case, may influence inflammation-induced colon carcinogenesis via modulation of nuclear factors participating in the transcription of genes implicated in the development of intestinal inflammation and cancer. This report opens yet another door for research involving these exciting molecules and it is now clear that further discoveries of the beneficial properties of CO-RMs will go on.


Successful Endoscopic Surgery for L5 Radiculopathy Caused by Far-Lateral Disc Herniation at L5-S1 and L5 Isthmic Grade 2 Spondylolisthesis in a Professional Baseball Player.
We report the case of a professional baseball player who had severe leg pain due to lumbar lateral disc herniation at L4-5 and isthmic spondylolisthesis at L5 (double crash syndrome). For early recovery to competitive level, we performed minimally invasive endoscopic decompression surgery without fusion. There are few reports to discuss the usefulness of minimally invasive treatment for top athletes. A 29-year-old professional baseball player who played catcher was referred to us with a complaint of right leg pain. The previous doctor diagnosed far-lateral disc herniation and Grade 2 isthmic spondylolisthesis and recommended arthrodesis at L5-S1 as treatment for both pathologies. Radiological imaging showed that the right L5 nerve root was impinged by the 2 lumbar disorders, namely, far-lateral disc herniation and a ragged edge around a pars defect. We had taken into account the patient's occupation and his wish to avoid a lengthy sick leave, and we had performed endoscopic decompression surgery during the offseason. The far-lateral disc herniation at L5-S1 was removed under local anesthesia by percutaneous endoscopic discectomy, after which the ragged edge at the pars defect was removed under general anesthesia using a microendoscopic discectomy system. Given that the patient did not have any low back pain, arthrodesis was not considered. The leg pain resolved after surgery. The following year (2015), the patient resumed playing baseball from the beginning of the season and played in 41 games. In the 2016 season, he played in 71 games without any symptoms. No further slippage was observed at radiological follow up 1 year after the surgery. Minimally invasive endoscopic surgery is an option for radiculopathy in very active patients who need an early return to their previous level of physical activity.


Observation of the B_{c}^{+} Meson in Pb-Pb and pp Collisions at sqrt[s_{NN}]=5.02 TeV and Measurement of its Nuclear Modification Factor.
The B_{c}^{+} meson is observed for the first time in heavy ion collisions. Data from the CMS detector are used to study the production of the B_{c}^{+} meson in lead-lead (Pb-Pb) and proton-proton (pp) collisions at a center-of-mass energy per nucleon pair of sqrt[s_{NN}]=5.02 TeV, via the B_{c}^{+}→(J/ψ→μ^{+}μ^{-})μ^{+}ν_{μ} decay. The B_{c}^{+} nuclear modification factor, derived from the Pb-Pb-to-pp ratio of production cross sections, is measured in two bins of the trimuon transverse momentum and of the Pb-Pb collision centrality. The B_{c}^{+} meson is shown to be less suppressed than quarkonia and most of the open heavy-flavor mesons, suggesting that effects of the hot and dense nuclear matter created in heavy ion collisions contribute to its production. This measurement sets forth a promising new probe of the interplay of suppression and enhancement mechanisms in the production of heavy-flavor mesons in the quark-gluon plasma.


