Satisfaction and Regret Following Uterosacral Ligament Suspension and Sacrocolpopexy: A Prospective Multicenter Analysis From the Fellows' Pelvic Research Network.
The primary objective was to compare levels of satisfaction, regret, and Patient Global Impression of Improvement (PGI-I) scores between women who underwent vaginal uterosacral ligament suspension (USLS) and minimally invasive sacrocolpopexy (SCP). Secondary objectives were to identify which preoperative counseling resources were most useful. This was a multicenter, retrospective cohort study through the Fellows' Pelvic Research Network that included women who underwent a USLS or SCP between January 2013 and January 2016 with 1-year follow-up. Women completed the Decision Regret Scale for Pelvic Floor Disorders, Satisfaction with Decision Scale for Pelvic Floor Disorders, and PGI-I. Data were also collected on usefulness of various educational preoperative resources. A total of 175/367 (47.6%) women participated; 45 (25.7%) and 130 (74.3%) in the USLS and SCP groups, respectively. Mean Decision Scale for Pelvic Floor Disorders scores were 4.6 ± 0.8 and 4.5 ± 0.7 (P = 0.30) in the USLS and SCP groups, respectively, indicating a high level of satisfaction with surgical decision. The mean Decision Regret Scale for Pelvic Floor Disorders score was 1.5 ± 0.8 in USLS and 1.6 ± 0.8 in SCP (P = 0.53). The SCP group had higher PGI-I scores (1.7 ± 1.4 vs 2.0 ± 1.3, P = 0.02), indicating lower perceived postoperative improvement. Most women (151 [86.3%] of 175) reported that verbal counseling was sufficient and would not have found additional resources helpful. Women have high satisfaction and low regret with their decision to pursue surgical correction with USLS or SCP. Most are satisfied with only verbal preoperative counseling.


Thermoplastic microfluidic platform for single-molecule detection, cell culture, and actuation.
We have developed a multipurpose microfluidic platform that allows for sensitive fluorescence detection on inexpensive disposable chips. The fabrication scheme involves rapid injection molding of thermoplastics, followed by silica deposition and covalent attachment of an unstructured flexible lid. This combines the virtues of elastomer technology with high-throughput compact disk injection molding. Using this technique, the time to produce 100 chips using a single master can be lowered from more than 1 week by standard PDMS technologies to only a couple hours. The optical properties of the fabricated chips were evaluated by studying individual fluorescence-labeled DNA molecules in a microchannel. Concatemeric DNA molecules were generated through rolling circle replication of circular DNA molecules, which were labeled by hybridization of fluorescence-tagged oligonucleotides. Rolling circle products (RCPs) were detected after as little as 5 min of DNA polymerization, and the RCPs in solution showed no tendency for aggregation. To illustrate the versatility of the platform, we demonstrate two additional applications: The flexible property of the lid was used to create a peristaltic pump generating a flow rate of 9 nL/s. Biocompatibility of the platform was illustrated by culturing Chinese hamster ovary cells for 7 days in the microfluidic channels.


Expression of p16(INK4A) but not hypoxia markers or poly adenosine diphosphate-ribose polymerase is associated with improved survival in patients with pancreatic adenocarcinoma.
Pancreatic cancer is associated with mutations in the tumor suppressor gene cyclin-dependent kinase inhibitor 2A (p16(INK4A) ), a regulator of the cell cycle and apoptosis. This study investigates whether immunohistochemical expression of p16(INK4A) as well as hypoxia markers and poly adenosine diphosphate-ribose polymerase (PARP) correlates with survival in patients with resected pancreatic adenocarcinoma. Seventy-three patients with pancreatic adenocarcinoma who underwent curative resection at Stanford University were included. From the surgical specimens, a tissue microarray was constructed using triplicate tissue cores from the primary tumor and used for immunohistochemical staining for the following markers: carbonic anhydrase IX, dihydrofolate reductase, p16(INK4A) , and PARP1/2. Staining was scored as either positive or negative and percentage positive staining. Staining score was correlated with overall survival (OS) and progression-free survival (PFS). Of the markers tested, only immunohistochemical expression of p16(INK4A) correlated with clinical outcome. On univariate analysis, p16(INK4A) expression in the tumor was associated with improved OS (P = .038) but not PFS (P = .28). The median survival for patients with positive versus negative p16(INK4A) staining was 28.8 months versus 18 months. On multivariate analysis, p16(INK4A) expression was associated with improved OS (P = .026) but not PFS (P = .25). Age (P = .0019) and number of nodes involved (P = .025) were also significant for OS. Adjuvant chemotherapy and margin status did not correlate with OS or PFS. Expression of p16(INK4A) is associated with improved OS in patients with resected pancreatic adenocarcinoma. Further investigation is needed for validation, given conflicting data in the published literature. .


Neighbourhood environment, sitting time and motorised transport in older adults: a cross-sectional study in Hong Kong.
Sitting time is a public health concern. This study examined associations of objectively measured neighbourhood environmental attributes with non-transport sitting time and motorised transport in 484 Hong Kong older adults. Neighbourhood attributes encouraging walking may help older adults replace some sitting time at home and on motorised transport with light-to-moderate-intensity activities such as strolling around the neighbourhood or walking to/from neighbourhood destinations. Thus, we hypothesised environmental attributes found to be related to walking would show associations with non-transport sitting time and motorised transport opposite to those seen for walking. Cross-sectional. Hong Kong, an ultradense urban environment. 484 ethnic Chinese Hong Kong residents aged 65+ recruited from membership lists of four Hong Kong Elderly Health Centres representing catchment areas of low and high transport-related walkability stratified by socioeconomic status (response rate: 78%). Attributes of participants' neighbourhood environments were assessed by environmental audits, while non-transport sitting time and motorised transport were ascertained using the International Physical Activity Questionnaire-Long Form (Chinese version). Daily non-transport sitting minutes were 283 (SD=128) and motorised transport 23 (SD=28). Prevalence of signs of crime/disorder, streetlights, public facilities (toilets and benches) and pedestrian safety were independently negatively related, and sloping streets positively related, to sitting outcomes. Places of worship in the neighbourhood were predictive of more, and prevalence of public transit points of less, non-transport sitting. Associations of either or both sitting outcomes with prevalence of food/grocery stores and presence of parks were moderated by path obstructions and signs of crime/disorder. The findings suggest that access to specific destinations and relatively low-cost, minimal impact modifications to the urban form, such as street lighting, public toilets, benches and public transit points, could potentially reduce sitting time and associated negative health outcomes in Hong Kong older adults.


Activation of the MEF2 transcription factor in skeletal muscles from myotonic mice.
Becker syndrome, a recessive nondystrophic myotonia caused by mutations in the chloride channel 1 gene (CLCN1), is characterized by delayed muscle relaxation after contraction. The ADR (arrested development of righting response) mouse is an animal model for Becker syndrome. Skeletal muscles from ADR myotonic animals show an increased number of oxidative fibers with a lack of glycolytic fibers as well as signs of muscle hypertrophy. Through breeding ADR myotonic mice with mice harboring a MEF2-dependent reporter gene, we found that the transcriptional activity of MEF2 was dramatically enhanced in myotonic muscles. Post-translational induction of MEF2 transcriptional activity correlated with the activation of p38 MAPK and did not affect MEF2 DNA-binding affinity. Expression of class II histone deacetylases (HDACs), which repress MEF2-dependent gene expression, was significantly reduced in skeletal muscles from myotonic mice. These findings suggest that the combined effects of class II HDAC deficiency and p38 MAPK activation lead to potent upregulation of MEF2 transcriptional activity, which contributes to the long-term changes in gene expression and fiber-type transformation observed in myotonic skeletal muscles. These findings provide new molecular targets for potential treatment of congenital myotonia.


Neighborhood Differences in Post-Stroke Mortality.
Post-stroke mortality is higher among residents of disadvantaged neighborhoods, but it is not known whether neighborhood inequalities are specific to stroke survival or similar to mortality patterns in the general population. We hypothesized that neighborhood disadvantage would predict higher poststroke mortality, and neighborhood effects would be relatively larger for stroke patients than for individuals with no history of stroke. Health and Retirement Study participants aged ≥50 years without stroke at baseline (n=15 560) were followed ≤12 years for incident stroke (1715 events over 159 286 person-years) and mortality (5325 deaths). Baseline neighborhood characteristics included objective measures based on census tracts (family income, poverty, deprivation, residential stability, and percent white, black, or foreign-born) and self-reported neighborhood social ties. Using Cox proportional hazard models, we compared neighborhood mortality effects for people with versus people without a history of stroke. Most neighborhood variables predicted mortality for both stroke patients and the general population in demographic-adjusted models. Neighborhood percent white predicted lower mortality for stroke survivors (hazard ratio, 0.75 for neighborhoods in highest 25th percentile versus below, 95% confidence interval, 0.62-0.91) more strongly than for stroke-free adults (hazard ratio, 0.92; 95% confidence interval, 0.83-1.02; P=0.04 for stroke-by-neighborhood interaction). No other neighborhood characteristic had different effects for people with versus without stroke. Neighborhood-mortality associations emerged within 3 months after stroke, when associations were often stronger than among stroke-free individuals. Neighborhood characteristics predict mortality, but most effects are similar for individuals without stroke. Eliminating disparities in stroke survival may require addressing pathways that are not specific to traditional poststroke care.


Clinical correlates of acute bipolar depressive episode with psychosis.
Psychotic bipolar depressive episodes remain remarkably understudied despite being common and having a significant impact on bipolar disorder. The aim of this study is to identify the characteristics of depressed bipolar patients with current psychosis compared to those without psychosis. We used baseline data of a comparative effectiveness study of lithium and quetiapine for bipolar disorder (the Bipolar CHOICE study) to compare demographic, clinical, and functioning variables between those with and without psychotic symptoms. Of the 482 participants, 303 (62.9%) were eligible for the present study by meeting DSM-IV criteria for an acute bipolar depressive episode. Univariate analyses were conducted first, and then included in a model controlling for symptom severity. The sample was composed mostly of women (60.7%) and the mean age was 39.5±12.1 years. Psychosis was present in 10.6% (n=32) of the depressed patients. Psychotic patients had less education, lower income, and were more frequently single and unemployed. Psychosis was also associated with a more severe depressive episode, higher suicidality, more comorbid conditions and worse functioning. Most group differences disappeared when controlling for depression severity. Only outpatients were included and the presence of psychosis in previous episodes was not assessed. Psychosis during bipolar depressive episodes is present even in an outpatient sample. Psychotic, depressed patients have worse illness outcomes, but future research is necessary to confirm if these outcomes are only associated with the severity of the disorder or if some of them are independent of it.


