Low expression of ryanodine receptor 2 is associated with poor prognosis in thyroid carcinoma.
Genetic alterations are vital in the progression of thyroid carcinoma. Ryanodine receptor 2 (RyR2) is reported to serve an important role in several types of human carcinoma. However, the expression and effect of RyR2 in thyroid carcinoma remain unknown. Therefore, the present study analyzed the status of RyR2 in thyroid carcinoma using bioinformatics tools. The mRNA profiles of thyroid carcinoma were downloaded from The Cancer Genome Atlas. RyR2 was distinguished as a differentially expressed gene that has not been reported in thyroid carcinoma. Further analysis indicated that there was selective downregulation of RyR2 expression in thyroid carcinoma tissues compared with that in normal thyroid tissues. Survival analysis showed that RyR2 expression was associated with poorer disease-free survival (DFS) for all patients with thyroid carcinoma. Univariate analysis revealed that a low expression of RyR2 was significantly associated with lymphatic metastasis, extracapsular extension, and the Tumor-Node-Metastasis stage. Cox analysis demonstrated that RyR2 was an independent prognostic factor in thyroid carcinoma for DFS. The biological processes and signaling pathways of RyR2 were reviewed with Gene Set Enrichment Analysis. In conclusion, the present study has revealed that RyR2 is downregulated in thyroid carcinoma, and that low expression of RyR2 is associated with poor prognosis in patients with thyroid carcinoma. RyR2 may therefore serve as a promising tumor suppressor gene in thyroid carcinoma.


Cardiac xenotransplantation in primates.
Successful cardiac xenotransplantation would alleviate the severe shortage of donor organs that presently limits the availability of cardiac transplantation. Early attempts at human xenotransplantation achieved minimal success. However, the effectiveness of cyclosporine in nonhuman xenotransplant models has received little experimental investigation. We have therefore studied the effect of cyclosporine-based immunosuppression in primate cardiac xenograft models using cynomolgus monkey donors and baboon recipients. Donor hearts were transplanted heterotopically into the necks of recipients or in the orthotopic position. Recipients were treated with no immunosuppression (controls), cyclosporine and steroids, or cyclosporine, steroids, azathioprine, and antithymocyte globulin. Statistically significant prolongation of graft survival compared to the control group was observed in the heterotopic groups. Mean survival time of the cyclosporine-treated and steroid-treated heterotopic grafts was 61 days compared to 6 days for grafts in the control group (p = 0.01); the addition of azathioprine and antithymocyte globulin yielded a mean survival of 84 days (p less than 0.01). No significant increase in graft survival was noted in the orthotopic groups treated with either immunosuppressive regimen. Although long-term use of human xenografts as an alternative for heart replacement is not supported by these data, further investigation of the orthotopic model is clearly justified.


Tailoring anisotropic perfect absorption in monolayer black phosphorus by critical coupling at terahertz frequencies.
A metamaterial perfect absorber composed of a black phosphorus (BP) monolayer, a photonic crystal, and a metallic mirror is designed and investigated to enhance light absorption at terahertz frequencies. Numerical results reveal that the absorption is enhanced greatly with narrow spectra due to critical coupling, which is enabled by guided resonances. Intriguingly, the structure manifests the unusual polarization-dependent feature attributable to the anisotropy of black phosphorus. The quality factor of the absorber can be as high as 95.1 for one polarization while 63.5 for another polarization, which is consistent with the coupled wave theory. The absorption is tunable by varying key parameters, such as period, radius, slab thickness, incident angle, and polarization angle. Furthermore, the state of the system (i.e., critical coupling, over coupling, and under coupling) can be tuned by changing the electron doping of BP, thus achieving various applications. This work offers a paradigm to enhance the light-matter interaction in monolayer BP without plasmonic response, and this easy-to-fabricate structure will provide potential applications in BP-based devices.


Occupational risk factors for pancreatic cancer among female textile workers in Shanghai, China.
To investigate whether occupational exposures to dusts and chemicals in the Shanghai textile industry are associated with risk of pancreatic cancer. A case cohort study nested in a cohort of 267,400 female textile workers in Shanghai, China was conducted among 180 incident pancreatic cancer cases and an age stratified randomly selected comparison subcohort (n = 3188). A complete occupational history of work in the textile industry was obtained for each woman, and was linked to a job exposure matrix developed for the textile industry to estimate exposures to specific dusts and chemicals. Cumulative exposures to cotton dust and endotoxin were reconstructed from historical and contemporaneous measurements. After adjusting for smoking status, a trend of decreasing risk of pancreatic cancer was observed for increasing cumulative exposures to cotton dust and endotoxin with a lag of 20 years. The hazard ratios for women cumulatively exposed to >143.4 mg/m3 x years of cotton dust and >3530.6 EU/m3 x years of endotoxin were 0.6 (95% CI 0.3 to 0.9) and 0.5 (95% CI 0.3 to 0.9), respectively, compared to unexposed women. There was little evidence that exposures to other textile dusts and chemicals were associated with risk of pancreatic cancer. Occupational exposure to cotton dust and endotoxin in the textile industry may have reduced risks of pancreatic cancer in this cohort. These associations should be replicated by others before making a firm conclusion of their possible effects on pancreatic cancer.


Hematopoietic Cell Transplantation for Acute Panmyelosis with Myelofibrosis: A Retrospective Study in Japan.
Acute panmyelosis with myelofibrosis (APMF) is a rare subtype of acute myeloid leukemia characterized by acute onset of cytopenias and bone marrow fibrosis in the absence of splenomegaly. Because the prognosis of APMF is extremely poor even after chemotherapy, hematopoietic cell transplantation (HCT) has been used to treat APMF. However, the outcome after HCT for APMF remains unclear. To evaluate the outcomes and prognostic factors after HCT as a therapeutic modality for APMF, we retrospectively analyzed the Japanese registration data of 40 APMF patients who received allogeneic and syngeneic HCT between 2005 and 2015. The median age at HCT was 53.5 years (range, 16 to 70). The disease status at HCT was first complete remission (CR1) in 13 patients (33%). The probability of overall survival and the cumulative incidence of relapse at 3 years were 24% and 59%, respectively. Univariate analysis identified that female sex and disease status CR1 at the time of HCT were significantly associated with higher overall survival. Although APMF patients have a poor long-term prognosis even after syngeneic and allogeneic HCT, these data suggested that allogeneic HCT offered a curative option for APMF.


Nuclear morphology and c-Jun N-terminal kinase 1 expression differentiate serum-starved oxidative stress signalling from hydrogen peroxide-induced apoptosis in retinal neuronal cell line.
Oxidative stress induced by serum starvation and H2O2 exposure, both triggers apoptosis in retinal neuronal cell line RGC-5 (retinal ganglion cell-5). We have examined whether, despite excess generation of ROS (reactive oxygen species) and apoptosis induction, there is any dissimilarity in nuclear morphology and apoptotic signalling pathway in RGC-5 under these conditions. Sub-confluent cells were treated either with H2O2 or maintained in SFM (serum-free medium). ROS level was detected along with nuclear morphology and ultrastructural analysis. Generation of excess intracellular ROS, nuclear localization of Bax and caspase 3 activation along with decrease of cellular viability, confirmed apoptosis induction in RGC-5 by 72 h serum starvation and 500 M H2O2 exposure for 1 h. Nuclear swelling as supported by nuclear cytoplasmic ratio and conspicuous black spots with nuclear remodelling were observed only upon SFM, but not with H2O2 treatment. Serum starvation did not alter JNK1 (c-Jun N-terminal kinase 1) expression, although nuclear translocation and higher level of pJNK (phospho-JNK) was evident. Conversely, H2O2 exposure blocked the expression and activation of JNK1 to phospho-JNK as a negligible level of pJNK was present in the cytoplasm. Despite similar ROS generation in both the conditions, difference in nuclear morphology and JNK1 expression leads to the hypothesis that RGC-5 cells may follow different signalling pathways when challenged with serum starvation and H2O2.


The role of cardiovascular disease-associated iron overload in Libby amphibole-induced acute pulmonary injury and inflammation.
Pulmonary toxicity induced by asbestos is thought to be mediated through redox-cycling of fiber-bound and bioavailable iron (Fe). We hypothesized that Libby amphibole (LA)-induced cute lung injury will be exacerbated in rat models of cardiovascular disease (CVD)-associated Fe-overload and oxidative stress. Healthy male Wistar Kyoto (WKY), spontaneously hypertensive (SH) and SH heart failure (SHHF) rats were intratracheally instilled with 0.0, 0.25 or 1.0 mg/rat LA and examined at 1 day, 1 week or 1 month. Although histologically it was not possible to distinguish severity differences between strains in LA-induced initial inflammation and later fibrosis, quantitative assessment of biomarkers showed strain-related differences. LA-induced neutrophilic inflammation was reversible in WKY but persisted more in SH and SHHF. Lung MIP-2 mRNA increased only in WKY at 1 day in response to LA but not in SH and SHHF. Bronchoalveolar lavage fluid (BALF) protein increased in SH but not WKY at 1 week and 1 month, while γ-glutamyltransferase and N-acetyl-β-D-glucosaminidase activities increased in all strains (WKY>SH=SHHF). BALF ferritin levels were high at baseline and increased following LA exposure only in SH and SHHF. Ferritin heavy chain mRNA increased only in SHHF at 1 day. At 1 month ferritin light chain mRNA declined from already high baseline levels in SHHF but increased in WKY and SH suggesting its differential involvement in LA-induced injury in Fe-overload. Unlike WKY, both SHHF and SH failed to increase the lung lining antioxidant, ascorbate, in response to LA. We conclude that underlying CVD-associated Fe-overload is likely linked to persistent lung injury, inflammation and antioxidant decompensation following LA exposure in rats.


Low dose of gamma irradiation enhanced boronophenylalanine uptake in head and neck carcinoma cells for boron neutron capture therapy.
This study attempted to increase the boron uptake of human head and neck carcinoma SAS cells for BNCT by using a gamma dose of 0.1 Gy for combined treatment. Intracellular boron concentrations in 25 μgB/mL medium of BPA treated and BPA combined gamma-irradiation treated SAS cells were 73.8±1.73 and 95.15±1.36 ppm, respectively. After neutron irradiation, the G2/M-phase cell populations of untreated, BPA treated and BPA combined gamma-irradiation treated SAS cells were 19.31±1.71%, 52.47±2.25% and 59.19±2.63%, respectively. Experimental results indicate that the low dose gamma radiation with combination BPA treatment has the highest killing rate after neutron irradiation. Capable of significantly increasing the G2/M arrest after neutron irradiation, the combined treatment of a low dose of gamma irradiation with 25 μg B/mL medium of BPA also provided a higher killing effect for BNCT.