Clinical, neurophysiological and serological clues for the diagnosis of neuromyotonia and distinction from cramp-fasciculation syndrome.
Neuromyotonia and cramp-fasciculation syndrome diagnosis currently relies on neurophysiological examination. In this study we investigated the clinical features and neural antibody profile of patients with neuromyotonia and cramp-fasciculation syndrome to assess the diagnostic value of serological testing. Available sera from adult patients with electromyography-defined neuromyotonia and cramp-fasciculation syndrome were tested for neural antibodies by indirect immunofluorescence on mouse brain sections and live cell-based assays. Forty patients were included, 14 with neuromyotonia and 26 with cramp-fasciculation syndrome. Neural antibodies were detected in 10/10 neuromyotonia sera, most commonly against contactin-associated protein 2 (7/10, 70%), and in 1/20 (5%) cramp-fasciculation syndrome sera. Clinical myokymia, hyperhidrosis, and paresthesia or neuropathic pain were more common in neuromyotonia and mostly associated with contactin-associated protein 2 antibodies. Central nervous system involvement was present in 4/14 (29%) neuromyotonia patients. A tumor was detected in 13/14 (93%) neuromyotonia patients (thymoma, 13), and in 4/26 (15%) with cramp-fasciculation syndrome (thymoma, 1; other neoplasms, 3). Twenty-one/27 (78%) patients achieved a significant improvement or complete remission. Our findings highlight clinical, neurophysiological and serological clues that can be useful in the diagnosis of neuromyotonia and cramp-fasciculation syndrome. Antibody testing is valuable for neuromyotonia diagnosis, while its usefulness in cramp-fasciculation syndrome confirmation is limited.


Internal iliac artery embolization in the stent-graft treatment of aortoiliac aneurysms: analysis of outcomes and complications.
To analyze the complications of internal iliac artery (IIA) embolization in conjunction with stent-graft treatment of aortoiliac aneurysms. Seventy-one patients with aortoiliac (n = 47) or iliac (n = 24) aneurysms were treated with endoluminal placement of stent-grafts. Thirty-two patients (31 men, one woman; mean age, 73 years; range, 56-88 years) had embolization or occlusion of one (n = 27) or both (n = 5) IIAs. Status of the IIAs and the collateral circulation was assessed by retrospective review of angiographic images. Follow-up consisted of a standardized patient questionnaire and review of radiologic and medical records. The mean follow-up time was 35 months (range, 5-64 months). Eleven of the 47 patients with abdominal aortic aneurysms (AAA) (23%) and 19 of the 24 patients with iliac aneurysms (79%) required IIA embolization. One patient with AAA and another with iliac aneurysm had unintentional occlusion of an IIA by extension of the stent-graft over their origins. A total of seven patients had bilateral occlusion of the IIAs after the procedure. Additionally, the inferior mesenteric arteries (IMAs) of two other patients with AAA were also embolized. In six patients, all three vessels were occluded after placement of the stent-grafts. Symptoms were reported in nine of the 20 (45%) patients with iliac aneurysms and in three of the 12 (25%) patients with AAA. Symptoms consisted of buttock claudication (nine of 32, 28%), new sexual dysfunction (two of 16, 12%), and transient urinary retention (3%). Seven of the claudicants had resolution of symptoms after a mean interval of 14 months (range, 1-36 months). There were no instances of bowel ischemia, neurologic sequelae, or buttock necrosis related to these procedures. Embolization of the IIA is associated with symptoms in a significant number of patients. While symptoms are transient in most patients, they can be problematic. Efforts should be made to preserve the pelvic circulation if possible.


Mitochondrial decay in the brains of old rats: ameliorating effect of alpha-lipoic acid and acetyl-L-carnitine.
To investigate the mitochondrial decay and oxidative damage resulting from aging, the activities/kinetics of the mitochondrial complexes were examined in the brains of young and old rats as well as in old rats fed R-alpha-lipoic acid plus acetyl-L-carnitine (LA/ALC). The brain mitochondria of old rats, compared with young rats, had significantly decreased endogenous antioxidants and superoxide dismutase activity; more oxidative damage to lipids and proteins; and decreased activities of complex I, IV and V. Complex I showed a decrease in binding affinity (increase in K(m)) for substrates. Feeding LA/ALC to old rats partially restored age-associated mitochondrial dysfunction to the levels of the young rats. These results indicate that oxidative mitochondrial decay plays an important role in brain aging and that a combination of nutrients targeting mitochondria, such as LA/ALC, could ameliorate mitochondrial decay through preventing mitochondrial oxidative damage.