Development of real-time RT-PCR assays for detection of three classes of HHV-6A gene transcripts.
Human herpesvirus 6 (HHV-6), a member of the betaherpesvirus family, has two distinct species: HHV-6A and HHV-6B. HHV-6B real-time reverse transcription polymerase chain reaction (RT-PCR) has been used to distinguish between active and latent viral infection. In this study, we developed a real-time RT-PCR assay to detect HHV-6A-specific transcripts and evaluated its reliability for analysis of clinical samples. To develop HHV-6A-specific real-time RT-PCR assays, three different classes of gene transcripts (immediate early: U90; early: U12; and late: U100) were selected as targets. Serial d ilutions of plasmid DNAs containing target sequences and RNAs extracted from HHV-6A-infected cells were used to determine assay specificity and sensitivity. Peripheral blood mononuclear cells (PBMCs) collected from patients with either primary or reactivated HHV-6B infection, and one patient with X-linked severe combined immunodeficiency (X-SCID) with HHV-6A reactivation, were used to evaluate assay reliability. The HHV-6A-specific real-time RT-PCR assays amplified plasmids containing the target sequences at concentrations between 10 and 1 × 106 copies per reaction. The intra-assay coefficients of variation were less than 5%. The three classes of HHV-6A gene transcripts were not detected in any HHV-6B sample isolated from the patients. In the X-SCID patient, high copy numbers of HHV-6A U12 and U100 transcripts were detected in PBMC samples during viremia. Thus, we successfully established highly sensitive and reproducible real-time RT-PCR methods targeting three classes of HHV-6A gene transcripts. This method should be useful for discriminating active HHV-6A infection from either latent infection or chromosomally integrated HHV-6A (ciHHV-6A).


Higher Rates of Misdiagnosis in Pediatric Patients Versus Adults Hospitalized With Imported Malaria.
Despite the availability of effective antimalarial prophylaxis, imported adult and pediatric malaria occurs in the United States, and this can pose diagnostic issues. We examined the clinical characteristics and diagnostic challenges of imported malaria requiring adult or pediatric inpatient admission at Montefiore Medical Center in the Bronx which provides care for a large population of immigrants from malaria endemic areas. We conducted a retrospective single center review of patients admitted with a diagnosis of malaria at Montefiore Medical Center from 2005 through 2012. We extracted historical, clinical, and laboratory values from the electronic medical record and patient charts. We identified 95 patients who were diagnosed and hospitalized with malaria from 2005 to 2012, 33 (35%) of them were children and 17 (18%) were with severe malaria. Most patients contracted malaria while visiting friends and relatives in West Africa. Only 38% of travelers took prophylaxis, and fewer than half reported taking it as prescribed. Misdiagnosis by emergency room or primary care doctors was observed in almost one quarter of all of the patients. Misdiagnosis occurred significantly more frequently in children (43%) compared to adults (13%) (P = 0.002). Pediatric patients were more likely to present with abdominal pain (42% vs. 15%; P = 0.005). Pediatric patients admitted for imported malaria at Montefiore Medical Center had a higher rate of misdiagnosis and presented with more gastrointestinal symptoms than hospitalized adults. By describing the clinical characteristics of patients with imported malaria, we hope to improve diagnostic accuracy by health care workers and raise awareness that friends and relatives may require more intensive pretravel counseling.


The impact of HIV on tuberculosis control--towards concerted action.
The well-established international control strategy for tuberculosis is based upon passive case-finding of the most infectious cases followed by effective chemotherapy with sufficient support to ensure and record a successful outcome. However, no country with a severe HIV epidemic is successfully controlling tuberculosis. HIV exerts a double blow. Not only must the health service manage a greatly increased number of patients (as many as fourfold higher in many African settings) but each individual patient needs to be managed more effectively if the control programme is to have a similar impact on transmission as it did in the pre-HIV era. In this paper, we discuss some of the effects of increased burden and stigmatization. We consider the potential of preventive therapy to reduce the impact of HIV on tuberculosis control and describe a more integrated approach to both infections that is being piloted in several sites in Southern Africa.


Impact of microorganisms and entomopathogenic nematodes used for plant protection on solitary and social bee pollinators: Host range, specificity, pathogenicity, toxicity, and effects of experimental parameters.
Pollinating bees are stressed by highly variable environmental conditions, malnutrition, parasites and pathogens, but may also by getting in contact with microorganisms or entomopathogenic nematodes that are used to control plant pests and diseases. While foraging for water, food, or nest material social as well as solitary bees have direct contact or even consume the plant protection product with its active substance (e.g., viruses, bacteria, fungi, etc.). Here, we summarize the results of cage, microcolony, observation hive assays, semi-field and field studies using full-size queen-right colonies. By now, some species and subspecies of the Western and Eastern honey bee (Apis mellifera, A. cerana), few species of bumble bees, very few stingless bee species and only a single species of leafcutter bees have been studied as non-target host organisms. Survival and reproduction are the major criteria that have been evaluated. Especially sublethal effects on the bees' physiology, immune response and metabolisms will be targets of future investigations. By studying infectivity and pathogenic mechanisms, individual strains of the microorganism and impact on different bee species are future challenges, especially under field conditions. Overall, it became evident that honey bees, bumble bees and few stingless bee species may not be suitable surrogate species to make general conclusions for biological mechanisms of bee-microorganism interactions of other social bee species. Solitary bees have been studied on leafcutter bees (Megachile rotundata) only, which shows that this huge group of bees (∼20,000 species worldwide) is right at the beginning to get an insight into the interaction of wild pollinators and microbial plant protection organisms.


Prognostic value of dynamic MRI in assessing post-traumatic femoral head vascularity.
The vascular status of femoral heads in the post-traumatic period of intracapsular femoral neck fracture (ICFNF) remains uncertain until the patient actually develops avascular necrosis (AVN). Several methods for predicting the viability of femoral head have been reported, that are not effective or widely used because of unreliability, potential complications, and technical difficulties. The present study involved the use of Dynamic MRI (DMRI) in assessing femoral head vascularity to predict AVN. The role of DMRI was studied prospectively in 30 patients with 31 ICFNF. Fractures were divided in to three types (Type A, B, or C) based on the femoral head vascularity shown by dynamic curve patterns on MRI evaluation. Type A was preserved vascularity, Type B was some decrease in vascularity but still viable while Type C was significantly reduced vascularity. These were followed-up for 6 months to 2 years to observe the final outcome in terms of union, non-union, or AVN. We found that Type A curves correlate well with vascular status and Type C curves correlate well with poor vascularity of the femoral heads. No AVN was seen in any of Type A (13/31) or Type B (eight out of 31). Five cases showed AVN and all of them were of Type C dynamic curves. Dynamic MRI is a reliable tool to evaluate vascularity of femoral heads and thus reduces the uncertainty of outcome of treatment of ICFNFs. DMRI can be a useful tool to formulate a treatment algorithm in management of ICFNF.


Making her end of life her own: further reflections on supporting a loved one with motor neurone disease.
People can live for many months without knowing why their body is failing prematurely before being diagnosed with motor neurone disease (MND); a terminal neurodegenerative disease which can be experienced as 'devastating' for the person and their family. This study aimed to explore the meaning of supporting a loved one with MND to die. This study uses reflection and autobiographical story to connect with broader cultural, political and social meaning and understandings of dying. Four themes were identified relating to the end-of-life trajectory of MND. Loss of person (lived body experienced in silence); loss of relationships (lived relations are challenged); loss of home and loss of time (lived space and lived time take on new meaning); loss of future (dying-facing it alone). Dying with MND is a complex phenomenon. When a person can no longer move and communicate, relationships between those involved in end-of-life care are challenging. A person with MND needs the support from those acting as power of attorney to make their end of life their own, and they themselves need support to find meaning in their suffering. This autoethnographic reflection provides vicarious experiences for nurses and other healthcare professionals working with people with MND and similar conditions.


Comparison of inhibition of Escherichia coli topoisomerase IV by quinolones with DNA gyrase inhibition.
In order to examine the inhibitory activities of quinolones against topoisomerase IV, both subunits of this enzyme, ParC and ParE, were purified from Escherichia coli. The specific activity of topoisomerase IV decatenation was found to be more than five times greater than that of topoisomerase IV relaxation. Thus, the decatenation activity of topoisomerase IV seems the most relevant activity for use in studies of drug inhibition of this enzyme. Although topoisomerase IV was less sensitive to quinolones than DNA gyrase, the 50% inhibitory concentrations for decatenation were significantly lower than those for type I topoisomerases. Moreover, there was a positive correlation between the inhibitory activity against topoisomerase IV decatenation and that for DNA gyrase supercoiling. These results imply that topoisomerase IV could be a target for the quinolones in intact bacteria and that quinolones could inhibit not only supercoiling of DNA gyrase but also decatenation of topoisomerase IV when high concentrations of drug exist in bacterial cells.


Facile synthesis of photoluminescent inorganic-organic hybrid carbon dots codoped with B and N: towards an efficient lubrication additive.
A novel environmentally friendly bis-functional dicationic ionic liquid containing chelated orthoborate was synthesized and polycondensed with glutamic acid in order to synthesize inorganic-organic carbon dots (CD/IL) consisting of an ionic liquid moiety inserted in the carbon skeleton. The obtained CD/IL was found to be a new kind of nitrogen/boron-codoped nanomaterial, one with a mean particle diameter of 2.66 nm. CD/IL was verified to be a high-performance lubricant additive: in particular, the anti-wear and friction-reducing properties of poly(ethylene glycol) (PEG) were improved by 89.34% and 62.18%, respectively, when 1% CD/IL was added. Lubricants consisting of a mixture of CD/IL and PEG showed intense blue photo-fluorescence, and the corresponding photoluminescence (PL) intensity decreased considerably after carrying out a tribo-test. Moreover, CD/IL became transferred onto a rubbing steel interface during the tribo-test according to EDX and Raman analyses of a worn surface. CD/IL showed poor crystallinity, and interestingly, an intense G (∼1600 cm-1) signature was detected on the steel surface after a high-load and long-duration tribo-test, which indicated that ordered carbon materials were generated on the interface, inhibiting the undesirable wear.