A Study to Find Out the Full Immunization Coverage of 12 to 23-month old Children and Areas of Under-Performance using LQAS Technique in a Rural Area of Tripura.
It is very important to analyze the factors which acts as obstacle in achieving 100% immunization among children. Lot Quality Assurance Sampling (LQAS) is one of the effective method to assess such barriers. To assess the full immunization coverage among 12 to 23-month old children of rural field practice area under Department of Community Medicine, Agartala Government Medical College and identify the factors for failure of full immunization. A community based cross-sectional study was conducted from November 2013 to October 2014 on children aged 12 to 23 months old of area under Mohanpur Community health centre. Using LQAS technique 330 samples were selected with multi-stage sampling, each sub-centre being one lot and two calculated to be the decision value. Data was collected using pre-designed pre-tested questionnaire during home visit and verifying immunization card and analysed by computer software SPSS version 21.0. The full immunization coverage among 12 to 23 months old children of Mohanpur area was found as 91.67%. Out of all the 22 sub-centres, 36.36% was found under performing as per pre-fixed criteria and the main reasons for failure of full immunization in those areas are unawareness of need of subsequent doses of vaccines and illness of the children. LQAS is an effective method to identify areas of under-performance even though overall full immunization coverage is high.


Effects of chronic ethanol treatment on monoamine levels in rat hippocampus and striatum.
We studied the effects of ethanol on concentrations of noradrenaline (NE), dopamine (DA) and serotonin (5-HT) and their metabolites in rat hippocampus and striatum. Ethanol (2 or 4 g/kg, po, from a 20% aqueous solution) was administered daily to male Wistar rats (4-13 per group) for 30 days and animals were sacrificed 30 min or 48 h after the last administration. Monoamines were measured by HPLC and considered significant at P < 0.05. A 47% increase in 5-HT levels was observed in the hippocampus with 4 g/kg ethanol in the 30-min protocol. Ethanol (2 and 4 g/kg) decreased DA (2114.5 +/- 126.4 and 1785.1 +/- 234.2 ng/g wet tissue, respectively) and 3,4-dihydroxyphenylacetic acid (DOPAC, 1477.6 +/- 132.1 and 1218.8 +/- 271.7 ng/g wet tissue, respectively) levels, while the higher dose also decreased NE (159.8 +/- 13.5), 5-HT (228.0 +/- 46.8) and 5-hydroxy-3-indoleacetic acid (5-HIAA, 304.4 +/- 37.2 ng/g wet tissue), in the striatum after a 48-h withdrawal as compared to controls (DA: 3063.9 +/- 321.3; DOPAC: 2379.6 +/- 256.0; NE: 292.8 +/- 50.2; 5-HT: 412.4 +/- 36.2; 5-HIAA: 703.9 +/- 61.4 ng/g wet tissue). In the 30-min protocol, ethanol (2 or 4 g/kg) decreased striatal NE (66 and 70%) and DA (50 and 36%) levels. On the other hand, increases were seen in 5-HIAA (146 and 153%) and 5-HT (59 and 86%) levels. Ethanol (2 g/kg, po) increased the homovanillic acid (HVA)/DA ratio (129%) in the striatum in the 30-min protocol, while at the higher dose it increased the HVA/DA ratio in the 48-h protocol (61%). These results indicate alterations in monoamines, mainly in the striatum, after chronic ethanol, which are influenced by dose and by the length of time after the last drug administration.


Fluorescent antitumor titanium(iv) salen complexes for cell imaging.
Two differently substituted fluorescent salen Ti(iv) complexes were developed. One was inactive on human cancer cells, whereas the other showed high cytotoxicity. Based on live cell imaging, both complexes penetrated the cell, but were not detected in the nuclei. Moreover, the inactive complex was trapped in endocytic vesicles, whereas the active complex accumulated in the perinuclear region and inflected phototoxicity upon continuous irradiation.


Public Health Efforts Can Impact Adoption of Current Susceptibility Breakpoints, but Closer Attention from Regulatory Bodies Is Needed.
Microbiological testing, including interpretation of antimicrobial susceptibility testing results using current breakpoints, is crucial for clinical care and infection control. Continued use of obsolete Enterobacteriaceae carbapenem breakpoints is common in clinical laboratories. The purposes of this study were (i) to determine why laboratories failed to update breakpoints and (ii) to provide support for breakpoint updates. The Los Angeles County Department of Public Health conducted a 1-year outreach program for 41 hospitals in Los Angeles County that had reported, in a prior survey of California laboratories, using obsolete Enterobacteriaceae carbapenem breakpoints. In-person interviews with hospital stakeholders and customized expert guidance and resources were provided to aid laboratories in updating breakpoints, including support from technical representatives from antimicrobial susceptibility testing device manufacturers. Forty-one hospitals were targeted, 7 of which had updated breakpoints since the prior survey. Of the 34 remaining hospitals, 27 (79%) assumed that their instruments applied current breakpoints, 17 (50%) were uncertain how to change breakpoints, and 10 (29%) lacked resources to perform a validation study for off-label use of the breakpoints on their systems. Only 7 hospitals (21%) were familiar with the FDA/CDC Antibiotic Resistance Isolate Bank. All hospitals launched a breakpoint update process; 16 (47%) successfully updated breakpoints, 12 (35%) received isolates from the CDC in order to validate breakpoints on their systems, and 6 (18%) were planning to update within 1 year. The public health intervention was moderately successful in identifying and overcoming barriers to updating Enterobacteriaceae carbapenem breakpoints in Los Angeles hospitals. However, the majority of targeted hospitals continued to use obsolete breakpoints despite 1 year of effort. These findings have important implications for the quality of patient care and patient safety. Other public health jurisdictions may want to utilize similar resources to bridge the patient safety gap, while manufacturers, the FDA, and others determine how best to address this growing public health issue.


Commit to Quit in the YMCAs: translating an evidence-based quit smoking program for women into a community setting.
Approximately 22% of women continue to smoke cigarettes despite the increased risk of cancer associated with smoking. Regular aerobic exercise added to our Commit to Quit smoking cessation program for women improved cessation rates compared with the same cessation program plus equal contact time. This trial tested the feasibility of conducting Commit to Quit in the YMCA setting. Among the 77 women who attended informational sessions, 68% (n = 52) were eligible and 56% (N = 43) enrolled in one of five cohorts. All cohorts received the same intervention: the Commit to Quit smoking cessation program, led by Ph.D.-level psychologists, coupled with the YMCA Personal Fitness Program, led by YMCA personal trainers. On quit day in the program 17 women (39.5%) reported a 24-hr quit, and by the end of treatment 3 women (7.0%) reported a 7-day quit. Intent-to-treat analysis (baseline values carried forward) revealed a decrease in the mean number of cigarettes smoked from 9.9 at baseline (SD = 5.0) to 4.8 at the end of treatment (SD = 5.2; t = 4.7; p<.001). Self-reported exercise increased from 530.3 kcal (SD = 587.0) at baseline to 1,256.4 kcal (SD = 1,263.1) at end of treatment (t = -2.489 p = .017). Participants reported high ratings of satisfaction with the smoking cessation program and Personal Fitness Program. Preliminary feasibility and acceptability were demonstrated as we translated an evidence-based intervention into the YMCA setting.


Dual-target cost in visual search for multiple unfamiliar faces.
The efficiency of visual search for one (single-target) and either of two (dual-target) unfamiliar faces was explored to understand the manifestations of capacity and guidance limitations in face search. The visual similarity of distractor faces to target faces was manipulated using morphing (Experiments 1 and 2) and multidimensional scaling (Experiment 3). A dual-target cost was found in all experiments, evidenced by slower and less accurate search in dual- than single-target conditions. The dual-target cost was unequal across the targets, with performance being maintained on one target and reduced on the other, which we label "preferred" and "non-preferred" respectively. We calculated the capacity for each target face and show reduced capacity for representing the non-preferred target face. However, results show that the capacity for the non-preferred target can be increased when the dual-target condition is conducted after participants complete the single-target conditions. Analyses of eye movements revealed evidence for weak guidance of fixations in single-target search, and when searching for the preferred target in dual-target search. Overall, the experiments show dual-target search for faces is capacity- and guidance-limited, leading to superior search for 1 face over the other in dual-target search. However, learning faces individually may improve capacity with the second face. (PsycINFO Database Record


Flexible & Stretchable EMG Sensor for Lower Extremity Amputee.
EMG signals can be widely used for indicators of muscle activity, and it can be used for robot control. However, the practical use of the EMG sensor for the amputee has been limited due to harsh conditions in the socket where strong pressure and friction exist. In this paper, thus we suggested a flexible and stretchable EMG Sensor. It is designed to withstand the pressure of the socket and to be used repeatedly with soft adhesive material. The performance of mechanical and electrical properties is investigated, and the muscle signals are recorded in static and dynamic (jump and gait) conditions. The selectivity of the recorded muscle signals during dorsiflexion and plantar flexion shows better than that of commercial electrodes indicating that it could be used for control of robotic legs in the future.Clinical Relevance- The flexible material and stretchable electrode pattern could be helpful in clinical research for an amputee.


Extent of atrial participation in atrioventricular-reciprocating tachycardia.
Twenty-one patients with atrioventricular (AV) bypass tracts underwent electrophysiologic studies. The bypass tract was left-sided in 15 patients, septal in five and right-sided in one patient. Orthodromic AV-reciprocating tachycardia was induced in all 21 patients, with a mean tachycardia cycle length of 342 +/- 59 msec. The introduction of single stimuli in the high right atrium during tachycardia resulted in simultaneous dissociation of the high right atrial and low septal atrial electrograms in nine patients. In six patients, high right atrial overdrive pacing during tachycardia resulted in simultaneous dissociation of the high right atrial and low septal atrial electrograms for two to five consecutive beats. All patients in whom the low septal atrial electrogram was dissociated from the tachycardia had a left-sided bypass tract. In no patient was the coronary sinus atrial electrogram dissociated from the tachycardia by high right atrial pacing. Dissociation of the low septal atrial electrogram (as recorded in the His bundle electrogram) from AV-reciprocating tachycardia suggests that the portion of the right atrium adjacent to the AV node may not be a necessary link in the tachycardia circuit. This observation suggests that the site of entry of left-sided impulses into the AV node may be different from that of right-sided impulses.