Laryngeal nerve monitoring and minimally invasive thyroid surgery: complementary technologies.
To determine the feasibility of the combined use of laryngeal nerve monitoring and minimally invasive thyroid surgery. Prospective, nonrandomized analysis of single-surgeon experience. Academic institution. Consecutive series of patients undergoing both minimally invasive thyroid surgery and laryngeal nerve monitoring. Incision length and incidence of temporary or permanent laryngeal nerve injury. Two hundred eighty-three patients underwent thyroid surgery at the Medical College of Georgia, Augusta, between January 2004 and November 2006. Some type of minimal-access approach (endoscopic or nonendoscopic) was used in 137 cases (48.4%) in which general anesthesia was administered. Laryngeal nerve monitoring was performed in 73 (53.3%) of these 137 cases, although the proportion of cases in which it was performed increased significantly from 8.7% (2 of 23 cases) in 2004 to 95.2% (58 of 61 cases) in 2006 (P < .001). There were no cases of permanent nerve injury. The incidence of temporary recurrent laryngeal nerve paresis was 4.3% (4 of 92 nerves at risk) in the cases in which laryngeal nerve monitoring was used and 6.0% (5 of 84 nerves at risk) in the cases in which the nerve was visually identified without use of a monitor. This difference failed to reach statistical significance (P = .73), which may reflect an insufficient sample size. Monitoring of the laryngeal nerves is feasible in minimal-access thyroid surgery and may serve as a meaningful adjunct to the visual identification of nerves.


Plastic deformation and twinning mechanisms in magnesian calcites: a non-equilibrium computer simulation study.
Deformation twinning provides a mechanism for energy dissipation in crystalline structures, with important implications on the mechanical response of carbonate biogenic materials. Carbonate crystals can incorporate magnesium, e.g. in the sea, modifying their elastic response significantly. We present a full atom computational investigation of the dependence of the twinning response of calcite with magnesium content, covering compositions compatible with three main structures, calcite, dolomite and magnesite. We find, in agreement with experiments that the incorporation of magnesium disfavors twinning as a dissipation mechanism in ordered structures (dolomite, magnesite), however the response is strongly dependent on the arrangement of the magnesium ions in the crystal structure. We show that structures with a high content of magnesium (>33%) in a disordered arrangement, lead to plastic response before twinning or fracturing. We demonstrate that the position of the magnesium ions plays a key role in the determination of the crystal deformation mode. This observation is correlated with the formation of percolation clusters of magnesium in magnesian calcites.


Monoclonal antibodies against human T cell leukemia-lymphoma virus (HTLV) p24 internal core protein. Use as diagnostic probes and cellular localization of HTLV.
Four monoclonal antibodies, human T cell leukemia-lymphoma virus (HTLV) 6, 7, 8, and 9, which react with the 24,000 dalton internal core protein of HTLVI, have been developed. These monoclonal antibodies reacted with only HTLV-infected cells and not with a broad spectrum of normal, neoplastic, mitogen-stimulated, or virus-infected cells and tissues. HTLV 6, 7, 8, and 9 identified at least two different antigenic determinants on HTLV p24 that were also recognized by antibodies present in HTLV+ patient sera. Monoclonal antibodies HTLV 6, 7, 8, and 9 reacted in indirect immunofluorescence assays with HTLV p24 localized at the cell surface of 5-d cultures of HTLV-infected T cells and, as well, reacted with T cells infected with HTLVII, a new type of HTLV isolated from a patient (MO) with a T cell variant of hairy cell leukemia. Thus, HTLV 6, 7, 8, and 9 should prove to be useful diagnostic reagents in the identification of HTLV- and HTLVII-infected T cells.