Optimal selection of metabolic fluxes for in vivo measurement. II. Application to Escherichia coli and hybridoma cell metabolism.
A method of analysis was presented in part I of this series for determining the fluxes in a biochemical network that are the optimal choices for experimental measurement. This algorithm is applied to two important biological models: Escherichia coli and a hybridoma cell line (167.4G5.3). Our results show that potentially poor choices for in vivo measurement of metabolic fluxes exist for both model systems. For the subset of reactions in E. coli that was studied, the condition number of the augmented stoichiometric matrix reveals that a 60-fold amplification of experimental error during computations is possible. The biochemical network of the hybridoma cell is more complex than the E. coli system, and thus results in much larger possible error amplification--up to 100,000-fold. The physiological situations appear to have sensitivities that are less than 1/4 to 1/10 of those estimated by the condition number, and the maximum sensitivities are proportional to the condition number. These maximum sensitivities calculated using estimates of the fluxes and the worst possible error vector are upper bounds on the system's actual sensitivity. By examining the effect of measurement error on the sensitivity, the most probable sensitivity is calculated. These results indicate that an approximate two-fold increase in sensitivity of the E. coli system is likely when the worst set of fluxes are measured rather than the best set. The most likely sensitivity of the hybridoma system can range three orders of magnitude, depending on the set of fluxes that are measured. The propagation of experimental error during computations can be diminished for both systems by increasing the number of flux measurements over and above the minimum number of experimental measurements. The findings from these two model systems indicate that the calculation of the condition number can be a useful method for efficient experimental design, and that the usefulness of this method increases as the order of the system increases.


Seasonality of human leptospirosis in Reunion Island (Indian Ocean) and its association with meteorological data.
Leptospirosis is a disease which occurs worldwide but particularly affects tropical areas. Transmission of the disease is dependent on its excretion by reservoir animals and the presence of moist environment which allows the survival of the bacteria. A retrospective study was undertaken to describe seasonal patterns of human leptospirosis cases reported by the Centre National de Références des Leptospiroses (CNRL, Pasteur Institute, Paris) between 1998 and 2008, to determine if there was an association between the occurrence of diagnosed cases and rainfall, temperature and global solar radiation (GSR). Meteorological data were recorded in the town of Saint-Benoît (Météo France "Beaufonds-Miria" station), located on the windward (East) coast. Time-series analysis was used to identify the variables that best described and predicted the occurrence of cases of leptospirosis on the island. Six hundred and thirteen cases were reported during the 11-year study period, and 359 cases (58.56%) were diagnosed between February and May. A significant correlation was identified between the number of cases in a given month and the associated cumulated rainfall as well as the mean monthly temperature recorded 2 months prior to diagnosis (r = 0.28 and r = 0.23 respectively). The predictive model includes the number of cases of leptospirosis recorded 1 month prior to diagnosis (b = 0.193), the cumulated monthly rainfall recorded 2 months prior to diagnosis (b = 0.145), the average monthly temperature recorded 0 month prior to diagnosis (b = 3.836), and the average monthly GSR recorded 0 month prior to diagnosis (b = -1.293). Leptospirosis has a seasonal distribution in Reunion Island. Meteorological data can be used to predict the occurrence of the disease and our statistical model can help to implement seasonal prevention measures.


Household transmissibility and other characteristics of seasonal oseltamivir-resistant influenza A(H1N1) viruses, Germany, 2007-8.
During the influenza season 2007-8, the proportion of seasonal influenza A(H1N1) viruses resistant to the neuraminidase inhibitor oseltamivir increased worldwide. We conducted an investigation to compare patients infected with oseltamivir-resistant (ose-R) and oseltamivir- susceptible (ose-S) influenza A(H1N1) viruses regarding risk factors for resistance and the capability to transmit in the household setting. Within a cohort of 396 laboratory confirmed influenza patients from sentinel physicians we conducted a nested case-control study among patients infected with A(H1N1). Thirty patients in the cohort were infected with influenza B, none with influenza A(H3N2) and 366 with A(H1N1). Of the 366 A(H1N1) viruses 52 (14%) were ose-R. Demographic characteristics, oseltamivir exposure, travel history and outcome were not significantly different between ose-S and ose-R patients. Among 133 households in the nested case-control study, secondary household attack rates in households with ose-R cases and households with ose-S cases were similar (23 versus 26%; p-value=0.54). Ose-R household status and occurrence of secondary cases were associated with an odds ratio of 0.85 (95% confidence interval 0.38-1.88). We conclude that seasonal ose-R influenza A(H1N1) viruses have transmitted well in the household setting.


Maintenance treatment with antipsychotic drugs for schizophrenia.
The symptoms and signs of schizophrenia have been firmly linked to high levels of dopamine in specific areas of the brain (limbic system). Antipsychotic drugs block the transmission of dopamine in the brain and reduce the acute symptoms of the disorder. This review examined whether antipsychotic drugs are also effective for relapse prevention. To review the effects of maintaining antipsychotic drugs for people with schizophrenia compared to withdrawing these agents. We searched the Cochrane Schizophrenia Group's Specialised Register (November 2008), with additional searches of MEDLINE, EMBASE and clinicaltrials.gov (June 2011). We included all randomised trials comparing maintenance treatment with antipsychotic drugs and placebo for people with schizophrenia or schizophrenia-like psychoses. We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated mean differences (MD) or standardised mean differences (SMD) again based on a random-effects model. The review currently includes 65 randomised controlled trials (RCT(s)) and 6493 participants comparing antipsychotic medication with placebo. The trials were published from 1959 to 2011 and their size ranged between 14 and 420 participants. In many studies the methods of randomisation, allocation and blinding were poorly reported. Although this and other potential sources of bias limited the overall quality, the efficacy of antipsychotic drugs for maintenance treatment in schizophrenia was clear. Antipsychotic drugs were significantly more effective than placebo in preventing relapse at seven to 12 months (primary outcome; drug 27%, placebo 64%, 24 RCT(s), n=2669, RR 0.40 CI 0.33 to 0.49, number needed to treat for an additional beneficial outcome (NNTB 3 CI 2 to 3). Hospitalisation was also reduced, however, the baseline risk was lower (drug 10%, placebo 26%, 16 RCT(s), n=2090, RR 0.38 CI 0.27 to 0.55, NNT 5 CI 4 to 9). More participants in the placebo group than in the antipsychotic drug group left the studies early due to any reason (at 7-12 months: drug 38%, placebo 66%, 18 RCT(s), n=2420, RR 0.55 CI 0.46 to 0.66, NNTB 4 CI 3 to 5) and due to inefficacy of treatment (at 7-12 months: drug 20%, placebo 50%, 18 RCT(s), n=2420, RR 0.36 CI 0.28 to 0.45, NNTB 3 CI 2 to 4). Quality of life was better in drug-treated participants (3 RCT(s), n=527, SMD -0.62 CI -1.15 to -0.09). Conversely, antipsychotic drugs as a group and irrespective of duration, were associated with more participants experiencing movement disorders (e.g. at least one movement disorder: drug 16%, placebo 9%, 22 RCT(s), n=3411, RR 1.55 CI 1.25 to 1.93, NNTH 25 CI 13 to 100), sedation (drug 13%, placebo 9%, 10 RCT(s), n=146, RR 1.50 CI 1.22 to 1.84, number needed to treat for an additional harmful outcome (NNTH) not significant) and weight gain (drug 10%, placebo 6%, 10 RCT(s), n=321, RR 2.07 CI 1.31 to 3.25, NNTH 20 CI 14 to 33). The results of the primary outcome were robust in a number of subgroup, meta-regression and sensitivity analyses, the main exception being that the drug-placebo difference in longer trials was smaller than in shorter trials. The results clearly demonstrate the superiority of antipsychotic drugs compared to placebo in preventing relapse. This effect must be weighed against the side effects of antipsychotic drugs. Future studies should focus on outcomes of social participation and clarify the long-term morbidity and mortality associated with these drugs.


Stable Isotope Phenotyping via Cluster Analysis of NanoSIMS Data As a Method for Characterizing Distinct Microbial Ecophysiologies and Sulfur-Cycling in the Environment.
Stable isotope probing (SIP) is a valuable tool for gaining insights into ecophysiology and biogeochemical cycling of environmental microbial communities by tracking isotopically labeled compounds into cellular macromolecules as well as into byproducts of respiration. SIP, in conjunction with nanoscale secondary ion mass spectrometry (NanoSIMS), allows for the visualization of isotope incorporation at the single cell level. In this manner, both active cells within a diverse population as well as heterogeneity in metabolism within a homogeneous population can be observed. The ecophysiological implications of these single cell stable isotope measurements are often limited to the taxonomic resolution of paired fluorescence in situ hybridization (FISH) microscopy. Here we introduce a taxonomy-independent method using multi-isotope SIP and NanoSIMS for identifying and grouping phenotypically similar microbial cells by their chemical and isotopic fingerprint. This method was applied to SIP experiments in a sulfur-cycling biofilm collected from sulfidic intertidal vents amended with (13)C-acetate, (15)N-ammonium, and (33)S-sulfate. Using a cluster analysis technique based on fuzzy c-means to group cells according to their isotope ((13)C/(12)C, (15)N/(14)N, and (33)S/(32)S) and elemental ratio (C/CN and S/CN) profiles, our analysis partitioned ~2200 cellular regions of interest (ROIs) into five distinct groups. These isotope phenotype groupings are reflective of the variation in labeled substrate uptake by cells in a multispecies metabolic network dominated by Gamma- and Deltaproteobacteria. Populations independently grouped by isotope phenotype were subsequently compared with paired FISH data, demonstrating a single coherent deltaproteobacterial cluster and multiple gammaproteobacterial groups, highlighting the distinct ecophysiologies of spatially-associated microbes within the sulfur-cycling biofilm from White Point Beach, CA.