Unsuccessful control of abdominal aortic aneurysm by bypass and ligation.
Two patients developed abdominal aortic aneurysm rupture following bilateral iliac artery ligation and axillobifemoral bypass. The first patient developed his rupture several weeks after outflow ligation and apparent thrombosis of the aneurysm. At autopsy, the aneurysmal rupture occurred in the left posterior junction between the thrombosed aneurysm and the normal aorta. In the second case, the aneurysm was not completely thrombosed and plans were in progress for thrombosis of the aneurysm when the patient developed frank rupture, necessitating operative intervention. The authors await the published experience of others with bilateral common iliac artery ligation and extra-anatomic bypass for abdominal aortic aneurysm, but these authors do not currently recommend this management plan.


Replication and Excretion of the Live Attenuated Tetravalent Dengue Vaccine CYD-TDV in a Flavivirus-Naive Adult Population: Assessment of Vaccine Viremia and Virus Shedding.
We assessed replication and excretion of the live attenuated tetravalent dengue vaccine (CYD-TDV) into biological fluids following vaccination in dengue-naive adults in Australia. Vaccinal viremia/shedding was assessed in a subset of participants enrolled in a lot-to-lot consistency study; 95 participants received 3 subcutaneous doses of CYD-TDV from phase 2/3 lots of the vaccine, and 8 received placebo; doses were administered 6 months apart. Quantitative reverse-transcription polymerase chain reaction (qR-PCR) analysis was used to initially detect the yellow fever virus (YFV) core protein gene in the backbone of CYD-TDV in serum, saliva and urine, followed by serotype-specific qRT-PCR analysis of samples positive for YFV by qRT-PCR (lower limit of detection, 5.16 GEq/mL). YFV viremia was detected by qRT-PCR in 69.5% of participants (66 of 95) who received CYD-TDV, mainly 6-14 days after injection 1. The serotypes detected were serotype 4 (in 68.2% of participants [45 of 95]), serotype 3 (in 19.7% [13 of 95]), and serotype 1 (in 12.1% [8 of 95]); serotype 2 was not detected. None of the placebo recipients had vaccinal viremia/shedding. No participants had detectable viral shedding into saliva at levels above the lower limit of quantitation. Two participants had low-level viral shedding (serotype 3) in urine (5.47 and 5.77 GEq/mL). None of the participants with viremia or shedding experienced concomitant fever. Low-level vaccinal viremia may occur following vaccination with CYD-TDV, but this is not associated with any symptom or adverse event. NCT01134263.


Regulation of calcium current by low-Km cyclic AMP phosphodiesterases in cardiac cells.
The voltage-gated Ca2+ current (ICa) in cardiac myocytes is regulated by cAMP-dependent phosphorylation. Although the regulation of ICa via mechanisms involving modulation of cAMP synthesis is well understood, the regulation of cAMP degradation has been less thoroughly investigated. The goal of the present study was to investigate the participation of different subclasses of cAMP phosphodiesterase (PDE) in regulating cAMP-dependent phosphorylation of Ca2+ channels in frog ventricular myocytes. Cardiomyocytes were isolated enzymatically and mechanically and were patch-clamped using the whole-cell configuration of the patch-clamp technique. The effects of various low-Km cAMP PDE inhibitors on ICa were examined. None of the inhibitors tested [milrinone, indolidan, 1-methyl 3-isobutyl xanthine (MIX), rolipram, or Ro 20-1724] were able to elevate ICa in the absence of elevated cAMP, although they all increased ICa in the presence of submaximal levels of cAMP. This result suggests that these compounds do not act directly on Ca2+ channels but rather modulate cAMP degradation. Half-maximal effects were observed with 1.4 microM milrinone and 3.4 microM MIX. Milrinone was effective when applied from either the extracellular or intracellular surface, whereas MIX was effective only when applied from the extracellular solution. In the presence of internal cGMP, which stimulates the cGMP-stimulated PDE, the low-Km cAMP PDE inhibitors had no effect on ICa, whereas high concentrations of MIX, which inhibit the cGMP-stimulated PDE, increased ICa. This would support the hypothesis that cGMP-stimulated PDE either has a much stronger capacity to hydrolyze cAMP or is more efficiently coupled to Ca2+ channels than the low-Km cAMP PDEs.


Therapeutic advantage of high-affinity anticarcinoma radioimmunoconjugates.
The effect of the relative affinity (Ka) on the antitumor efficacy of monoclonal antibodies (MAbs) has been questioned. It has previously been shown in experimental models that the use of MAbs with higher relative Kas manifests itself in a higher percentage of injected dose of MAb bound to tumor. On the other hand, mathematical models have proposed that the use of higher affinity MAbs may be disadvantageous for antitumor effects, since higher Ka MAbs would bind more antigen and prevent penetration of MAb through tumor. To test this hypothesis, three MAbs reacting to the human pancarcinoma antigen TAG-72 were used as radioimmunoconjugates for therapeutic efficacy versus the LS-174T human colon carcinoma xenograft. MAbs B72.3, CC49, and CC83 have all been shown by depletion studies to react to the same molecule and to all react with overlapping epitopes. While the relative Ka of B72.3 is 2.5 x 10(9) M-1, the relative Kas of CC49 and CC83 are 16.2 and 27.7 x 10(9) M-1, respectively. Each MAb was radiolabeled with 131I, and each radioimmunoconjugate was assayed at five dose levels for therapeutic efficacy using the human xenograft model. The results of these studies demonstrate substantial therapeutic advantage of the higher affinity MAbs CC49 and CC83 versus B72.3 at every dose level. While 500 microCi of B72.3 were required to reduce tumor growth in only a minority of tumor-bearing animals, the use of the same amount or less of the radioimmunoconjugates of CC49 or CC83 resulted in strong antitumor effects in 80 to 100% of tumor-bearing animals. Thus, stronger antitumor effects were seen using as little as 2.5- to 3-fold less of the higher Ka immunoconjugates CC49 and CC83 as compared with B72.3. While we acknowledge the potential disadvantages of higher Ka MAbs in some situations, at least the experimental studies and model system described here show that a distinct therapeutic advantage exists with the use of higher affinity immunoconjugates.


Factors associated with dropout in a group weight-loss programme: a longitudinal investigation.
Attrition is a major limitation of most weight management intervention programmes. The present study aimed to conduct an extensive investigation of personal, sociodemographic and treatment-related factors associated with attrition at different stages of a 10-week group weight-loss programme. The present study is part of a longitudinal, clinical intervention study comparing three conditions in a 10-week group programme: Control, Behavioural Intentions and Implementation Intentions. The study included 587 participants with a mean (SD) age of 46 (11) years (range 18-78 years) and a mean (SD) body mass index (BMI) of 31.9 (5.5) kg m(-2), with 90% being female. To characterise dropout in each week separately, as well as overall dropout (dropout until week 9, the median time of dropout), we tested several logistic regression models, including multiple imputations to cope with missing data. The results of the different dropout models consistently showed that a smaller reduction in BMI in the first 2 weeks of the programme was the strongest predictor of dropout. Dropout in the tenth and last week differed from the earlier weeks both in the relatively high dropout rate (56% of total dropout) and in that, in contrast to earlier weeks, the week 10 model included the reduction in BMI during the last 2 weeks before dropout but did not include the reduction in BMI at the initiation of the intervention. Weight-loss in the beginning of the programme is a crucial independent determinant of dropout in each week except the last one. This finding is important because it suggests a simple assessment for a major dropout risk factor in adult weight-loss intervention programmes.


Restoration of congenitally missing maxillary lateral incisors using mini implants.
In this author's opinion, the advent of mini implants, or small diameter implants (SDIs) as they are more frequently being called, is becoming in many situations a viable alternative to the more traditional root form implants. They offer advantages of less cost, a more simplified placement technique, usually faster healing times, and generally less post-operative complications. A case presentation is given to demonstrate their usage for a narrow ridge application to restore congenitally missing maxillary lateral incisors.


Necrotizing Ulcerative Gingivitis.
Necrotizing ulcerative gingivitis (NUG) is a typical form of periodontal diseases. It has an acute clinical presentation with the distinctive characteristics of rapid onset of interdental gingival necrosis, gingival pain, bleeding, and halitosis. Systemic symptoms such as lymphadenopathy and malaise could be also found. There are various predisposing factors such as stress, nutritional deficiencies, and immune system dysfunctions, especially, HIV infection that seems to play a major role in the pathogenesis of NUG. The treatment of NUG is organized in successive stages: first, the treatment of the acute phase that should be provided immediately to stop disease progression and to control patient's feeling of discomfort and pain; second, the treatment of the preexisting condition such as chronic gingivitis; then, the surgical correction of the disease sequelae like craters. Moreover, finally, maintenance phase that allows stable outcomes. This case report describes the diagnosis approach and the conservative management with a good outcome of NUG in a 21-year-old male patient with no systemic disease and probable mechanism of pathogenesis of two predisposing factors involved.


Computerized Ultrasonic Imaging Inspection: From Shallow to Deep Learning.
For many decades, ultrasonic imaging inspection has been adopted as a principal method to detect multiple defects, e.g., void and corrosion. However, the data interpretation relies on an inspector's subjective judgment, thus making the results vulnerable to human error. Nowadays, advanced computer vision techniques reveal new perspectives on the high-level visual understanding of universal tasks. This research aims to develop an efficient automatic ultrasonic image analysis system for nondestructive testing (NDT) using the latest visual information processing technique. To this end, we first established an ultrasonic inspection image dataset containing 6849 ultrasonic scan images with full defect/no-defect annotations. Using the dataset, we performed a comprehensive experimental comparison of various computer vision techniques, including both conventional methods using hand-crafted visual features and the most recent convolutional neural networks (CNN) which generate multiple-layer stacking for representation learning. In the computer vision community, the two groups are referred to as shallow and deep learning, respectively. Experimental results make it clear that the deep learning-enabled system outperformed conventional (shallow) learning schemes by a large margin. We believe this benchmarking could be used as a reference for similar research dealing with automatic defect detection in ultrasonic imaging inspection.