Hormone-sensitive lipase knockouts.
All treatments for obesity, including dietary restriction of carbohydrates, have a goal of reducing the storage of fat in adipocytes. The chief enzyme responsible for the mobilization of FFA from adipose tissue, i.e., lipolysis, is thought to be hormone-sensitive lipase (HSL). Studies of HSL knockouts have provided important insights into the functional significance of HSL and into adipose metabolism in general. Studies have provided evidence that HSL, though possessing triacylglycerol lipase activity, appears to be the rate-limiting enzyme for cholesteryl ester and diacylglycerol hydrolysis in adipose tissue and is essential for complete hormone stimulated lipolysis, but other triacylglycerol lipases are important in mediating triacylglycerol hydrolysis in lipolysis. HSL knockouts are resistant to both high fat diet-induced and genetic obesity, displaying reduced quantities of white with increased amounts of brown adipose tissue, increased numbers of adipose macrophages, and have multiple alterations in the expression of genes involved in adipose differentiation, including transcription factors, markers of adipocyte differentiation, and enzymes of fatty acid and triglyceride synthesis. With disruption of lipolysis by removal of HSL, there is a drastic reduction in lipogenesis and alteration in adipose metabolism.


Nanoscale residual stress-field mappingaround nanoindents in SiCby IR s-SNOM and confocal Raman microscopy.
We map a nanoindent in a silicon carbide (SiC) crystal by infrared (IR) scattering-type scanning near-field optical microscopy (s-SNOM) and confocal Raman microscopy and interpret the resulting images in terms of local residual stress-fields. By comparing near-field IR and confocal Raman images, we find that the stress-induced shifts of the longitudinal optical phonon-frequencies (LO) and the related shift of the phonon-polariton near-field resonance give rise to Raman and s-SNOM image contrasts, respectively. We apply single-frequency IR s-SNOM for nanoscale resolved imaging of local stress-fields and confocal Raman microscopy to obtain the complete spectral information about stress-induced shifts of the phonon frequencies at diffraction limited spatial resolution. The spatial extension of the local stress-field around the nanoindent agrees well between both techniques. Our results demonstrate that both methods ideally complement each other, allowing for the detailed analysis of stress-fields at e.g. material and grain boundaries, in Micro-Electro-Mechanical-Systems (MEMS), or in engineered nanostructures.


Influence of ADRB2 Gln27Glu and ADRB3 Trp64Arg polymorphisms on body weight and body composition changes after a controlled weight-loss intervention.
The β-2 and β-3 adrenergic receptors (ADRB2 and ADRB3) are thought to play a role in energy expenditure and lipolysis. However, the effects of the ADRB2 glutamine (Gln) 27 glutamic acid (glutamate) (Glu) and ADRB3 tryptophan (Trp) 64 arginine (Arg) polymorphisms on weight loss remain controversial. The aim of this study was to investigate the effect of these polymorphisms on changes in weight and body composition during a controlled weight-loss program. One hundred seventy-three healthy overweight and obese participants (91 women, 82 men) aged 18-50 years participated in a 22-week-long intervention based on a hypocaloric diet and exercise. They were randomly assigned to 1 of 4 groups: strength, endurance, strength and endurance combined, and physical activity recommendations only. Body weight, body mass index (BMI), and body composition variables were assessed before and after the intervention. Genetic analysis was carried out according to standard protocols. No effect of the ADRB2 gene was shown on final weight, BMI, or body composition, although in the supervised male group, Glu27 carriers tended to have greater weight (p = 0.019, 2.5 kg) and BMI (p = 0.019, 0.88 kg/m(2)) reductions than did noncarriers. There seems to be an individual effect of the ADRB3 polymorphism on fat mass (p = 0.004) and fat percentage (p = 0.036), in addition to an interaction with exercise for fat mass (p = 0.038). After the intervention, carriers of the Arg64 allele had a greater fat mass and fat percentage than did noncarriers (p = 0.004, 2.8 kg). In conclusion, the ADRB2 Gln27Glu and ADRB3 Trp64Arg polymorphisms may influence weight loss and body composition, although the current evidence is weak; however, further studies are necessary to clarify their roles.