A population-based estimate of the economic burden of influenza in Peru, 2009-2010.
Influenza disease burden and economic impact data are needed to assess the potential value of interventions. Such information is limited from resource-limited settings. We therefore studied the cost of influenza in Peru. We used data collected during June 2009-December 2010 from laboratory-confirmed influenza cases identified through a household cohort in Peru. We determined the self-reported direct and indirect costs of self-treatment, outpatient care, emergency ward care, and hospitalizations through standardized questionnaires. We recorded costs accrued 15-day from illness onset. Direct costs represented medication, consultation, diagnostic fees, and health-related expenses such as transportation and phone calls. Indirect costs represented lost productivity during days of illness by both cases and caregivers. We estimated the annual economic cost and the impact of a case of influenza on a household. There were 1321 confirmed influenza cases, of which 47% sought health care. Participants with confirmed influenza illness paid a median of $13 [interquartile range (IQR) 5-26] for self-treatment, $19 (IQR 9-34) for ambulatory non-medical attended illness, $29 (IQR 14-51) for ambulatory medical attended illness, and $171 (IQR 113-258) for hospitalizations. Overall, the projected national cost of an influenza illness was $83-$85 millions. Costs per influenza illness represented 14% of the monthly household income of the lowest income quartile (compared to 3% of the highest quartile). Influenza virus infection causes an important economic burden, particularly among the poorest families and those hospitalized. Prevention strategies such as annual influenza vaccination program targeting SAGE population at risk could reduce the overall economic impact of seasonal influenza.


Protecting genomic data analytics in the cloud: state of the art and opportunities.
The outsourcing of genomic data into public cloud computing settings raises concerns over privacy and security. Significant advancements in secure computation methods have emerged over the past several years, but such techniques need to be rigorously evaluated for their ability to support the analysis of human genomic data in an efficient and cost-effective manner. With respect to public cloud environments, there are concerns about the inadvertent exposure of human genomic data to unauthorized users. In analyses involving multiple institutions, there is additional concern about data being used beyond agreed research scope and being prcoessed in untrused computational environments, which may not satisfy institutional policies. To systematically investigate these issues, the NIH-funded National Center for Biomedical Computing iDASH (integrating Data for Analysis, 'anonymization' and SHaring) hosted the second Critical Assessment of Data Privacy and Protection competition to assess the capacity of cryptographic technologies for protecting computation over human genomes in the cloud and promoting cross-institutional collaboration. Data scientists were challenged to design and engineer practical algorithms for secure outsourcing of genome computation tasks in working software, whereby analyses are performed only on encrypted data. They were also challenged to develop approaches to enable secure collaboration on data from genomic studies generated by multiple organizations (e.g., medical centers) to jointly compute aggregate statistics without sharing individual-level records. The results of the competition indicated that secure computation techniques can enable comparative analysis of human genomes, but greater efficiency (in terms of compute time and memory utilization) are needed before they are sufficiently practical for real world environments.


Potential use of melatonergic drugs in analgesia: mechanisms of action.
Melatonin is a remarkable molecule with diverse physiological functions. Some of its effects are mediated by receptors while other, like cytoprotection, seem to depend on direct and indirect scavenging of free radicals not involving receptors. Among melatonin's many effects, its antinociceptive actions have attracted attention. When given orally, intraperitoneally, locally, intrathecally or through intracerebroventricular routes, melatonin exerts antinociceptive and antiallodynic actions in a variety of animal models. These effects have been demonstrated in animal models of acute pain like the tail-flick test, formalin test or endotoxin-induced hyperalgesia as well as in models of neuropathic pain like nerve ligation. Glutamate, gamma-aminobutyric acid, and particularly, opioid neurotransmission have been demonstrated to be involved in melatonin's analgesia. Results using melatonin receptor antagonists support the participation of melatonin receptors in melatonin's analgesia. However, discrepancies between the affinity of the receptors and the very high doses of melatonin needed to cause effects in vivo raise doubts about the uniqueness of that physiopathological interpretation. Indeed, melatonin could play a role in pain through several alternative mechanisms including free radicals scavenging or nitric oxide synthase inhibition. The use of melatonin analogs like the MT(1)/MT(2) agonist ramelteon, which lacks free radical scavenging activity, could be useful to unravel the mechanism of action of melatonin in analgesia. Melatonin has a promising role as an analgesic drug that could be used for alleviating pain associated with cancer, headache or surgical procedures.


SurvExpress: an online biomarker validation tool and database for cancer gene expression data using survival analysis.
Validation of multi-gene biomarkers for clinical outcomes is one of the most important issues for cancer prognosis. An important source of information for virtual validation is the high number of available cancer datasets. Nevertheless, assessing the prognostic performance of a gene expression signature along datasets is a difficult task for Biologists and Physicians and also time-consuming for Statisticians and Bioinformaticians. Therefore, to facilitate performance comparisons and validations of survival biomarkers for cancer outcomes, we developed SurvExpress, a cancer-wide gene expression database with clinical outcomes and a web-based tool that provides survival analysis and risk assessment of cancer datasets. The main input of SurvExpress is only the biomarker gene list. We generated a cancer database collecting more than 20,000 samples and 130 datasets with censored clinical information covering tumors over 20 tissues. We implemented a web interface to perform biomarker validation and comparisons in this database, where a multivariate survival analysis can be accomplished in about one minute. We show the utility and simplicity of SurvExpress in two biomarker applications for breast and lung cancer. Compared to other tools, SurvExpress is the largest, most versatile, and quickest free tool available. SurvExpress web can be accessed in http://bioinformatica.mty.itesm.mx/SurvExpress (a tutorial is included). The website was implemented in JSP, JavaScript, MySQL, and R.


Biodegradation of nonylphenol during aerobic composting of sewage sludge under two intermittent aeration treatments in a full-scale plant.
The urbanization and industrialization of cities around the coastal region of the Bohai Sea have produced large amounts of sewage sludge from sewage treatment plants. Research on the biodegradation of nonylphenol (NP) and the influencing factors of such biodegradation during sewage sludge composting is important to control pollution caused by land application of sewage sludge. The present study investigated the effect of aeration on NP biodegradation and the microbe community during aerobic composting under two intermittent aeration treatments in a full-scale plant of sewage sludge, sawdust, and returned compost at a ratio of 6:3:1. The results showed that 65% of NP was biodegraded and that Bacillus was the dominant bacterial species in the mesophilic phase. The amount of NP biodegraded in the mesophilic phase was 68.3%, which accounted for 64.6% of the total amount of biodegraded NP. The amount of NP biodegraded under high-volume aeration was 19.6% higher than that under low-volume aeration. Bacillus was dominant for 60.9% of the composting period under high-volume aeration, compared to 22.7% dominance under low-volume aeration. In the thermophilic phase, high-volume aeration promoted the biodegradation of NP and Bacillus remained the dominant bacterial species. In the cooling and stable phases, the contents of NP underwent insignificant change while different dominant bacteria were observed in the two treatments. NP was mostly biodegraded by Bacillus, and the rate of biodegradation was significantly correlated with the abundance of Bacillus (r = 0.63, p < 0.05). Under aeration, Bacillus remained the dominant bacteria, especially in the thermal phase; this phenomenon possibly increased the biodegradation efficiency of NP. High-volume aeration accelerated the activity and prolonged the survival of Bacillus. The risk of organic pollution could be decreased prior to sewage sludge reuse in soil by adjusting the ventilation strategies of aerobic compost measurements.


Genomic sequencing identifies novel Bacillus thuringiensis Vip1/Vip2 binary and Cry8 toxins that have high toxicity to Scarabaeoidea larvae.
The Bacillus thuringiensis strain HBF-18 (CGMCC 2070), which has previously been shown to encode the cry8Ga toxin gene, is active against both Holotrichia oblita and Holotrichia parallela. Recombinant Cry8Ga however is only weakly toxic to these insect pests suggesting the involvement of additional toxins in the native strain. We report that through the use of Illumina sequencing three additional, and novel, genes, namely vip1Ad1, vip2Ag1, and cry8-like, were identified in this strain. Although no protein corresponding to these genes could be identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the HBF-18 proteome, reverse transcription (RT)-PCR indicated that all three genes were transcribed in the native strain. The two vip genes were cloned and expressed and, as with other Vip1/2 toxins, appeared to function as a binary toxin and showed strong activity against H. oblita, H. parallela and Anomala corpulenta. This is the first report to demonstrate that the Vip1/Vip2 binary toxin is active against these Scarabaeoidea larvae. The cry8-like gene appeared to be a C-terminally truncated form of a typical cry8 gene and was not expressed in our usual recombinant Bt expression system. When however the missing C-terminal region was replaced with the corresponding sequence from cry8Ea, the resulting hybrid expressed well and the toxin was active against the three test insects.


Novel lead-free ferroelectric film by ultra-small Ba0.8Sr0.2TiO3 nanocubes assembled for a large electrocaloric effect.
A giant electrocaloric effect (ECE) can be achieved in ferroelectric thin films, which demonstrates the applications of thin films in alternative cooling. However, electrocaloric thin films fabricated by conventional techniques, such as the pulsed laser deposition or sol-gel methods, may be limited by high costs, low yield and their dependence on substrates. In this study, we present a new bottom-up strategy to construct electrocaloric Ba0.8Sr0.2TiO3 thin films by assembling precisely designed building blocks of ferroelectric nanocubes, which is supported by detailed structural characterization. Moreover, it is found that our assembled Ba0.8Sr0.2TiO3 films differ remarkably from both individual Ba0.8Sr0.2TiO3 NPs and bulk Ba0.8Sr0.2TiO3 ceramics in terms of new collective ferroelectric properties, including superior and diffused permittivity constants and polarization-electric field loops. Benefiting from these unique ferroelectric properties, a giant ECE (9.1 K) over a broad temperature range (20 °C to 60 °C) is achieved, which is very large in the lead-free oxide film. Clearly, this bottom-up strategy provides a promising pathway for developing high electrocaloric effect devices.