Parental posttraumatic stress disorder as a vulnerability factor for low cortisol trait in offspring of holocaust survivors.
Lower cortisol levels in posttraumatic stress disorder (PTSD) may reflect a preexisting vulnerability associated with developing the disorder after trauma exposure. Because offspring of trauma survivors with PTSD have a greater prevalence of PTSD after their own life events than offspring of trauma survivors without PTSD and offspring of nonexposed persons, examination of patterns of basal cortisol secretion in such offspring provides an opportunity to test this hypothesis. To characterize the patterns of basal cortisol secretion in offspring of Holocaust survivors with and without parental PTSD and children of nonexposed parents. Cortisol secretion was measured every 30 minutes for 24 hours. The raw hormonal data were subjected to a chronobiological analysis by applying single-oscillator and multioscillator cosinor analyses, a nonlinear least squares curve-fitting program, to determine circadian and ultradian regulatory dynamics. The study was conducted under controlled conditions at the General Clinical Research Center at the Mount Sinai School of Medicine. Twenty-three Holocaust offspring with parental PTSD and 10 without parental PTSD were compared with 16 children of nonexposed parents. No participant had PTSD. Mean cortisol levels during the 24-hour cycle and other chronobiological parameters (amplitude, acrophase, circadian quotient, and goodness-of-fit coefficient) derived from single-oscillator and multioscillator models. Offspring with parental PTSD displayed lower mean cortisol levels, reflected by the circadian mesor and reduced cortisol amplitude, compared with offspring without parental PTSD and children of nonexposed parents. This effect seemed to be specifically related to the presence of maternal PTSD. Low cortisol levels and other chronobiological alterations in offspring are associated with the risk factor of maternal PTSD, raising the possibility that these alterations are acquired via glucocorticoid programming either from in utero exposures or in response to maternal behaviors early in life.


Microbes, the 'silent third partners' of bee-angiosperm mutualisms.
While bee-angiosperm mutualisms are widely recognized as foundational partnerships that have shaped the diversity and structure of terrestrial ecosystems, these ancient mutualisms have been underpinned by 'silent third partners': microbes. Here, we propose reframing the canonical bee-angiosperm partnership as a three-way mutualism between bees, microbes, and angiosperms. This new conceptualization casts microbes as active symbionts, processing and protecting pollen-nectar provisions, consolidating nutrients for bee larvae, enhancing floral attractancy, facilitating plant fertilization, and defending bees and plants from pathogens. In exchange, bees and angiosperms provide their microbial associates with food, shelter, and transportation. Such microbial communities represent co-equal partners in tripartite mutualisms with bees and angiosperms, facilitating one of the most important ecological partnerships on land.


[Helping smokers kick the habit].
The family doctor has an increasingly important role to play as a "gatekeeper", with many advantages for the initiation and implementation of a successful weaning program. Controlled studies have demonstrated the effectiveness of a short-term intervention based on motivational talks by the family doctor together with the application of such weaning drugs as nicotine substitutes and bupropion. The latter substance should be offered to adult smokers consuming in excess of ten cigarettes daily. The chances that a smoker can successfully stop smoking is doubled by the use of weaning medication. Ideally,the physician should, at the same time, draw the patient's attention to the significance of a healthy diet and physical exercise.


Di(2-ethylhexyl) phthalate and diethyl phthalate disrupt lipid metabolism, reduce fecundity and shortens lifespan of Caenorhabditis elegans.
The widespread use of phthalates is of major concern as they have adverse effects on many different physiological functions, including reproduction, metabolism and cell differentiation. The aim of this study was to compare the toxicity of the widely-used di (2-ethydlhexyl) phthalate (DEHP) with its substitute, diethyl phthalate (DEP). We analyzed the toxicity of these two phthalates using Caenorhabditis elegans as a model system. Gene expression analysis following exposure during the L1 to young adult stage showed that DEHP and DEP alter the expression of genes involved in lipid metabolism and stress response. Genes associated with lipid metabolism, including fasn-1, pod-2, fat-5, acs-6 and sbp-1, and vitellogenin were upregulated. Among the stress response genes, ced-1 wah-1, daf-21 and gst-4 were upregulated, while ctl-1, cdf-2 and the heat shock proteins (hsp-16.1, hsp-16.48 and sip-1) were downregulated. Lipid staining revealed that DEHP significantly increased lipid content following 1 μM exposure, however, DEP required 10 μM exposure to elicit an effect. Both DEHP and DEP reduced the fecundity at 1 μM concentration. Lifespan analysis indicated that DEHP and DEP reduced the average lifespan from 14 days in unexposed worms to 13 and 12 days, respectively. Expression of lifespan associated genes showed a correlation to shortened lifespan in the exposed groups. As reported previously, our data also indicates that the banned DEHP is toxic to C. elegans, however its substitute DEP has not been previously tested in this model organism and our data revealed that DEP is equally potent as DEHP in regulating C. elegans physiological functions.


Habenular and striatal activity during performance feedback are differentially linked with state-like and trait-like aspects of tobacco use disorder.
The habenula, an epithalamic nucleus involved in reward and aversive processing, may contribute to negative reinforcement mechanisms maintaining nicotine use. We used a performance feedback task that differentially activates the striatum and habenula and administered nicotine and varenicline (versus placebos) to overnight-abstinent smokers and nonsmokers to delineate feedback-related functional brain alterations both as a function of smoking trait (smokers versus nonsmokers) and drug administration state (drug versus placebo). Smokers showed less striatal responsivity to positive feedback, an alteration not mitigated by drug administration, but rather correlated with trait-level addiction severity. Conversely, nicotine administration reduced habenula activity following both positive and negative feedback among abstinent smokers, but not nonsmokers, and increased habenula activity among smokers correlated with elevated state-level tobacco cravings. These outcomes highlight a dissociation between neurobiological processes linked with the dependence severity trait and the nicotine withdrawal state. Interventions simultaneously targeting both aspects may improve currently poor cessation outcomes.


Sympathetic responses to exercise in myocardial infarction rats: a role of central command.
In congestive heart failure (CHF), exaggerated sympathetic activation is observed during exercise, which elicits excess peripheral vasoconstriction. The mechanisms causing this abnormality are not fully understood. Central command is a central neural process that induces parallel activation of motor and cardiovascular systems. This study was undertaken to determine whether central command serves as a mechanism that contributes to the exaggerated sympathetic response to exercise in CHF. In decerebrated rats, renal and lumbar sympathetic nerve responses (RSNA and LSNA, respectively) to 30 s of fictive locomotion were examined. The fictive locomotion was induced by electrical stimulation of the mesencephalic locomotor region (MLR). The study was performed in control animals (fractional shortening > 40%) and animals with myocardial infarctions (MI; fractional shortening < 30%). With low stimulation of the MLR (current intensity = 20 microA), the sympathetic responses were not significantly different in the control (RSNA: +18 +/- 4%; LSNA: +3 +/- 2%) and MI rats (RSNA: +16 +/- 5%; LSNA: +8 +/- 3%). With intense stimulation of the MLR (50 microA), the responses were significantly greater in MI rats (RSNA: +127 +/- 15%; LSNA: +57 +/- 10%) than in the control rats (RSNA: +62 +/- 5%; LSNA: +21 +/- 6%). In this study, the data demonstrate that RSNA and LSNA responses to intense stimulation of the MLR are exaggerated in MI rats. We suggest that intense activation of central command may play a role in evoking exaggerated sympathetic activation and inducing excessive peripheral vasoconstriction during exercise in CHF.


Pallidal deep brain stimulation for dystonia: a long term study.
Pallidal deep brain stimulation (globus pallidus internus (GPi) DBS) is the best therapeutic option for disabling isolated idiopathic (IID) and inherited (INH) dystonia. Acquired dystonia (AD) may also benefit from GPi DBS. Efficacy and safety in the long-term remained to be established. To retrospectively assess long-term clinical outcomes and safety in dystonic patients who underwent GPi DBS. Patients were videotaped and assessed preoperatively and postoperatively (1-year and at last available follow-up) using the Burke-Fahn-Marsden Dystonia Rating Scale (motor score (BFMDRS-M); disability score (BFMDRS-D)). Sixty-one patients were included (follow-up 7.9±5.9 years; range 1-20.7). In IID and INH (n=37), the BFMDRS-M improved at first (20.4±24.5; p<0.00001) and last (22.2±18.2; p<0.001) follow-ups compared with preoperatively (50.5±28.0). In AD (n=19), the BFMDRS-M ameliorated at 1-year (40.8±26.5; p<0.02) and late follow-ups (44.3±24.3; p<0.04) compared with preoperatively (52.8±24.2). In INH dystonia with other neurological features (n=4) there was no motor benefit. In IID and INH, the BFMDRS-D improved at 1-year (9.5±7.5; p<0.0002) and late follow-ups (10.4±7.8; p<0.016) compared with preoperatively (13.3±6.9). In AD, the BFMDRS-D reduced at 1-year (12.0±8.1; p<0.01) and late follow-ups (12.7 ±6.1; p=0.2) compared with preoperatively (14.35±5.7). Most adverse events were hardware related. GPi DBS is an effective and safe treatment in most patients with dystonia.


Measuring intrinsic hand strength in healthy adults: The accuracy intrarater and inter-rater reliability of the Rotterdam Intrinsic Hand Myometer.
Clinical measurement study. Measuring the isometric strength generated during isolated hand joint motions is a challenging feat. The Rotterdam Intrinsic Hand Myometer (RIHM; med.engineers, Rotterdam, Netherlands) permits measurement of isolated movements of the hand. To date, there is limited evidence on the inter-rater reliability and limited adult normative data of RIHM. Given that multiple raters, often with varying degrees of experience, are needed to collect normative data, inter-rater reliability testing and a comparison of novice and experienced raters are needed. The purposes of this study were to test the accuracy, intrarater reliability, and inter-rater reliability of the RIHM in healthy-handed adults. RIHM accuracy was tested through use of precision class F weights. Adults 18 years or older without upper limb dysfunction were recruited. Each participant was tested by 4 raters, 3 occupational therapy graduate students, and an experienced certified hand therapist, through use of a calibrated RIHM. Five strength measures were tested bilaterally (ie, thumb carpometacarpal palmar abduction, index finger metacarpophalangeal [MP] abduction, index finger MP flexion, thumb MP flexion, and small finger MP abduction) 3 times per a standardized protocol. Statistical methods were used to test accuracy, inter-rater reliability, and intrarater/response stability. The accuracy of RIHM device error was 5% or less. Reliability testing included the participation of 19 women and 10 men (n = 29). All raters were in excellent agreement across all muscles (intraclass correlation coefficient, ≥0.81). Low standard error of measurement values of ≤8.3 N (1.9 lb) across raters were found. The response stability and/or intrarater reliability of the novice and certified hand therapist raters were not statistically different. The RIHM has an acceptable instrument error; the RIHM and its standardized procedure have excellent inter-rater reliability and response stability when testing those without hand limitations; and the response stability and/or intrarater reliability of expert and novice raters were consistent. The use of the RIHM is justified when multiple raters of varying expertise collect normative data or conduct cohort studies on persons with healthy hands. Future research is warranted. Not applicable.