Antibacterial activity of vegetables and juices.
We evaluated the antibacterial activities of various fruit and vegetable extracts on common potential pathogens including antibiotic-resistant strains. Standardized bacterial inocula were added to serial dilutions of sterile vegetable and fruit extracts in broth, with final bacterial concentrations of 10(4-5) cells/mL. After overnight incubation at 35 degrees C, antibacterial activity was measured by minimum inhibitory and minimum bactericidal dilutions (for raw juices) or concentrations (for tea). Among the vegetable and fruit extracts tested, all green vegetables showed no antibacterial activity on Staphylococcus epidermidis and Klebsiella pneumoniae. All purple and red vegetable and fruit juices had antibacterial activities in dilutions ranging from 1:2 to 1:16. Garlic juice had significant activity, with bactericidal action in dilutions ranging up to 1:128 of the original juice. Tea also had significant activity, with bactericidal action in concentrations ranging up to 1.6 mg/mL, against a spectrum of pathogens including resistant strains such as methicillin- and ciprofloxacin-resistant staphylococci, vancomycin-resistant enterococci, and ciprofloxacin-resistant Pseudomonas aeruginosa. Tea and garlic have the potential for exploration of broader applications as antibacterial agents.


Congenital Brain Abnormalities and Zika Virus: What the Radiologist Can Expect to See Prenatally and Postnatally.
Purpose To document the imaging findings associated with congenital Zika virus infection as found in the Instituto de Pesquisa in Campina Grande State Paraiba (IPESQ) in northeastern Brazil, where the congenital infection has been particularly severe. Materials and Methods From June 2015 to May 2016, 438 patients were referred to the IPESQ for rash occurring during pregnancy or for suspected fetal central nervous system abnormality. Patients who underwent imaging at IPESQ were included, as well as those with documented Zika virus infection in fluid or tissue (n = 17, confirmed infection cohort) or those with brain findings suspicious for Zika virus infection, with intracranial calcifications (n = 28, presumed infection cohort). Imaging examinations included 12 fetal magnetic resonance (MR) examinations, 42 postnatal brain computed tomographic examinations, and 11 postnatal brain MR examinations. Images were reviewed by four radiologists, with final opinion achieved by means of consensus. Results Brain abnormalities seen in confirmed (n = 17) and presumed (n = 28) congenital Zika virus infections were similar, with ventriculomegaly in 16 of 17 (94%) and 27 of 28 (96%) infections, respectively; abnormalities of the corpus callosum in 16 of 17 (94%) and 22 of 28 (78%) infections, respectively; and cortical migrational abnormalities in 16 of 17 (94%) and 28 of 28 (100%) infections, respectively. Although most fetuses underwent at least one examination that showed head circumference below the 5th percentile, head circumference could be normal in the presence of severe ventriculomegaly (seen in three fetuses). Intracranial calcifications were most commonly seen at the gray matter-white matter junction, in 15 of 17 (88%) and 28 of 28 (100%) confirmed and presumed infections, respectively. The basal ganglia and/or thalamus were also commonly involved with calcifications in 11 of 17 (65%) and 18 of 28 (64%) infections, respectively. The skull frequently had a collapsed appearance with overlapping sutures and redundant skin folds and, occasionally, intracranial herniation of orbital fat and clot in the confluence of sinuses. Conclusion The spectrum of findings associated with congenital Zika virus infection in the IPESQ in northeastern Brazil is illustrated to aid the radiologist in identifying Zika virus infection at imaging. (©) RSNA, 2016 Online supplemental material is available for this article.