Efficient fiber-to-chip grating coupler for micrometric SOI rib waveguides.
Grating couplers are an efficient means for fiber to chip coupling, as they require no facet preparation and enable wafer scale testing. While grating couplers are commonly used in silicon wire waveguides, their application to micrometric silicon-on-insulator rib waveguides is complicated due to the presence of high-order Bloch modes. We study the Bloch modes behavior and their excitation determined by access waveguide design. The latter is implemented to enable single Bloch mode excitation. The use of a design process based on modal analysis is proposed. A grating coupler is proposed in silicon-on-insulator with 1.5 microm thick silicon layer that achieves a coupling efficiency of 65.6% at 1.55 microm. The structure, including interconnection waveguides, access waveguide and grating can be fabricated using a single lithography step.


The Sexuality of Adults with Intellectual Disability in Poland.
Sexuality is one of the most important aspects of human life that relates to sex, one's identification, sexual role, sexual preferences, eroticism, pleasure and intimacy. It fulfils such functions as procreative, hedonistic and relationship-building as well as constitutes an integral part of human's personality. The sexuality of people with intellectual disability is a special case - both from medical, pedagogical, psychological and ethical point of view. Little available research shows that it may become a significant factor that modifies their psychological and sexual functioning. The basic poll involved altogether 133 people with mild intellectual disability. The work was carried out in 11 schools and special institutions of three provinces in Poland: kujawsko - pomorskie, wielkopolskie and dolnośląskie (provinces of Kujavy and Pomerania, Great Poland and Lower Silesia) The respondents qualified to take part in the poll constituted a very uniform group - homogenous as regards their age of 18-25 as well as IQ level that was average for the people with higher degree of intellectual disability (HDID). Their age was of importance as in that life period one can observe the formation of first partner relationships with the clear aim of establishing a family. It is accompanied by a quick development of sexual desire and taking up various forms of sexual activity. People with intellectual disability don't form a homogenous group as regards their psychological and sexual development. In this group, one can observe both different forms of clinical mental handicap which definitely affects the whole process of sexual development. The sexual development is delayed by an average period of 3 years. The people with intellectual disability take up mostly autoerotic behaviour whereas partner relationships wthin that group are more seldom. The phenomenon of sexuality of people with higher degree of intellectual disability is an issue that needs further constant analysis. The research has also made it possible to detect what kind of sexual behaviour people with intellectual disability undertake and the value of sexuality for such people. The article deals also with some important dilemmas connected with sexual education and what factors trigger off incorrect sexual reaction including their lack in the above mentioned group.


Breakfast Skipping, Extreme Commutes, and the Sex Composition at Birth.
A growing body of literature has shown that environmental exposures in the period around conception can affect the sex ratio at birth through selective attrition that favors the survival of female conceptuses. Glucose availability is considered a key indicator of the fetal environment, and its absence as a result of meal skipping may inhibit male survival. We hypothesize that breakfast skipping during pregnancy may lead to a reduction in the fraction of male births. Using time use data from the United States we show that women with commute times of 90 minutes or longer are 20 percentage points more likely to skip breakfast. Using U.S. census data we show that women with commute times of 90 minutes or longer are 1.2 percentage points less likely to have a male child under the age of 2. Under some assumptions, this implies that routinely skipping breakfast around the time of conception leads to a 6 percentage point reduction in the probability of a male child. Skipping breakfast during pregnancy may therefore constitute a poor environment for fetal health more generally.


Insulin increases the release of proinflammatory mediators.
Strict glucose control with insulin is associated with decreased mortality in a mixed patient population in the intensive care unit. Controversy exists regarding the relative benefits of glucose control versus a direct advantageous effect of exogenous insulin. As a combined medical/surgical population differs significantly from the critically injured patient primed for secondary insult, our purpose was to determine the influence of insulin on activated macrophages. Our hypothesis was that insulin would directly abrogate the inflammatory cascade. Differentiated human monocytic THP-1 cells were stimulated with endotoxin (lipopolysaccharide [LPS], 100 ng/mL) for 6 hours. Cells were treated +/-10(-7) M insulin for 1 hour and 24 hours. Total RNA was isolated and gene expression for TNF-alpha and IL-6 performed using Q-RT-PCR. Supernatants were assayed for TNF-alpha and IL-6 protein by ELISA. At 1 hour, compared with macrophages treated with LPS alone, macrophages treated with insulin produced significantly more TNF-alpha protein (11.4 +/- 5.9 pg/mL vs. 32.5 +/- 3.1 pg/mL; p < 0.03). At 24 hours compared with macrophages treated with LPS alone, macrophages treated with insulin produced significantly more TNF-alpha protein (83 +/- 2.02 pg/mL vs. 114 +/- 6.54 pg/mL; p < 0.01). However, gene expression of TNF-alpha and IL-6 was not different in LPS stimulated macrophages with and without insulin treatment at both 1 hour and 24 hours. Contrary to our hypothesis, insulin does not have direct anti-inflammatory properties in this experimental model. In fact, insulin increases proinflammatory cytokine protein levels from activated macrophages.


Genome-wide transcriptional analysis of silica nanoparticle-induced toxicity in zebrafish embryos.
Although silica nanoparticles (SiNPs) have a promising application in biomedical fields, there is still a lack of comprehensive understanding of genome-wide transcriptional analysis. This study aims to clarify the toxic effect and molecular mechanisms of SiNPs in zebrafish embryos based on microarray analysis and bioinformatics analysis. Microarray data analysis demonstrated that SiNP-induced toxicity in zebrafish embryos affected expression of 2515 genes, including 1107 genes that were up-regulated and 1408 genes that were down-regulated. These differentially expressed genes were subjected to bioinformatics analysis for exploring the biological processes triggered by SiNPs in zebrafish embryos. Gene ontology analysis showed that SiNPs caused significant changes in gene expression patterns related to many important functions, including response to stimuli, immune response, cellular processes, and embryonic development. In addition, pathway analysis and Signal-net analysis indicated that the gap junction, vascular smooth muscle contraction, and metabolic pathways, apoptosis, the MAPK signaling pathway, the calcium signaling pathway and the JAK-STAT signaling pathway were the most prominent significant pathways in SiNP-induced toxicity in zebrafish embryos. In addition, the results from qRT-PCR and western blot analysis showed that the IL-6 dependent JAK1/STAT3 signaling pathway was activated by SiNPs in zebrafish embryos. In summary, our data will provide compelling clues for further exploration of SiNP-induced toxicity in zebrafish embryos.


Redefining the role of Broca's area in speech.
For over a century neuroscientists have debated the dynamics by which human cortical language networks allow words to be spoken. Although it is widely accepted that Broca's area in the left inferior frontal gyrus plays an important role in this process, it was not possible, until recently, to detail the timing of its recruitment relative to other language areas, nor how it interacts with these areas during word production. Using direct cortical surface recordings in neurosurgical patients, we studied the evolution of activity in cortical neuronal populations, as well as the Granger causal interactions between them. We found that, during the cued production of words, a temporal cascade of neural activity proceeds from sensory representations of words in temporal cortex to their corresponding articulatory gestures in motor cortex. Broca's area mediates this cascade through reciprocal interactions with temporal and frontal motor regions. Contrary to classic notions of the role of Broca's area in speech, while motor cortex is activated during spoken responses, Broca's area is surprisingly silent. Moreover, when novel strings of articulatory gestures must be produced in response to nonword stimuli, neural activity is enhanced in Broca's area, but not in motor cortex. These unique data provide evidence that Broca's area coordinates the transformation of information across large-scale cortical networks involved in spoken word production. In this role, Broca's area formulates an appropriate articulatory code to be implemented by motor cortex.


Pathogenesis of Atopic Dermatitis: Current Paradigm.
Atopic dermatitis (AD) is characterized by skin inflammation, barrier dysfunction and chronic pruritus. In this review, recent advances in the pathogenesis of AD are summarized. Clinical efficacy of the anti-IL-4 receptor antibody dupilumab implies that type 2 cytokines IL-4 and IL-13 have pivotal roles in atopic inflammation. The expression of IL-4 and IL-13 as well as type 2 chemokines such as CCL17, CCL22 and CCL26 is increased in the lesional skin of AD. In addition, IL-4 and IL-13 down-regulate the expression of filaggrin in keratinocytes and exacerbate epidermal barrier dysfunction. Keratinocytes in barrier-disrupted epidermis produce large amounts of thymic stromal lymphopoietin, IL-25 and IL-33, conducing to type 2 immune deviation via OX40L/OX40 signaling. IL-31, produced by type 2 T cells, is a cardinal pruritogenic cytokine. IL-4 and IL-13 also amplify the IL-31-mediated sensory nerve signal. These molecules are particularly important targets for future drug development for AD.


Force and affinity in ligand discrimination by the TCR.
T cell recognition of antigen is a physical process that requires formation of a cell-cell junction that is rich in active force generation. Recently a biomolecular force probe was used to examine how the T cell receptor (TCR)-pMHC interaction responds to force and the consequences of force-dependent interactions for T cell activation. While adhesion and costimulatory molecules in the immunological synapse impact upon the overall force of the interaction, these results suggest that the TCR uses a force-dependent bond - a catch bond - and that it may therefore be important to consider the TCR-pMHC interaction in isolation in the early phases of the decision process. We discuss here these findings in the context of other work on the impact of forces on the TCR and the quantification of interaction in interfaces.


Consumers Buy Lower-Cost Plans On Covered California, Suggesting Exposure To Premium Increases Is Less Than Commonly Reported.
With the notable exception of California, states have not made enrollment data for their Affordable Care Act (ACA) Marketplace plans publicly available. Researchers thus have tracked premium trends by calculating changes in the average price for plans offered (a straight average across plans) rather than for plans purchased (a weighted average). Using publicly available enrollment data for Covered California, we found that the average purchased price for all plans was 11.6 percent less than the average offered price in 2014, 13.2 percent less in 2015, and 15.2 percent less in 2016. Premium growth measured by plans purchased was roughly 2 percentage points less than when measured by plans offered in 2014-15 and 2015-16. We observed shifts in consumer choices toward less costly plans, both between and within tiers, and we estimate that a $100 increase in a plan's net annual premium reduces its probability of selection. These findings suggest that the Marketplaces are helping consumers moderate premium cost growth.