Cerebellar infarction in adolescent males associated with acute marijuana use.
To demonstrate the clinical characteristics, radiologic findings, and neuropathological features of tetrahydrocannabinol-related posterior fossa ischemic stroke in adolescent patients. A retrospective case and chart review of 3 cases encountered at a tertiary care institution over a span of 5 years. Inpatient and intensive care hospitalization units managing children and adolescents. Male adolescent patients with ischemic cerebellar stroke after use of marijuana. DIAGNOSTIC INVESTIGATIONS: Computed tomography brain scans (3 subjects), magnetic resonance imaging brain study (1 subject), cerebral arteriography (1 subject), cerebellar biopsy (1 subject), and necropsy (2 subjects). Three adolescent males had similar presentations of headache, fluctuating level of consciousness or lethargy, visual disturbance, and variable ataxia after self-administration of marijuana. They developed primary cerebellar infarctions within days after the exposure that could not be attributed to supratentorial herniation syndromes and only minimally involved brainstem structures. Episodic marijuana use may represent a risk factor for stroke in childhood, particularly in the posterior circulation. Early recognition of the cerebellar stroke syndrome may allow prompt neurosurgical intervention, reducing morbidity.


Endogenous Alzheimer's brain factor and oxidized glutathione inhibit antagonist binding to the muscarinic receptor.
An endogenous inhibitor (< 3,500 Da) of antagonist binding to the muscarinic acetylcholine receptor has been extracted from Alzheimer's disease (AD) brain with trifluoracetic acid. Oxidized glutathione, (GSSG) has also been found to inhibit antagonist binding to the receptor. However, in its reduced form, glutathione (GSH) like other reducing agents, markedly enhances the inhibitory effect of both GSSG and the endogenous AD inhibitor. EDTA and the free radical scavengers Mn(2+) and Trolox, a vitamin E analog, block the action of the endogenous AD inhibitor but not of GSSG in the presence of GSH. Further, while GSSG inhibition is reversible, the action of the endogenous AD inhibitor is irreversible, consistent with a free radical mechanism. The enhancement of endogenous AD inhibitor activity by GSH suggested that GSH may be involved in formation of the free radical generated by the inhibitor. The glutathione thiyl radical is shown to inhibit antagonist binding to the receptor and is, therefore, a good candidate for the free radical formed by the endogenous AD inhibitor. The ability of Trolox to block the reduction in muscarinic receptor binding caused by the endogenous AD inhibitor is encouraging and suggests that free radical scavengers, such as vitamin E, may have a potential therapeutic role in AD by protecting the integrity of the muscarinic receptor.


Comprehensive analysis of expression and prognostic value of the claudin family in human breast cancer.
Claudins (CLDN) are structural components of tight junctions that function in paracellular transport and maintain the epithelial barrier function. Altered expression and distribution of members of the claudin family have been implicated in several cancers including breast cancer (BC). We performed a comprehensive analysis of the expression and prognostic value of claudins in BC using various online databases. Compared with normal tissues, CLDN3, 4, 6, 7, 9, and 14 were upregulated in BC tissues, whereas CLDN2, 5, 8, 10, 11, 15, 19, and 20 were downregulated. A high expression of CLDN2, 5, 6, 9, 10, 11, and 14-20 was associated with better relapse-free survival (RFS), whereas a high CLDN3 expression correlated with poor RFS. In addition, a high expression of CLDN3, 4, 14, and 20 was associated with poor overall survival (OS), whereas that of CLDN5 and CLDN11 was linked to a better OS. Although METABRIC and TCGA datasets revealed 22% and 27% gene alterations, respectively, in the members of the claudin family, these were not associated with survival. These findings suggest CLDN3, 5, and 11 could be promising therapeutic targets for patients with BC.


Platelet adhesion to subendothelium--effect of shear rate, hematocrit and platelet count on the dynamic equilibrium between platelets adhering to and detaching from the surface.
The adherence of human 3H-adenine-labeled platelets to rat subendothelium was quantitated using a rotating probe device. Platelet adhesion increased in relation to the rotation time, reaching a plateau value in about 4-6 min without any further increase. A non-linear fitting analysis of experimental data allowed calculations of initial rate and plateau value of platelet adhesion. Increasing the shear rates (from 35 to 150 sec-1) or the hematocrit (from 10% to 40%), both the adhesion rate and the plateau value were increased. When different platelet concentrations were used the adhesion rate and the plateau calculated increased with platelet concentration. Different plateau values were obtained in the experimental conditions considered. This suggests that the plateau was not reached for the complete occupation of the subendothelial surface by the adherent platelets. Experiments using two different vessels rotated in the same platelet suspension or, viceversa, the same vessel rotated successively in two fresh platelet suspensions, showed that the plateau was not determined by reduced platelet reactivity. Rotating the same vessel first in radiolabeled platelets, until the plateau was reached, and secondly in non labeled platelets, or viceversa, showed that the plateau was indeed a dynamic condition where the number of platelets adhering and detaching reached equilibrium. These observations suggest that the platelet adhesion to subendothelium is the final equilibrium of two platelet fluxes, one adhering to the surface and another detaching from the surface.


Transcription of the myogenic regulatory gene Mef2 in cardiac, somatic, and visceral muscle cell lineages is regulated by a Tinman-dependent core enhancer.
The MADS-box transcription factor MEF2 is expressed specifically in developing cardiac, somatic, and visceral muscle cell lineages during Drosophila embryogenesis and is required for myoblast differentiation and muscle morphogenesis. To define the mechanisms that regulate Mef2 transcription, we have analyzed the Mef2 upstream region for sequences sufficient to recapitulate the expression pattern of the gene in Drosophila embryos. Here we describe a complex enhancer located 5.8 kb upstream of the Drosophila Mef2 gene that controls transcription in cardial cells of the dorsal vessel, a subset of somatic muscle founder cells, and the visceral muscle cells. The core of this enhancer contains two evolutionarily conserved binding sites for the homeodomain protein Tinman (Tin), expressed in developing cardiac, somatic, and visceral muscle lineages. Both Tin binding sites are required for enhancer activity in all three muscle cell lineages. Whereas the 285-bp enhancer core alone is sufficient for expression in cardiac cells, expression in somatic founder cells and visceral muscle is dependent on the core enhancer plus unique flanking sequences that include an evolutionarily conserved E box. These results reveal an essential role for Tin in activation of Mef2 transcription in multiple myogenic lineages and demonstrate that transcriptional activity of Tin is dependent on combinatorial interactions with other factors unique to different muscle cell types.


Role of viruses in human evolution.
The study of viral molecular genetics has produced a considerable body of research into the sequences and phylogenetic relationships of human and animal viruses. A review of this literature suggests that humans have been afflicted by viruses throughout their evolutionary history, although the number and types have changed. Some viruses show evidence of long-standing intimate relationship and cospeciation with hominids, while others are more recently acquired from other species, including African monkeys and apes while our line was evolving in that continent, and domesticated animals and rodents since the Neolithic. Viral selection for specific resistance polymorphisms is unlikely, but in conjunction with other parasites, viruses have probably contributed to selection pressure maintaining major histocompatibility complex (MHC) diversity and a strong immune response. They may also have played a role in the loss in our lineage of N-glycolylneuraminic acid (Neu5Gc), a cell-surface receptor for many infectious agents. Shared viruses could have affected hominid species diversity both by promoting divergence and by weeding out less resistant host populations, while viruses carried by humans and other animals migrating out of Africa may have contributed to declines in other populations. Endogenous retroviral insertions since the divergence between humans and chimpanzees were capable of directly affecting hominid evolution through changes in gene expression and development.


The requirement of SUMO2/3 for SENP2 mediated extraembryonic and embryonic development.
Small ubiquitin-related modifier (SUMO)-specific protease 2 (SENP2) is essential for the development of healthy placenta. The loss of SENP2 causes severe placental deficiencies and leads to embryonic death that is associated with heart and brain deformities. However, tissue-specific disruption of SENP2 demonstrates its dispensable role in embryogenesis and the embryonic defects are secondary to placental insufficiency. SENP2 regulates SUMO1 modification of Mdm2, which controls p53 activities critical for trophoblast cell proliferation and differentiation. Here we use genetic analyses to examine the involvement of SUMO2 and SUMO3 for SENP2-mediated placentation. The results indicate that hyper-SUMOylation caused by SENP2 deficiency can be compensated by reducing the level of SUMO modifiers. The placental deficiencies caused by the loss of SENP2 can be alleviated by the inactivation of gene encoding SUMO2 or SUMO3. Our findings demonstrate that SENP2 genetically interacts with SUMO2 and SUMO3 pivotal for the development of three major trophoblast layers. The alleviation of placental defects in the SENP2 knockouts further leads to the proper formation of the heart structures, including atrioventricular cushion and myocardium. SUMO2 and SUMO3 modifications regulate placentation and organogenesis mediated by SENP2.


The folding thermodynamics and kinetics of crambin using an all-atom Monte Carlo simulation.
We present a novel Monte Carlo simulation of protein folding, in which all heavy atoms are represented as interacting hard spheres. This model includes all degrees of freedom relevant to folding, all side-chain and backbone torsions, and uses a Go potential. In this study, we focus on the 46 residue alpha/beta protein crambin and two of its structural components, the helix and helix hairpin. For a wide range of temperatures, we recorded multiple folding events of these three structures from random coils to native conformations that differ by less than 1 A C(alpha) dRMS from their crystal structure coordinates. The thermodynamics and kinetic mechanism of the helix-coil transition obtained from our simulation shows excellent agreement with currently available experimental and molecular dynamics data. Based on insights obtained from folding its smaller structural components, a possible folding mechanism for crambin is proposed. We observed that the folding occurs via a cooperative, first order-like process, and that many folding pathways to the native state exist. One particular sequence of events constitutes a "fast-folding" pathway where kinetic traps are avoided. At very low temperatures, a kinetic trap arising from the incorrect packing of side-chains was observed. These results demonstrate that folding to the native state can be observed in a reasonable amount of time on desktop computers even when an all-atom representation is used, provided the energetics sufficiently stabilize the native state.