Understanding family-school engagement across and within elementary- and middle-school contexts.
Although family-school engagement is important across child and adolescent development, most research, programs, and policies have focused primarily on elementary students and contexts. The current study extends beyond elementary settings by exploring the unique and shared contributions of developmental context on family-school engagement (i.e., across and within elementary- and middle-school settings). Data were drawn from two randomized controlled trials that evaluated the efficacy of teacher training in universal classroom-management practices. Participants included 3,174 students and 207 teachers across 21 elementary and middle schools in the Midwest. Using hierarchical linear modeling, results revealed that family-school engagement was significantly higher in elementary than in middle schools. Student-level characteristics (i.e., identifying as White, participation in the free/reduced-price lunch program, and having lower levels of disruptive behavior) were also associated with higher levels of family-school engagement. In addition, student characteristics (i.e., race/ethnicity and level of disruptive behavior) moderated the relations between family-school engagement and developmental context. Regardless of developmental context, family-school engagement predicted positive end-of-year behavioral outcomes (i.e., increases in youth prosocial skills and decreases in youth concentration problems, disruptive behaviors, and emotional dysregulation). Last, moderation analyses revealed that these effects of family-school engagement were especially pronounced in middle school for concentration problems and emotional dysregulation. Overall, findings provide further support for the value of family-school engagement across development in fostering positive youth outcomes. However, it is evident that more steps must be taken to ensure family-school engagement practices are developed to support the unique needs of middle-school students and contexts. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Use of epidemiological and entomological tools in the control and elimination of malaria in Ethiopia.
Malaria is the leading public health problem in Ethiopia where over 75% of the land surface is at risk with varying intensities depending on altitude and season. Although the mortality because of malaria infection has declined much during the last 15-20 years, some researchers worry that this success story may not be sustainable. Past notable achievements in the reduction of malaria disease burden could be reversed in the future. To interrupt, or even to eliminate malaria transmission in Ethiopia, there is a need to implement a wide range of interventions that include insecticide-treated bed nets, indoor residual spraying, improved control of residual malaria transmission, and improved diagnostics, enhanced surveillance, and methods to deal with the emergence of resistance both to drugs and to insecticides. Developments during the past years with increasing awareness about the role of very low levels of malaria prevalence can sustain infections, may also demand that tools not used in the routine control efforts to reduce or eliminate malaria, should now be made available in places where malaria transmission occurs.


Graft IL-33 regulates infiltrating macrophages to protect against chronic rejection.
Alarmins, sequestered self-molecules containing damage-associated molecular patterns, are released during tissue injury to drive innate immune cell proinflammatory responses. Whether endogenous negative regulators controlling early immune responses are also released at the site of injury is poorly understood. Herein, we establish that the stromal cell-derived alarmin interleukin 33 (IL-33) is a local factor that directly restricts the proinflammatory capacity of graft-infiltrating macrophages early after transplantation. By assessing heart transplant recipient samples and using a mouse heart transplant model, we establish that IL-33 is upregulated in allografts to limit chronic rejection. Mouse cardiac transplants lacking IL-33 displayed dramatically accelerated vascular occlusion and subsequent fibrosis, which was not due to altered systemic immune responses. Instead, a lack of graft IL-33 caused local augmentation of proinflammatory iNOS+ macrophages that accelerated graft loss. IL-33 facilitated a metabolic program in macrophages associated with reparative and regulatory functions, and local delivery of IL-33 prevented the chronic rejection of IL-33-deficient cardiac transplants. Therefore, IL-33 represents what we believe is a novel regulatory alarmin in transplantation that limits chronic rejection by restraining the local activation of proinflammatory macrophages. The local delivery of IL-33 in extracellular matrix-based materials may be a promising biologic for chronic rejection prophylaxis.