Splenic vein thrombosis and gastrointestinal bleeding in chronic pancreatitis.
The most common cause of isolated thrombosis of the splenic vein is chronic pancreatitis caused by perivenous inflammation. Although splenic vein thrombosis (SVT) has been reported in up to 45% of patients with chronic pancreatitis, most patients with SVT remain asymptomatic. In those patients with gastrointestinal bleeding secondary to esophageal or gastric varices, the diagnostic test of choice to assess for the presence of SVT is late-phase celiac angiography. Splenectomy effectively eliminates the collateral outflow and is the treatment of choice. Other underlying pathology, such as pseudocysts, can be treated at the same time.


Variation in enantiospecific attraction of Ips avulsus (Coleoptera: Curculionidae) to the pheromone ipsdienol in Georgia.
In 2006, we tested the responses of the small southern pine engraver, Ips avulsus (Eichhoff) (Coleoptera: Curculionidae), to multiple-funnel traps baited with (+)-, (-)-, and (+/-)-ipsdienol. Three experiments were conducted in Georgia with all traps co-baited with one of the following lure combinations, respectively: experiment 1, ipsenol; experiment 2, lanierone and (-)-alpha-pinene; and experiment 3, ipsenol, lanierone, and (-)-alpha-pinene. Ipsdienol and lanierone are aggregation pheromones used by I. avulsus, whereas ipsenol is an aggregation pheromone used by the eastern fivespined ips, Ips grandicollis (Eichhoff), a sympatric species also breeding in pines. In all experiments, the highest catches of I. avulsus were obtained in traps baited with (+/-)-ipsdienol. The relative attractiveness of (+)-ipsdienol varied across the three experiments. When traps were co-baited with ipsenol, lanierone, and (-)-alpha-pinene, catches of I. avulsus in traps baited with (+)-ipsdienol were high and no different from those in traps baited with (+/-)-ipsdienol. When traps were co-baited with lanierone and (-)-alpha-pinene, catches in traps baited with (+)-ipsdienol were lower than those in traps baited with (+/-)-ipsdienol by approximately 40%, whereas catches were reduced by approximately 95% when traps were co-baited with ipsenol alone. We hypothesize that the observed variation in enantiospecific responses of I. avulsus to ipsdienol may be explained by variation in semiochemical context (i.e., different co-baits among the experiments) or seasonal variation.


Patterns and rates of exonic de novo mutations in autism spectrum disorders.
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.


The efficacy of mindfulness-based stress reduction in the treatment of sleep disturbance in women with breast cancer: an exploratory study.
The diagnosis of breast cancer, the most common type of cancer among American women, elicits greater distress than any other diagnosis regardless of prognosis. Therefore, the present study examined the efficacy of a stress reduction intervention for women with breast cancer. As part of a larger, randomized, controlled study of the effects on measures of stress of a mindfulness-based stress reduction (MBSR) intervention for women with breast cancer, the current analyses examined the effects on sleep complaints. Analyses of the data indicated that both MBSR and a free choice (FC) control condition produced significant improvement on daily diary sleep quality measures though neither showed significant improvement on sleep-efficiency. Participants in the MBSR who reported greater mindfulness practice improved significantly more on the sleep quality measure most strongly associated with distress. MBSR appears to be a promising intervention to improve the quality of sleep in woman with breast cancer whose sleep complaints are due to stress.


Unexpected timely fracture union in matrix metalloproteinase 9 deficient mice.
Immediately following a fracture, a fibrin laden hematoma is formed to prevent bleeding and infection. Subsequently, the organized removal of fibrin, via the protease plasmin, is essential to permit fracture repair through angiogenesis and ossification. Yet, when plasmin activity is lost, the depletion of fibrin alone is insufficient to fully restore fracture repair, suggesting the existence of additional plasmin targets important for fracture repair. Previously, activated matrix metalloproteinase 9 (MMP-9) was demonstrated to function in fracture repair by promoting angiogenesis. Given that MMP-9 is a defined plasmin target, it was hypothesized that pro-MMP-9, following plasmin activation, promotes fracture repair. This hypothesis was tested in a fixed murine femur fracture model with serial assessment of fracture healing. Contrary to previous findings, a complete loss of MMP-9 failed to affect fracture healing and union through 28 days post injury. Therefore, these results demonstrated that MMP-9 is dispensable for timely fracture union and cartilage transition to bone in fixed femur fractures. Pro-MMP-9 is therefore not a significant target of plasmin in fracture repair and future studies assessing additional plasmin targets associated with angiogenesis are warranted.


Secretion of complement components of the alternative pathway (C3 and factor B) by the human alveolar type II epithelial cell line A549.
The complement system participates in the local immune system of the lung. In this study, we investigated the secretion of complement components of the alternative pathway (C3 and factor B) in the alveolar type II epithelial cell line A549. The levels of C3 and factor B protein in the culture medium were determined by enzyme-linked immunosorbent assay (ELISA). The C3 and factor B mRNA expression was assessed by reverse transcription polymerase chain reaction (RT-PCR). The addition of interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha induced a dose- and time-dependent increase in C3 and factor B secretion. The addition of IL-6 or interferon (IFN)-gamma also induced a weak but significant increase in C3 and factor B secretion. These responses at the protein level were also observed at the mRNA level. Furthermore, the combination of IL-1beta plus TNF-alpha induced a marked increase in C3 and factor B secretion. Similarly, IL-6 and IFN-gamma potently enhanced IL-1beta- or TNF-alpha-induced C3 and factor B secretion, respectively. In this study, we demonstrated C3 and factor B secretion in A549 cells, and showed that the proinflammatory cytokines, IL-1beta, IL-6, TNF-alpha and IFN-gamma, acted as potent inducers of C3 and factor B secretion. It is likely that alveolar type II epithelial cells are the local sites of complement biosynthesis, and that various cytokines act as regulators of this local immune protection system.


Risk of adult acute leukemia in relation to prior immune-related conditions.
We explored the association between immune-related conditions and adult acute leukemia in a study of 624 patients with acute myeloid leukemia (AML), 124 patients with acute lymphoblastic leukemia (ALL), 63 patients with other acute leukemias, and 637 healthy population controls. Common childhood viral diseases were weakly associated with AML and ALL, particularly with early exposure (< or = 5 years of age). Odds ratios (ORs) were elevated for chicken pox and measles at any age, but only the associations with measles were statistically significant [OR = 1.89; 95% confidence interval (CI), 1.40-2.56 for AML and OR = 1.81; 95% CI, 1.07-3.06 for ALL]. There was no association between other infectious diseases, allergies, asthma, or eczema and risk for AML or ALL, although there was a significant association between psoriasis and ALL (OR = 3.23; 95% CI, 1.25-8.30). These results offer little support for either a protective effect of enhanced immune surveillance or a harmful effect from antigenic stimulation in relation to risk for acute leukemia in adults. However, the associations between cancer risk and childhood infectious diseases are intriguing and may warrant additional research.


Association between the FTO rs9939609 polymorphism and the metabolic syndrome in a non-Caucasian multi-ethnic sample.
The rs9939609 T>A single-nucleotide polymorphism (SNP) in the FTO gene has previously been found to be associated with obesity in European Caucasian samples. The objective of this study is to examine whether this association extends to metabolic syndrome (MetS) and applies in non-Caucasian samples. The FTO rs9939609 SNP was genotyped in 2121 subjects from four different non-Caucasian geographical ancestries. Subjects were classified for the presence or absence of MetS according to the International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III definitions. Carriers of > or = 1 copy of the rs9939609 A allele were significantly more likely to have IDF-defined MetS (35.8%) than non-carriers (31.2%), corresponding to a carrier odds ratio (OR) of 1.23 (95% confidence interval [CI] 1.01 to 1.50), with a similar trend for the NCEP ATP III-defined MetS. Subgroup analysis showed that the association was particularly strong in men. The association was related to a higher proportion of rs9939609 A allele carriers meeting the waist circumference criterion; a higher proportion also met the HDL cholesterol criterion compared with wild-type homozygotes. Thus, the FTO rs9939609 SNP was associated with an increased risk for MetS in this multi-ethnic sample, confirming that the association extends to non-Caucasian population samples.


Differential effects of elevating [K]o on three transient outward potassium channels. Dependence on channel inactivation mechanisms.
We carried out a systematic study on the effects of elevating [K]o on the properties of a transient outward potassium channel encoded by a cardiac cDNA (RHK1) and compared them with those on two Shaker potassium channels (H-4 and H-37). The amino acid sequences of all three channels are known, and their structure-function relations have been partially characterized. All three channels were expressed in Xenopus oocytes and studied under double-microelectrode voltage-clamp conditions. For all three channels, elevating [K]o caused an increase in the channels' chord conductances and a negative shift in the calculated activation curves. However, in other aspects of channel properties that are related to the channels' inactivation processes, there were differences in the changes induced by increasing [K]o: 1) Elevating [K]o caused a positive shift in the steady-state inactivation curves of RHK1 and H-4 but did not cause any shift in H-37. 2) Elevating [K]o slowed the time course of inactivation of H-37 but did not cause any significant changes in the time course of RHK1 or H-4. 3) Elevating [K]o accelerated the rate of recovery from inactivation of RHK1 and H-4 but slowed the recovery time course of H-37. Our experiments show that elevating [K]o can cause a wide range of effects on the transient outward potassium channels. Furthermore, raising [K]o induced similar changes in RHK1 and H-4 (inactivation mediated by an "N-type" mechanism) that were different from the changes in H-37 (inactivation mediated by a "C-type" mechanism). Therefore, our data suggest that part of the effects of elevating [K]o on channel properties may depend on the channel's inactivation mechanism. This hypothesis is supported by results from experiments studying the effects of elevating [K]o on a mutant RHK1 channel (RHK1 delta 3-25), which apparently lacks the N-type and C-type inactivation mechanisms.