Relationship Between Age and Pathology With Treatment of Pediatric and Adolescent Discoid Lateral Meniscus: A Report From the SCORE Multicenter Database.
Surgical treatment options of discoid lateral meniscus in pediatric patients consist of saucerization with or without meniscal repair, meniscocapular stabilization, and, less often, subtotal meniscectomy. To describe a large, prospectively collected multicenter cohort of discoid menisci undergoing surgical intervention, and further investigate corresponding treatment of discoid menisci. Cohort study; Level of evidence, 3. A multicenter quality improvement registry (16 institutions, 26 surgeons), Sports Cohort Outcomes Registry, was queried. Patient characteristics, discoid type, presence and type of intrasubstance meniscal tear, peripheral rim instability, repair technique, and partial meniscectomy/debridement beyond saucerization were reviewed. Discoid meniscus characteristics were compared between age groups (<14 and >14 years old), based on receiver operating characteristic curve, and discoid morphology (complete and incomplete). In total, 274 patients were identified (mean age, 12.4 years; range, 3-18 years), of whom 55.6% had complete discoid. Meniscal repairs were performed in 55.1% of patients. Overall, 48.5% of patients had rim instability and 36.8% had >1 location of peripheral rim instability. Of the patients, 21.5% underwent meniscal debridement beyond saucerization, with 8.4% undergoing a subtotal meniscectomy. Patients <14 years of age were more likely to have a complete discoid meniscus (P < .001), peripheral rim instability (P = .005), and longitudinal tears (P = .015) and require a meniscal repair (P < .001). Patients ≥14 years of age were more likely to have a radial/oblique tear (P = .015) and require additional debridement beyond the physiologic rim (P = .003). Overall, 70% of patients <14 years of age were found to have a complete discoid meniscus necessitating saucerization, and >50% in this young age group required peripheral stabilization/repair. To preserve physiological "normal" meniscus, a repair may be indicated in >50% of patients <14 years of age but occurred in <50% of those >14 years. Additional resection beyond the physiological rim may be needed in 15% of younger patients and 30% of those aged >14 years.


[Factors that influence sexual intercourse among middle school students: using data from the 8th (2012) Korea Youth Risk Behavior Web-based Survey].
The purpose of this study was to investigate factors that influence sexual intercourse among middle school students in South Korea. Using statistics from the 8th (2012) Korea Youth Risk Behavior Web-based Survey, hierarchical logistic regression analysis was conducted. The study sample comprised 37,297 middle school students aged primarily 12 to 15. The significant predictors of sexual intercourse were grade, ever smoking, ever drinking, habitual or purposeful drug use, economic status, weekly allowance, cohabitation with family, and type of school. The results suggest that intensified sex education is needed not only in the 1st grade of middle school, but also in the upper grades of elementary school. Sexual health interventions for high-risk groups may be needed, given the factors predicting sexual intercourse.


CRISPR/Cas9-mediated gene knockout for DNA methyltransferase Dnmt3a in CHO cells displays enhanced transgenic expression and long-term stability.
CHO cells are the preferred host for the production of complex pharmaceutical proteins in the biopharmaceutical industry, and genome engineering of CHO cells would benefit product yield and stability. Here, we demonstrated the efficacy of a Dnmt3a-deficient CHO cell line created by CRISPR/Cas9 genome editing technology through gene disruptions in Dnmt3a, which encode the proteins involved in DNA methyltransferases. The transgenes, which were driven by the 2 commonly used CMV and EF1α promoters, were evaluated for their expression level and stability. The methylation levels of CpG sites in the promoter regions and the global DNA were compared in the transfected cells. The Dnmt3a-deficent CHO cell line based on Dnmt3a KO displayed an enhanced long-term stability of transgene expression under the control of the CMV promoter in transfected cells in over 60 passages. Under the CMV promoter, the Dnmt3a-deficent cell line with a high transgene expression displayed a low methylation rate in the promoter region and global DNA. Under the EF1α promoter, the Dnmt3a-deficient and normal cell lines with low transgene expression exhibited high DNA methylation rates. These findings provide insight into cell line modification and design for improved recombinant protein production in CHO and other mammalian cells.


Serum concentration: effects on cycle and x-ray sensitivity of mammalian cells.
If the content of serum in the culture medium of exponentially growing Chinese hamster cells is below optimum (15 percent), the doubling time and the resistance to x-irradiation of the cells are increased. In synchronously dividing populations the increase in doubling time is primarily caused by increase in duration of the postmitotic (G(1)) phase of the cells; this phase is relatively radiation resistant. The response of the cells growing synchronously is related quantitatively to the response of the cells dividing randomly.


Frequency of juvenile idiopathic arthritis and associated uveitis in pediatric rheumatology clinics in Turkey: A retrospective study, JUPITER.
Juvenile idiopathic arthritis (JIA), is the most common pediatric rheumatologic disorder with unknown etiology. Currently, no population-based data are available regarding the distribution of categories and frequency of uveitis in patients with JIA in Turkey. The purpose of this study was to evaluate the frequency of JIA-associated uveitis (JIAU) and distribution of JIA categories in a Turkish JIA cohort. This was a retrospective study of 500 randomized patients in four pediatric rheumatology clinics in Turkey. Oligoarticular JIA (oJIA) was the most common JIA disease category in this study cohort (38.8%). The frequencies of the other categories were as follows: enthesitis-related arthritis (ERA), 23.2%; rheumatoid factor (RF)-negative polyarthritis, 15.6%; systemic arthritis, 12.2%; juvenile psoriatic arthritis, 5.2%; undifferentiated arthritis, 2.8%; and RF-positive polyarthritis, 2.2%. JIA-associated uveitis was observed in 6.8% of patients at a mean (Standard Deviation, SD) age of 9.1 (3.8) years over a mean JIA disease duration of 4 (1.9) years. Uveitis developed after joint disease, with a mean (SD) duration of 1.8 (1.9) years. Patients with oJIA had the highest rate of uveitis (12.9%) followed by patients with ERA (5.2%) and polyarticular RF-negative disease (3.8%). Compared with persistent oJIA, the extended oJIA category had a > 3-fold higher risk of uveitis (11.3% vs 27.7%; odds ratio, 3.38 [95% Confidence Interval, 1.09-10.4]). The most frequently administered drug after development of uveitis was tumor necrosis factor-alpha inhibitors (38.2%). Five patients (14.7%) had uveitis-related complications that required surgical intervention. Turkish pediatric patients with JIA experience a lower frequency of oJIA and higher frequency of ERA than their white European counterparts; the occurrence of uveitis is also somewhat lower than expected. Geographic and ethnic factors may affect these differences and need further investigation.


The F-Box protein Fbp1 regulates sexual reproduction and virulence in Cryptococcus neoformans.
Cryptococcus neoformans is the leading cause of fungal meningitis in immunocomprised populations. Although extensive studies have been conducted on signal transduction pathways important for fungal sexual reproduction and virulence, how fungal virulence is regulated during infection is still not understood. In this study, we identified the F-box protein Fbp1, which contains a putative F-box domain and 12 leucine-rich repeats (LRR). Although fbp1 mutants showed normal growth and produced normal major virulence factors, such as melanin and capsule, Fbp1 was found to be essential for fungal virulence, as fbp1 mutants were avirulent in a murine systemic-infection model. Fbp1 is also important for fungal sexual reproduction. Basidiospore production was blocked in bilateral mating between fbp1 mutants, even though normal dikaryotic hyphae were observed during mating. In vitro assays of stress responses revealed that fbp1 mutants are hypersensitive to SDS, but not calcofluor white (CFW) or Congo red, indicating that Fbp1 may regulate cell membrane integrity. Fbp1 physically interacts with Skp1 homologues in both Saccharomyces cerevisiae and C. neoformans via its F-box domain, suggesting it may function as part of an SCF (Skp1, Cullins, F-box proteins) E3 ligase. Overall, our study revealed that the F-box protein Fbp1 is essential for fungal sporulation and virulence in C. neoformans, which likely represents a conserved novel virulence control mechanism that involves the SCF E3 ubiquitin ligase-mediated proteolysis pathway.


The effect of carbon tetrachloride on the enzymatic hydrolysis of cellular triacylglycerol in adult rat hepatocytes in primary monolayer culture.
The effect of carbon tetrachloride on the intracellular hydrolysis of triacylglycerol and on the activity of acid triacylglycerol lipase was investigated with primary cultured rat hepatocytes. It was found that the concentration of the precursors in the medium did not affect the time course of the synthesis, secretion and the hydrolysis of triacylglycerol, and that carbon tetrachloride significantly suppressed the hydrolysis of intracellular triacylglycerol and the activity of acid triacylglycerol lipase with a concomitant accumulation of triacylglycerol. The results indicate a possibility that the triacylglycerol accumulation in the cultured rat hepatocytes caused by carbon tetrachloride might be mediated by the suppression of lysosomal acid triacylglycerol lipase activity in addition to the suppression of the secretion of triacylglycerol.


Adapting UASB technology for sewage treatment in Palestine and Jordan.
High rate anaerobic technologies offer cost-effective solutions for "sewage" treatment in the temperate climate of Palestine and Jordan. However, local sewage characteristics demand amendments to the conventional UASB reactor design. A solution is found in a parallel operating digester unit that stabilises incoming solids and enriches the UASB sludge bed with methanogenic activity. The digester operational conditions were assessed by operating eight CSTRs fed with primary sludge. The results showed a high degree of sludge stabilization in the parallel digesters at SRTs>or=10 and 15 days at process temperatures of 35 and 25 degrees C, respectively. The technical feasibility of the UASB-digester combination was demonstrated by continuous flow pilot-scale experiments. A pilot UASB reactor was operated for 81 days at 6 hours HRT and 15 degrees C and was fed with raw domestic sewage. This period was subsequently followed by an 83 day operation period incorporating a parallel digester unit, which was operated at 35 degrees C. The UASB-digester combination achieved removal efficiencies of total, suspended, colloidal and dissolved CODs of respectively 66, 87, 44 and 30%. Preliminary model calculations indicated that a total reactor volume of the UASB-digester system corresponding to 8.6 hours HRT might suffice for sewage treatment in Palestine.