Upregulation of Glutamate Transporter 1 by Clavulanic Acid Administration and Attenuation of Allodynia and Hyperalgesia in Neuropathic Rats.
Clavulanic acid (CLAV) is structurally similar to ceftriaxone, a potent stimulator of glial GlutamateTransporter-1 (GLT-1) expression. The present study aims at exploring the anti-nociceptive effects of CLAV, a beta-lactamase inhibitor in rats underwent sciatic nerve Chronic Constriction Injury (CCI). CLAV (12.5, 25, 50 mg/kg) was administered intraperitoneally after the surgery for 14 consecutive days. Behavioral pain parameters were evaluated before and 3, 5, 7, 10 and 14 days after injury. Spinal GLT-1 level was measured via western blotting at days 7 and 14. CCI led to mechanical allodynia, cold allodynia and thermal hyperalgesia which started on postoperative days 3 and continued until the end of study. We found that CLAV (12.5 and 25 mg/kg) significantly attenuated all pain related behaviors as compared to the CCI animals treated with normal saline. Protein level of GLT-1 was down-regulated on day 14 following CCI and this phenomenon was reversed by fourteen days treatment of CLAV at the low doses of 12.5 and 25 mg/kg. These results suggest that CLAV might provide a new therapeutic strategy for neuropathic pain and its effect might be partially associated with the up-regulation of GLT-1.


Changes in phosphatidylinositol-4,5-bisphosphate 10 seconds after stimulation of washed rabbit platelets with ADP.
Adenosine diphosphate (ADP) induced aggregation of rabbit platelets, without the release reaction, causes a significant decrease (7%) in the amount of phosphatidylinositol-4,5-bisphosphate (PIP2) at 10 sec and at 60 sec (11%). In platelets prelabeled with 32P-phosphate, this decrease in PIP2 is associated with a decrease in PIP2 radioactivity, which is significant at 50 sec. The decrease in PIP2 is sufficient to mobilize about 0.18 nmole Ca2+/10(9) platelets. In view of the key role played by Ca2+ in ADP-induced platelet shape change and aggregation, this evidence is compatible with the hypothesis that changes in PIP2 can be a source of calcium for cellular responses to agonists.


Influence of Copolymer Composition on In Vitro and In Vivo Performance of Celecoxib-PVP/VA Amorphous Solid Dispersions.
Previous studies suggested that an amorphous solid dispersion with a copolymer consisting of both hydrophobic and hydrophilic monomers could improve the dissolution profile of a poorly water-soluble drug compared to the crystalline form. Therefore, this study investigated the influence of the copolymer composition of polyvinylpyrrolidone/vinyl acetate (PVP/VA) on the non-sink in vitro dissolution behavior and in vivo performance of celecoxib (CCX) amorphous solid dispersions. The study showed that the hydrophilic monomer vinylpyrrolidone (VP) was responsible for the generation of CCX supersaturation whereas the hydrophobic monomer vinyl acetate (VA) was responsible for the stabilization of the supersaturated solution. For CCX, there was an optimal copolymer composition around 50-60% VP content where further replacement of VP monomers with VA monomers did not have any biopharmaceutical advantages. A linear relationship was found between the in vitro AUC(0-4h) and in vivo AUC(0-24h) for the CCX:PVP/VA systems, indicating that the non-sink in vitro dissolution method applied in this study was useful in predicting the in vivo performance. These results indicated that when formulating a poorly water-soluble drug as an amorphous solid dispersion using a copolymer, the copolymer composition has a significant influence on the dissolution profile and in vivo performance. Thus, the dissolution profile of a drug can theoretically be tailored by changing the monomer ratio of a copolymer with respect to the required in vivo plasma-concentration profile. As this ratio is likely to be drug dependent, determining the optimal ratio between the hydrophilic (dissolution enhancing) and hydrophobic (crystallization inhibiting) monomers for a given drug is imperative.


Embodied Perception and the Economy of Action.
Perception informs people about the opportunities for action and their associated costs. To this end, explicit awareness of spatial layout varies not only with relevant optical and ocular-motor variables, but also as a function of the costs associated with performing intended actions. Although explicit awareness is mutable in this respect, visually guided actions directed at the immediate environment are not. When the metabolic costs associated with walking an extent increase-perhaps because one is wearing a heavy backpack-hills appear steeper and distances to targets appear greater. When one is standing on a high balcony, the apparent distance to the ground is correlated with one's fear of falling. Perceiving spatial layout combines the geometry of the world with behavioral goals and the costs associated with achieving these goals.