The Association Between Supportive High School Environments and Depressive Symptoms and Suicidality Among Sexual Minority Students.
The purpose of this study was to determine if sexual minority students in supportive school environments experienced fewer depressive symptoms and lower rates of suicide ideation, plans and attempts ("suicidality") than sexual minority students in less supportive school environments. In 2007, a nationally representative sample (N = 9,056) of students from 96 high schools in New Zealand used Internet tablets to complete a health and well-being survey that included questions on sexual attractions, depressive symptoms, and suicidality. Students reported their experience of supportive environments at school and gay, lesbian, bisexual, and transgender (GLBT) bullying, and these items were aggregated to the school level. Teachers (n = 2,901) from participating schools completed questionnaires on aspects of school climate, which included how supportive their schools were toward sexual minority students. Multilevel models were used to estimate school effects on depressive symptoms and suicidality controlling for background characteristics of students. Sexual minority students were more likely to report higher levels of depressive symptoms and suicidality than their opposite-sex attracted peers (p < .001). Teacher reports of more supportive school environments for GLBT students were associated with fewer depressive symptoms among male sexual minority students (p = .006) but not for female sexual minority students (p = .09). Likewise in schools where students reported a more supportive school environment, male sexual minority students reported fewer depressive symptoms (p = .006) and less suicidality (p < .001) than in schools where students reported less favorable school climates. These results suggest that schools play an important role in providing safe and supportive environments for male sexual minority students.


An optimized purification and reconstitution method for the MscS channel: strategies for spectroscopical analysis.
The mechanosensitive channel of small conductance (MscS) plays a critical role in the osmoregulation of prokaryotic cells. The crystal structure of MscS revealed a homoheptamer with three transmembrane segments and a large cytoplasmic domain. It has been suggested that the crystal structure depicts an open state, but its actual functional conformation remains controversial. In the pursuit of spectroscopical approaches to MscS gating, we determined that standard purification methods yield two forms of MscS, with a considerable amount of unfolded channel. Here, we present an improved high-yield purification method based on Escherichia coli expression and a biochemical characterization of the reconstituted channel, optimized to yield approximately 4 mg of a single monodisperse product. Upon reconstitution into lipid vesicles, MscS is unusually prone to lateral aggregation depending on the lipid composition, particularly after sample freezing. Strategies for minimizing MscS aggregation in two dimensions for spectroscopic analyses of gating have been developed.


Genetic and expression analysis of cattle identifies candidate genes in pathways responding to Trypanosoma congolense infection.
African bovine trypanosomiasis caused by Trypanosoma sp., is a major constraint on cattle productivity in sub-Saharan Africa. Some African Bos taurus breeds are highly tolerant of infection, but the potentially more productive Bos indicus zebu breeds are much more susceptible. Zebu cattle are well adapted for plowing and haulage, and increasing their tolerance of trypanosomiasis could have a major impact on crop cultivation as well as dairy and beef production. We used three strategies to obtain short lists of candidate genes within QTL that were previously shown to regulate response to infection. We analyzed the transcriptomes of trypanotolerant N'Dama and susceptible Boran cattle after infection with Trypanosoma congolense. We sequenced EST libraries from these two breeds to identify polymorphisms that might underlie previously identified quantitative trait loci (QTL), and we assessed QTL regions and candidate loci for evidence of selective sweeps. The scan of the EST sequences identified a previously undescribed polymorphism in ARHGAP15 in the Bta2 trypanotolerance QTL. The polymorphism affects gene function in vitro and could contribute to the observed differences in expression of the MAPK pathway in vivo. The expression data showed that TLR and MAPK pathways responded to infection, and the former contained TICAM1, which is within a QTL on Bta7. Genetic analyses showed that selective sweeps had occurred at TICAM1 and ARHGAP15 loci in African taurine cattle, making them strong candidates for the genes underlying the QTL. Candidate QTL genes were identified in other QTL by their expression profile and the pathways in which they participate.


How many populations set foot through the Patagonian door? Genetic composition of the current population of Bahía Blanca (Argentina) based on data from 19 Alu polymorphisms.
The city of Bahía Blanca occupies a strategic place in Argentina south of the Pampean region in the north-east corner of the Patagonia. Since 1828, this city has been the historical and political border between Amerindian lands in the south, and the lands of European colonists. Nowadays, Bahía Blanca is an urban population mainly composed by descendents of immigrants from Spain and other European countries with apparently low admixture with Amerindians. In view of the unexpectedly high Amerindian admixture levels (about 46.7%) suggested by mtDNA data, and protein markers (19.5%), we analyzed a set of 19 Alu polymorphisms (18 autosomal, 1 of Chromosome Y) in a well-documented genealogical sample from Bahía Blanca. The genotyped sample was made up of 119 unrelated healthy individuals whose birth place and grandparent origins were fully documented. According to available genealogical records, the total sample has been subdivided into two groups: Bahía Blanca Original (64 individuals with all 4 gandparents born in Argentina) and Bahía Blanca Mix (55 individuals with one to three grandparents born out of Argentina). Allele frequencies and gene diversity values in Bahía Blanca fit well into the European ranges. Population relationships have been tested for 8 Alu markers, whose variation has been described in several Amerindian and European samples. Reynolds genetic distances underline the significant genetic similarity of Bahía Blanca to Europeans (mean distance 0.044) and their differentiation from Amerindians (0.146). Interestingly enough, when the general sample is divided, Bahía Blanca Original appears slightly closer to Amerindians (0.127) in contrast to Bahía Blanca Mix (0.161). Furthermore, the genetic relationships depicted through a principal components analysis emphasize the relative similarity of Bahía Blanca Original to Amerindians. A thorough knowledge of the sample origins has allowed us to make a subtle distinction of the genetic composition of Bahía Blanca.


Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data.
Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next-generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5-tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as "consensus" when classifications agreed, and shared internationally with LOVD and ClinVar. When classifications opposed (LB/B vs. LP/P), they were labeled "conflicting", while other nonconsensus observations were labeled "no consensus". We assessed our classifications using the InterVar software to compare to ACMG 2015 guidelines, showing 99.7% overall consistency with only 0.3% discrepancies. Differences in classifications between Dutch labs or between Dutch labs and ACMG were mainly present in genes with low penetrance or for late onset disorders and highlight limitations of the current 5-tier classification system. The data sharing boosted the quality of DNA diagnostics in Dutch labs, an initiative we hope will be followed internationally. Recently, a positive match with a case from outside our consortium resulted in a more definite disease diagnosis.


Atopic Dermatitis and Food Allergy: A Paediatric Approach.
Atopic dermatitis and food allergy are common conditions of childhood that are closely linked. 30% of children with moderate to severe eczema suffer from food allergy and can present with different types of reactions: immediate or IgE-mediated reactions, delayed or non-IgEmediated eczematous flares, or a combination of the two. A detailed history is very important when approaching such patients. The presence of IgE-mediated symptoms warrants investigation and management requires avoidance of the culprit allergen, an emergency care plan and appropriate follow up. Non-IgE-mediated reactions can be more difficult to diagnose, and investigations are more difficult to interpret. Topical treatment is paramount in all patients with atopic dermatitis, while food elimination diets remain the mainstay of the management of food allergy, and should be done under specialist supervision. In this review, we discuss the current understanding of atopic dermatitis and food allergy, the role of investigations and management of paediatric patients with both conditions. We propose an algorithm that can be used by paediatricians when dealing with children with food allergy and atopic dermatitis.


Dual regulation of a Dictyostelium STAT by cGMP and Ca2+ signalling.
When cells are exposed to hyperosmotic stress, the Dictyostelium STAT orthologue STATc is rapidly tyrosine phosphorylated. Previous observations suggest a non-paradigmatic mode of STAT activation, whereby stress-induced serine phosphorylation of the PTP3 protein tyrosine phosphatase inhibits its activity towards STATc. We show that two serine residues in PTP3, S448 and S747, are rapidly phosphorylated after osmotic stress. cGMP is a second messenger for hyperosmotic stress response and 8-bromo-cGMP, a membrane-permeable form of cGMP, is a known activator of STATc. GbpC, a cGMP-binding Ras guanine nucleotide exchange factor protein, is a founder member of a protein family that includes LRRK2, the gene commonly mutated in familial Parkinson's disease. Genetic ablation of gbpC prevents STATc activation by 8-bromo-cGMP. However, osmotic-stress-induced activation of STATc occurs normally in the gbpC null mutant. Moreover, 8-bromo-cGMP does not stimulate phosphorylation of S448 and S747 of PTP3 in a wild-type strain. These facts imply the occurrence of redundant activation pathways. We present evidence that intracellular Ca(2+) is a parallel second messenger, by showing that agents that elevate intracellular Ca(2+) levels are potent STATc activators that stimulate phosphorylation of S448 and S747. We propose that stress-induced cGMP signalling exerts its stimulatory effect by potentiating the activity of a semi-constitutive tyrosine kinase that phosphorylates STATc, whereas parallel, stress-induced Ca(2+) signalling represses STATc dephosphorylation through its inhibitory effect on PTP3.


Cardiovascular Benefits of Acarbose vs Sulfonylureas in Patients With Type 2 Diabetes Treated With Metformin.
Although α-glucosidase inhibitors (AGIs) have been shown to reduce the risk of myocardial infarction in patients with impaired glucose tolerance, the cardiovascular benefits of AGIs in those with type 2 diabetes (T2D) remains unclear. We compared the clinical outcomes of adding acarbose vs sulfonylureas to metformin therapy in patients with T2D. The study population was drawn from the database of the Diabetes Pay-for-Performance program in Taiwan. Sulfonylureas and acarbose were prescribed to 196,143 and 14,306 patients with T2D, respectively, from 2004 to 2015, who had been treated with metformin. A propensity score-matched cohort study was conducted. The patients were followed up for clinical adverse events of all-cause mortality and hospitalizations of major atherosclerotic events (i.e., myocardial infarction and ischemic stroke), heart failure, or hypoglycemia. A total of 14,306 propensity score-matched pairs (age, 55.8 ± 13.1 years; 47.8% men) were enrolled in the present analysis. Compared with sulfonylureas as the add-on therapy to metformin, the use of acarbose was associated with significantly lower risks of hospitalizations for major atherosclerotic events [hazard ratio (HR), 0.69; 95% CI, 0.52 to 0.91], ischemic stroke (HR, 0.68; 95% CI, 0.49 to 0.94), and hypoglycemia (HR, 0.23; 95% CI, 0.08 to 0.71), after accounting for major confounding factors. In T2D treatment, the use of acarbose as an add-on remedy to metformin was associated with lower risks of major atherosclerotic events, ischemic stroke, and hypoglycemia compared with the use of sulfonylurea as an add-on remedy.