Flow cytometric determination of the proportions of X- and Y-chromosome-bearing sperm in samples of purportedly separated bull sperm.
A rapid assay for determining the proportions of X- and Y-chromosome-bearing sperm in semen samples would benefit research aimed at sex ratio control through sperm separation. It also would be of value for quality control should a separation technique be developed. Flow cytometric methods capable of measuring sperm DNA content precisely enough to resolve and quantify the X and Y populations in many mammalian species have been developed. They are effective for fresh and cryopreserved sperm of most domestic animals. Results are reported of flow cytometric analyses of bull sperm samples from seven commercial and academic sources after processing with procedures purported to separate the X and Y populations. In no case was enrichment of either sperm population observed. Breeding trials carried out by the sources of two of the sets of samples showed these procedures were ineffective in altering the sex ratio.


Investigation on recent quartz-like materials for SAW applications.
Recent progress in growing and characterizing quartz-like materials of the trigonal system class 32 has been reported by several groups. The promising perspective for bulk acoustic wave frequency control applications indicates the potentiality of employing these materials for SAW applications as well. This paper reports results of investigations focused on SAW orientations of langasite (LGS), gallium phosphate (GaPO(4)), and langanite (LGN), both singly and doubly rotated cuts. Among the characteristics explored, major attention is paid to the temperature coefficient of delay (TCD), the electromechanical coupling coefficient (K(2)), and the power flow angle (PFA). Contour graphs are plotted based on our calculated results and show the regions in space in which low TCD and high K(2 ) can be obtained; they also exhibit the associated PFA and phase velocity characteristics. The influence of different sets of material constants is addressed. The spatial investigation performed shows that there are promising orientation regions in these materials at which zero or reduced TCD (<10 ppm/ degrees C) and PFA are obtained. Additional attractive characteristics for SAW applications have been observed: values of K(2) a few times higher than the K(2) of quartz ST-X, thus finding applications in larger bandwidth devices; variation of the TCD with respect to temperature, which is comparable to the variation found for quartz ST-X and less than that for zero TCD Li (2)B(4)O(7) cuts like 45 degrees X-Z and (0 degrees 78 degrees 90 degrees ); and phase velocity values circa 13 to 26% smaller than the phase velocity of quartz ST-X thus allowing a reduction in size for intermediate frequency device applications.


Concordance Between Self-Reported Completion of Advance Care Planning Documentation and Availability of Documentation in Australian Health and Residential Aged Care Services.
Advance care planning (ACP) documentation needs to be available at the point of care to guide and inform medical treatment decision-making. To examine concordance between self-reported completion of ACP documentation and self-reported storage of the documentation at the person's current point of care with the availability of the documentation in that person's health record. A national multicenter audit of health records and a self-report survey of eligible audit participants in 51 Australian health and residential aged care services. The audit assessed availability of ACP documentation in the health record, whereas the survey assessed self-reported completion and storage of the ACP documentation at the person's current place of care. To ascertain concordance, survey and audit data were cross-tabulated and concordance rates and kappa statistics were calculated overall and by health care sector and ACP documentation type. The audit included 2285 people, of whom 1082 were eligible for the survey. Of 507 who completed the survey (response rate = 47%), 272 (54%) reported completing ACP documentation, of whom 130 (48%) had documentation identified in the audit. Conversely, 39 of 235 people (17%) who reported not completing ACP documentation had documentation identified (concordance rate = 64%; κ = 0.303, P < .001). The concordance rate increased to 79% when self-reported storage of ACP documentation at the person's current point of care was compared with the existence of the document in their health record (κ = 0.510, P < .001). Concordance varied by health care setting and type of ACP documentation. Discrepancies exist between self-reported completion of ACP documentation and the presence of these documents in the health records of older adults, representing a significant patient safety issue. Public education campaigns and improvements to systems for document storage and accessibility are required to support person-centered medical and end-of-life care.


Speech-material and talker effects in speech band importance.
Band-importance functions created using the compound method [Apoux and Healy (2012). J. Acoust. Soc. Am. 132, 1078-1087] provide more detail than those generated using the ANSI technique, necessitating and allowing a re-examination of the influences of speech material and talker on the shape of the band-importance function. More specifically, the detailed functions may reflect, to a larger extent, acoustic idiosyncrasies of the individual talker's voice. Twenty-one band functions were created using standard speech materials and recordings by different talkers. The band-importance functions representing the same speech-material type produced by different talkers were found to be more similar to one another than functions representing the same talker producing different speech-material types. Thus, the primary finding was the relative strength of a speech-material effect and weakness of a talker effect. This speech-material effect extended to other materials in the same broad class (different sentence corpora) despite considerable differences in the specific materials. Characteristics of individual talkers' voices were not readily apparent in the functions, and the talker effect was restricted to more global aspects of talker (i.e., gender). Finally, the use of multiple talkers diminished any residual effect of the talker.


Region Specific Effects of Aging and the Nurr1-Null Heterozygous Genotype on Dopamine Neurotransmission.
The transcription factor Nurr1 is essential for dopamine neuron differentiation and is important in maintaining dopamine synthesis and neurotransmission in the adult. Reduced Nurr1 function, due to the Nurr1-null heterozygous genotype (+/-), impacts dopamine neuron function in a region specific manner resulting in a decrease in dopamine synthesis in the dorsal and ventral striatum and a decrease in tissue dopamine levels in the ventral striatum. Additionally, maintenance of tissue dopamine levels in the dorsal striatum and survival of nigrostriatal dopamine neurons with aging (>15 months) or after various toxicant treatments are impaired. To further investigate the effects of aging and the Nurr1-null heterozygous genotype, we measured regional tissue dopamine levels, dopamine neuron numbers, body weight, open field activity and rota-rod performance in young (3-5 months) and aged (15-17 months) wild-type +/+ and +/- mice. Behavioral tests revealed no significant differences in rota-rod performance or basal open field activity as a result of aging or genotype. The +/- mice did show a significant increase in open field activity after 3 min of restraint stress. No differences in tissue dopamine levels were found in the dorsal striatum. However, there were significant reductions in tissue dopamine levels in the ventral striatum, which was separated into the nucleus accumbens core and shell, in the aged +/- mice. These data indicate that the mesoaccumbens system is more susceptible to the combination of aging and the +/- genotype than the nigrostriatal system. Additionally, the effects of aging and the +/- genotype may be dependent on genetic background or housing conditions. As Nurr1 mutations have been implicated in a number of diseases associated with dopamine neurotransmission, further data is needed to understand why and how Nurr1 can have differential functions across different dopamine neuron populations in aging.


Plasma processing conditions substantially influence circulating microRNA biomarker levels.
Circulating, cell-free microRNAs (miRNAs) are promising candidate biomarkers, but optimal conditions for processing blood specimens for miRNA measurement remain to be established. Our previous work showed that the majority of plasma miRNAs are likely blood cell-derived. In the course of profiling lung cancer cases versus healthy controls, we observed a broad increase in circulating miRNA levels in cases compared to controls and that higher miRNA expression correlated with higher platelet and particle counts. We therefore hypothesized that the quantity of residual platelets and microparticles remaining after plasma processing might impact miRNA measurements. To systematically investigate this, we subjected matched plasma from healthy individuals to stepwise processing with differential centrifugation and 0.22 µm filtration and performed miRNA profiling. We found a major effect on circulating miRNAs, with the majority (72%) of detectable miRNAs substantially affected by processing alone. Specifically, 10% of miRNAs showed 4-30x variation, 46% showed 30-1,000x variation, and 15% showed >1,000x variation in expression solely from processing. This was predominantly due to platelet contamination, which persisted despite using standard laboratory protocols. Importantly, we show that platelet contamination in archived samples could largely be eliminated by additional centrifugation, even in frozen samples stored for six years. To minimize confounding effects in microRNA biomarker studies, additional steps to limit platelet contamination for circulating miRNA biomarker studies are necessary. We provide specific practical recommendations to help minimize confounding variation attributable to plasma processing and platelet contamination.


Associative encoding and retrieval are predicted by functional connectivity in distinct hippocampal area CA1 pathways.
Determining how the hippocampus supports the unique demands of memory encoding and retrieval is fundamental for understanding the biological basis of episodic memory. One possibility proposed by theoretical models is that the distinct computational demands of encoding and retrieval are accommodated by shifts in the functional interaction between the hippocampal CA1 subregion and its input structures. However, empirical tests of this hypothesis are lacking. To test this in humans, we used high-resolution fMRI to measure functional connectivity between hippocampal area CA1 and regions of the medial temporal lobe and midbrain during extended blocks of associative encoding and retrieval tasks. We found evidence for a double dissociation between the pathways supporting successful encoding and retrieval. Specifically, during the associative encoding task, but not the retrieval task, functional connectivity only between area CA1 and the ventral tegmental area predicted associative long-term memory. In contrast, connectivity between area CA1 and DG/CA3 was greater, on average, during the retrieval task compared with the encoding task, and, importantly, the strength of this connectivity significantly correlated with retrieval success. Together, these findings serve as an important first step toward understanding how the demands of fundamental memory processes may be met by changes in the relative strength of connectivity within hippocampal pathways.


Nano-sized fluorescent particles as new tracers for sentinel node detection: experimental model for decision of appropriate size and wavelength.
The concepts of made-to-order and low-invasiveness medicines are becoming widely accepted. A treatment for cancer, with minimum invasive surgery and without lymph nodes dissection based on sentinel lymph node (SN) navigation surgery, would adhere to these concepts. Dyes and/or radioisotopes are employed for SN detection in standard methods, however, each detection method has advantages and disadvantages. To make up for the disadvantages, we aimed at developing a new non-invasive method using fluorescent beads of uniform nano-size that could efficiently visualize SN from outside the body, and conducted experiments to determine the appropriate size and fluorescent wavelength. We examined various bead sizes and fluorescent wavelengths. The sizes were 20, 40, 100 and 200 nm. The fluorescent peak wavelengths of the beads were yellow-green (515 nm), dark red (680 nm), far red (720 nm) and infrared (755 nm). The beads were subcutaneously injected into the foot pad of the hind leg of a rat, and followed by laser scanning of the inguinal area for fluorescence observation. The beads exhibited different times for the fluorescence detection according to their sizes and wavelength. The 40 nm beads were considered to be the most appropriate size for SN detection in rats. The wavelength of near infrared was effective for avoiding attenuation by the tissue. In conclusion, we confirmed that uniformly nano-sized fluorescent beads have the potential to be an alternative to existing tracers in the detection of the SN in animal experiments if we select the appropriate particle size and wavelength.