Cancer incidence patterns among children and adolescents in Taiwan from 1995 to 2009: a population-based study.
Currently, little information is available on childhood cancer incidence rates in Eastern Asia. The objective of this study was to report the first population-based cancer surveillance of children and adolescents in Taiwan. Data from the Taiwan Cancer Registry were examined for cancer frequencies and incidence rates among individuals ages birth to 19 years from 1995 to 2009. Types of cancers were grouped according to the International Classification of Childhood Cancer. Rates were compared by sex and age. For further comparisons with other countries, rates were age standardized to the 2000 world standard population in 5-year age groups. Trends in incidence rates also were evaluated. In total, 12,315 individuals were diagnosed with childhood cancers, for an age-standardized incidence rate (ASR) of 132.1 per million person-years from 1995 to 2009. The male-to-female incidence rate ratio was 1.19. Overall, leukemias were the most common cancer (ASR, 39.1 per million person-years), followed by central nervous system neoplasms (15.8 per million person-years), and lymphomas (15.3 per million person-years). During the 15-year study period, the incidence rates increased by 1% annually. Compared with other countries, the rate of hepatic tumors was 2 times greater in Taiwan. The rate of germ cell neoplasms in Taiwan was similar to that in the United States and was 1.3 to 1.9 times greater compared with Canada, Brazil, Israel, and Japan. Based on the current data, the observed increase in overall incidence rates was attributable only marginally to improvements in case ascertainment and diagnostic procedures. The high rates of malignant hepatic tumors and germ cell neoplasms in Taiwan suggest variations in the background risk factors.


The timing of hibernation in Tasmanian echidnas: why do they do it when they do?
We investigated the patterns of hibernation and arousals in seven free-ranging echidnas Tachyglossus aculeatus setosus (two male, five female) in Tasmania using implanted temperature data loggers. All echidnas showed a 'classical' pattern of mammalian hibernation, with bouts of deep torpor interrupted by periodic arousals to euthermia (mean duration 1.04+/-0.05 (n=146). Torpor bout length increased as body temperature fell during the hibernation season, and became more variable as temperature rose again. Hibernation started in late summer (February 28+/-5 days, n=6) and males aroused just before the winter solstice (June 15+/-3 days, n=3), females that subsequently produced young aroused 40 days later (July 25+/-3, n=4) while females that did not produce young hibernated for a further two months (arousal Sept 27+/-5, n=7). We suggest that hibernation in Tasmanian echidnas can be divided into two phases, the first phase, marked by declining minimum body temperatures as ambient temperature falls, appears to be obligatory for all animals, while the second phase is 'optional' and is utilised to varying amounts by females. We suggest that early arousal and breeding is the favoured option for females in good condition, and that the ability to completely omit breeding in some years, and hibernate through to spring is an adaptation to an uncertain climate.


Does cinacalcet improve the prognosis of dialysis patients?
Appropriate control of serum calcium (Ca) and inorganic phosphate (Pi) levels is required for better prognosis of dialysis patients. Cinacalcet is known to reduce not only serum parathyroid hormone (PTH) but also Ca and Pi levels; however, it remains unclear whether cinacalcet can ultimately improve the prognosis of such patients. In this paper, the ongoing prospective observational study (Q Cohort Study) and double-blind randomized controlled study (EVOLVE Study) are introduced. In the Q Cohort Study, cinacalcet therapy is indicated when intact PTH levels exceed 180 pg/mL, accounting for 31.3% of the study population (N = 3009). In the EVOLVE Study, the primary endpoint is the time to occurrence of composite events including all-cause mortality or nonfatal cardiovascular events. There is a related pilot study that treated patients over a 6-month period with cinacalcet. The findings showed that cinacalcet reduced serum PTH, Ca, and Pi levels and that if the patient had lower PTH levels at baseline, the dosage of vitamin D could be greatly reduced. Thus, in some patients concomitant vitamin D and cinacalcet therapy may be preferred to vitamin D alone.