Angiogenic morphogenesis driven by dynamic and heterogeneous collective endothelial cell movement.
Angiogenesis is a complex process, which is accomplished by reiteration of modules such as sprouting, elongation and bifurcation, that configures branching vascular networks. However, details of the individual and collective behaviors of vascular endothelial cells (ECs) during angiogenic morphogenesis remain largely unknown. Herein, we established a time-lapse imaging and computer-assisted analysis system that quantitatively characterizes behaviors in sprouting angiogenesis. Surprisingly, ECs moved backwards and forwards, overtaking each other even at the tip, showing an unknown mode of collective cell movement with dynamic 'cell-mixing'. Mosaic analysis, which enabled us to monitor the behavior of individual cells in a multicellular structure, confirmed the 'cell-mixing' phenomenon of ECs that occurs at the whole-cell level. Furthermore, an in vivo EC-tracking analysis revealed evidence of cell-mixing and overtaking at the tip in developing murine retinal vessels. In parametrical analysis, VEGF enhanced tip cell behavior and directed EC migration at the stalk during branch elongation. These movements were counter-regulated by EC-EC interplay via γ-secretase-dependent Dll4-Notch signaling, and might be promoted by EC-mural cell interplay. Finally, multiple regression analysis showed that these molecule-mediated tip cell behaviors and directed EC migration contributed to effective branch elongation. Taken together, our findings provide new insights into the individual and collective EC movements driving angiogenic morphogenesis. The methodology used for this analysis might serve to bridge the gap in our understanding between individual cell behavior and branching morphogenesis.


Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure.
The similarities between the changes in cardiac gene expression in pathological ventricular hypertrophy and hypothyroidism suggest a role of impaired cardiac thyroid hormone (TH) action in the development of contractile dysfunction during chronic cardiac pressure overload. Here we studied the possible involvement of altered cardiac TH metabolism using a rat model of right-ventricular (RV) hypertrophy induced by pressure-overload. Pathological RV hypertrophy was indicated by decreased mRNA levels of sarcoplasmic reticulum(SR) Ca2-ATPase type 2a (SERCA2a) and myosin heavy chain a (MHCalpha), and increased levels of MHCbeta mRNA. Enzyme activity of type HI deiodinase (D3), which converts T4 and T3 to the inactive compounds rT3 and 3,3'-T2, respectively, was identified in ventricular tissue. This activity was stimulated up to five fold in hypertrophic RV, but remained unaltered in the non-hypertrophic left ventricle (LV). A low level of type Ideiodinase activity was also detected, which decreased significantly in both RV and LV. Stimulation of RV D3 activity was significantly higher in those animals in which hypertrophy progressed to heart failure, compared to animals that developed compensatory hypertrophy. The induction of a cardiac TR-degrading deiodinase maybe expected to result in reduced cellular levels of T3 and thereby contribute to a local hypothyroid state in the hypertrophic and, particularly, in the failing ventricle.


Responsibility for child and adolescent's psychosocial support associated with severe sports injuries.
The manner in which health professionals and coaches act and decide on treatment and prognosis can influence athletes in a way that not only strengthens them, but it can also reduce their confidence in their own ability. The purpose was to determine who has the responsibility for child and adolescent psychosocial support needed in connection with a severe sports injury as well as investigate whether coaches, physiotherapists and parents are aware of the support that is needed. Qualitative interviews with coaches, parents and physiotherapists with experience of serious sports injuries in young people aged 12 to 16 years old from different sports were analysed using content analysis. The study showed that all actors independently imparted communication as being the major problem and indicated that the role of a coordinator was missing. They imparted cognitive, emotional and behavioural reactions in children, which were considered to be more common in younger children as indicated in previous studies. Coaches felt they had lack of education and time; parents described their disappointment in caregivers and personality changes in their children in connection with the injury. Physiotherapists felt that rehabilitation was often served as a substitute for the sport and that they therefore had greater responsibility for the child than they had been educated for. Results should be communicated to participants who are involved in children's and adolescent's sports to increase their knowledge and thus allow them to be able to give our children the best possibility, regardless of whether they return to the sport or not.


SRD1 is involved in the auxin-mediated initial thickening growth of storage root by enhancing proliferation of metaxylem and cambium cells in sweetpotato (Ipomoea batatas).
A sweetpotato (Ipomoea batatas cv. 'Jinhongmi') MADS-box protein cDNA (SRD1) has been isolated from an early stage storage root cDNA library. The role of the SRD1 gene in the formation of the storage root in sweetpotato was investigated by an expression pattern analysis and characterization of SRD1-overexpressing (ox) transgenic sweetpotato plants. Transcripts of SRD1 were detected only in root tissues, with the fibrous root having low levels of the transcript and the young storage root showing relatively higher transcript levels. SRD1 mRNA was mainly found in the actively dividing cells, including the vascular and cambium cells of the young storage root. The transcript level of SRD1 in the fibrous roots increased in response to 1000 muM indole-3-acetic acid (IAA) applied exogenously. During the early stage of storage root development, the endogenous IAA content and SRD1 transcript level increased concomitantly, suggesting an involvement of SRD1 during the early stage of the auxin-dependent development of the storage root. SRD1-ox sweetpotato plants cultured in vitro produced thicker and shorter fibrous roots than wild-type plants. The metaxylem and cambium cells of the fibrous roots of SRD1-ox plants showed markedly enhanced proliferation, resulting in the fibrous roots of these plants showing an earlier thickening growth than those of wild-type plants. Taken together, these results demonstrate that SRD1 plays a role in the formation of storage roots by activating the proliferation of cambium and metaxylem cells to induce the initial thickening growth of storage roots in an auxin-dependent manner.


Isolation and characterization of Chinese hamster ovary cell lines sensitive to mitomycin C and bleomycin.
Seven Chinese hamster ovary K1 cell lines exhibiting sensitivity to anticancer drugs have been isolated by a replica-plating technique. Five of the mutants are hypersensitive (approximately 7-fold, as judged by D37 values) to the DNA cross-linking agent mitomycin C. Of these, one is also appreciably sensitive to UV light. Significant variations in their cross-sensitivity to cis-platinum(II) diammine dichloride, chlorambucil, and Adriamycin have also been observed. Two additional mutants have been isolated on the basis of sensitivity to the radiomimetic agent bleomycin. One of these shows greater than 6-fold sensitivity to bleomycin, while the other is approximately 14 times more sensitive than the parental strain to bleomycin and is also hypersensitive to a number of other DNA-damaging agents, including cis-platinum(II) diammine dichloride, chlorambucil, X-rays, and UV light. Both bleomycin-sensitive mutants also exhibit some degree of sensitivity to Adriamycin. In all cases, the cell lines have been grown in continuous culture for 3 months without evidence of reversion and should act as suitable recipients in DNA transfection experiments aimed at identifying human DNA repair genes.


Altered disposition of propylthiouracil in cats with hyperthyroidism.
The oral and intravenous disposition of the anti-thyroid drug propylthiouracil (PTU) was determined in six clinically healthy cats and four cats with naturally occurring hyperthyroidism. Compared with the normal cats, the mean plasma elimination half-life of PTU was significantly (P less than 0.001) shorter in the hyperthyroid cats (77.5 +/- 5.8 minutes compared with 125.5 +/- 3.7 minutes) and the total body clearance of PTU was significantly (P less than 0.05) more rapid in the cats with hyperthyroidism (5.1 +/- 0.8 ml kg-1 min-1 compared with 2.7 +/- 0.2 ml kg-1 min-1). Following oral administration, both the bioavailability (59.7 +/- 4.9 per cent compared with 73.3 +/- 3.7 per cent) and peak plasma concentrations (14.5 +/- 1.6 micrograms ml-1 compared with 18.9 +/- 0.9 micrograms ml-1) of PTU were significantly (P less than 0.05) lower in the hyperthyroid cats than in the control cats. No difference was noted, however, between the apparent volume of distribution for PTU in the two groups of cats. Overall, results of this study indicate that the oral bioavailability of PTU is decreased and PTU disposition is accelerated in cats with hyperthyroidism.


Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers?
Multiple sclerosis (MS) is a devastating autoimmune disease, afflicting people in the prime of their lives. Presently, after initial clinical presentation, there are no reliable markers for whether a patient will develop MS, or whether their prognosis will be aggressive or relapsing-remitting. Furthermore, many MS patients do not respond to treatment. Thus, markers for diagnosis, prognosis, and treatment-responsiveness are lacking for a disease, where a precision medicine approach would be valuable. The glycocalyx (GLX) is the carbohydrate-rich outer surface of the blood vessel wall and is the first interaction between the blood and the vessel. We hypothesized that cleavage of the GLX may be an early stage predictor of immune attack, blood-brain barrier (BBB) breakdown, and disease severity in MS. Two experimental models of MS, experimental autoimmune encephalitis (EAE), were included in this study. EAE was induced in C57BL/6J mice and Lewis rats, which were monitored for weight loss and clinical presentation in comparison to healthy controls. Plasma samples were obtained longitudinally from mice until peak disease severity and at peak disease severity in rats. Soluble GLX-associated glycosaminoglycans (GAG) and proteoglycans (PG) were detected in plasma samples. All animals receiving EAE emulsion developed fulminant EAE (100% penetrance). Increased plasma levels of chondroitin sulfate were detected before the onset of clinical symptoms and remained elevated at peak disease severity. Hyaluronic acid was increased at the height of the disease, whereas heparan sulfate was transiently increased during early stages only. By contrast, syndecans 1, 3, and 4 were detected in EAE samples as well as healthy controls, with no significant differences between the two groups. In this study, we present data supporting the shedding of the GLX as a new class of biomarker for MS. In particular, soluble, sugar-based GLX components are associated with disease severity in two models of MS, molecules that would not be detected in proteomics-based screens of MS patient samples. Patient studies are presently underway.