Safety of Antibiotic Irrigations for Acute Exacerbations of Chronic Rhinosinusitis in Patients with Identical Drug Allergies or Adverse Reactions: A Pilot Study.
Objectives: The use of topical antibiotics in the treatment of acute exacerbation of chronic rhinosinusitis (AECRS) represents a viable option prior to initiation of parenteral antibiotics when no oral antibiotic alternatives are available due to patient allergy or adverse reactions. The main objectives of this pilot study were to determine the safety and efficacy of antibiotic irrigations in the treatment of AECRS in patients with documented adverse reactions to the oral form of the drug. Methods: A retrospective review was performed of patients diagnosed with AECRS treated with antibiotic irrigations. Inclusion criteria included a documented allergy or adverse event to the systemic form of the same antibiotic. Patient demographics, medical history, prior sinus surgery, nasal endoscopy findings, and microbiology results were obtained. Side effects to the antibiotic irrigations were recorded. Results: Six patients met the inclusion criteria resulting in 7 treated cases of AECRS. Four patients with adverse effects to oral trimethoprim/sulfamethoxazole (TMP/SMZ) received TMP/SMZ irrigations, and 1 patient with an adverse reaction to oral ciprofloxacin was treated with ciprofloxacin irrigations. One patient with adverse effects to both oral TMP/SMZ and levofloxacin was treated with TMP/SMZ and levofloxacin irrigations, respectively during 2 separate AECRS episodes. Following treatment, 1 case (14.3%) resulted in complete resolution of infection, 1 (14.3%) had partial improvement, and 5 (71.4%) had minimal to no endoscopic improvement at the subsequent clinic visit. There were no adverse reactions to antibiotic irrigations among the entire cohort. Conclusions: Currently, no prior study has examined whether adverse reactions to a systemic antibiotic also occur when the medication is delivered topically via sinonasal irrigations. Our findings suggest that topical administration of antibiotics may be a safe alternative for patients with adverse effects to the systemic form.


A retrospective study of drug utilization and hospital readmissions among Medicare patients with hepatic encephalopathy.
Hepatic encephalopathy (HE) is a complication occurring in patients with cirrhosis and is associated with neuropsychiatric and motor abnormalities. Symptomatic HE episodes almost always require hospitalization and the frequent recurrence of episodes is associated with poor prognosis and increased medical costs. The utilization of existing therapies for management of HE and adherence to them has yet to be evaluated using real-world claims data.The aim of this study was to evaluate HE drug regimens and adherence and their association with hospital readmissions in Medicare Advantage plan patients.This was a retrospective cohort study of patients discharged from a HE-related hospitalization or emergency room visit. Based on subsequent enrollment in the plan they were categorized into cohorts of 1 month, 3, and 6 months follow-up, and medication regimen was evaluated within the first month. The drugs evaluated included lactulose, rifaximin, and neomycin. Multivariable logistic regression was conducted to evaluate the association of drug regimen and medication adherence measured as proportion of days covered with HE readmissions.There were 347 patients hospitalized for HE with 184 patients having 30-day enrollment and either a drug refill or an outpatient visit in this duration. Medications were not refilled by 67 (36.4%) patients. Various drug regimens had different adherence with mean (standard deviation) proportion of days covered ranging from 0.56 (0.29) to 0.82 (0.16) at 3 months and 0.48 (0.3) to 0.77 (0.15) at 6 months. The results of logistic regression at 3 and 6 months did not show a significant association of medication use or medication adherence with hospital readmissions.Despite availability of therapy, medication utilization was alarmingly low after discharge of patients from HE-related hospitalization. Medication adherence was also low, which may affect the rate of recurrence and costs associated with readmissions. Efforts are needed in both care coordination of these patients to ensure they are prescribed appropriate medications and to enhance adherence to them.


Switching Costs in Medicare Advantage.
This paper estimates the magnitude of switching costs in the Medicare Advantage program. Consumers are generally assumed to pick plans that provide the combination of benefits and premiums that maximize their individual utility. However, the plan choice literature has generally omitted prior choices from choice models. The analysis is based on five years of the Medicare Current Beneficiary Survey, a nationally representative longitudinal dataset. The MCBS data were combined with data on Medicare Advantage Part C plan benefits and premiums. Individual choices are modeled as a function of individual characteristics, plan characteristics and prior year plan choices using a mixed logit model. We found relatively high rates of switching between plans within insurer (20%), although less switching between insurers. Prior year plan choices were highly significant at both the contract and plan level. Premium was negative and significant. Loyalty (contract and plan), premium and plan structure were found to be heterogeneous in preferences. We found a statistically significant willingness to pay for a lower prescription drug deductible and lower copays. Switching costs were higher for sicker individuals. Switching costs between plans offered by the same insurer are far lower than switching costs between insurers; beneficiaries will switch plans if an alternative is perceived as $233 a month better than the current choice and switch insurers if the alternative is perceived as $944 better than the current plan/contract, on average. Premium elasticities would be 34% greater in magnitude if prior choices were irrelevant. We provide evidence that the state dependence is structural rather than spurious.


Effectiveness of saliva collection and enzyme-immunoassay for the quantification of cortisol in socially housed baboons.
Circulating cortisol levels are often used to assess the biological stress response in captive primates. Some methods commonly used to collect blood samples may alter the stress response. As such, noninvasive means to analyze cortisol levels are increasingly being developed. We adapted an existing collection method to simultaneously obtain saliva from multiple socially living hamadryas baboons (Papio hamadryas hamadryas) and validated an enzyme-immunoassay kit to quantify cortisol within the saliva samples. Over a period of 12 months, saliva samples were regularly collected from approximately half of the 18-member colony, representing younger monkeys who were more willing to participate. The assay met the four criteria typically used to assess the effectiveness of a new analytical technique: parallelism, precision, accuracy, and sensitivity. Cortisol levels were also proportional to those expected given published plasma levels of cortisol in baboons. Further, salivary cortisol levels increased in individuals following significant stress-related events, such as removal from the group, indicating biological validation. The technique provided a reliable and effective means to assess a physiological indicator of stress in a social group without initiating a stress response owing to handling or sedation, and provided a real-time assessment of cortisol levels and reactivity.


Neuroprognostication of Cardiac Arrest Patients: Outcomes of Importance.
During the last two decades, survival rates after cardiac arrest have increased while the fraction of patients surviving with a severe neurological disability or vegetative state has decreased in many countries. While improved survival is due to improvements in the whole "chain of survival," improved methods for prognostication of neurological outcome may be of major importance for the lower disability rates. Patients who are resuscitated and treated in intensive care will die mainly from the withdrawal of life-sustaining (WLST) therapy due to presumed poor chances of meaningful neurological recovery. To ensure high-quality decision-making and to reduce the risk of premature withdrawal of care, implementation of local protocols is crucial and should be guided by international recommendations. Despite rigorous neurological prognostication, cognitive impairment and related psychological distress and reduced participation in society will still be relevant concerns for cardiac arrest survivors. The commonly used outcome measures are not designed to provide information on these domains. Follow-up of the cardiac arrest survivor needs to consider the cardiovascular burden as an important factor to prevent cognitive difficulties and future decline.


Epidemiological characterization of dermatophytes at a tertiary care hospital in Eastern Uttar Pradesh, India.
Superficial mycosis is more prevalent in tropical and subtropical countries, such as India. Regarding this, the present study was conducted to determine the epidemiology of superficial mycosis and identify the most common dermatophytic species in this region. For the purpose of the study, a total of 220 skin scraping, nail, and hair root specimens were collected. Direct microscopic examination was performed using potassium hydroxide mount. Additionally, the samples were inoculated onto Sabouraud dextrose agar (SDA) and dermatophyte test medium (DTM). The fungal colony of each isolates was stained with lactophenol cotton blue mount, and observed under microscope for species identification. Out of 220 isolates, 172 samples, obtained from 108 males 64 females, were positive for skin fungal infections by either KOH mount or culture. Furthermore, 113 isolates were identified as dermatophytes, while 59 samples were found to be non-dermatophytes. Among the dermatophytes isolated from different clinical samples, Trichophyton verrucosum (42/113, 38%) was the most common species, and Tinea corporis was the most common infection (36.2%). As the findings indicated, dermatophytes had an isolation rate of 78%, which is higher than normal. This can be due to the fact that the majority of the patients were from a rural background (71.7%) with a low socioeconomic status and poor personal hygiene who were exposed to climatic changes.


Citalopram in the treatment of binge-eating disorder: a placebo-controlled trial.
Binge-eating disorder is a newly recognized eating disorder characterized by recurrent episodes of binge eating without compensatory weight loss behaviors. It commonly co-occurs with depressive disorders and obesity. Citalopram is a highly selective serotonin reuptake inhibitor antidepressant. The purpose of this study was to assess the efficacy and safety of citalopram in the treatment of binge-eating disorder. Thirty-eight outpatients with a DSM-IV diagnosis of binge-eating disorder were enrolled in the study between August 2000 and July 2001 and were randomly assigned to receive either citalopram (N = 19) or placebo (N = 19) in a 6-week, double-blind, flexible-dose (20-60 mg/day) study. The primary measure of efficacy was frequency of binge-eating episodes. Secondary measures included frequency of binge days, body mass index (BMI), weight, Clinical Global Impressions-Severity of Illness scale scores, Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (YBOCS-BE) scores, Hamilton Rating Scale for Depression (HAM-D) scores, and response categories. The outcome measures were analyzed using 2 random regression methods, with a time trend analysis (primary analysis) and an endpoint analysis. In addition, response categories were analyzed using an exact trend test. Compared with placebo-treated subjects, subjects receiving citalopram (mean dose of 57.9 mg/day) had a significantly greater rate of reduction in frequency of binge eating (p =.003), frequency of binge days (p <.001), BMI (p <.001), weight (p <.001), severity of illness (p =.028), and YBOCS-BE score (p =.007) and a marginally significant rate of reduction in HAM-D score (p =.053). Differences between groups in response categories were marginally significant (p =.068 for intent-to-treat analysis). In a 6-week, placebo-controlled, flexible-dose trial, citalopram was efficacious in reducing binge-eating frequency, weight, and severity of illness and was generally well tolerated in subjects with binge-eating disorder.