The prevalence of mental health problems among users of NHS stop smoking services: effects of implementing a routine screening procedure.
Tobacco dependence among people with mental health problems is an issue that deserves attention both from a clinical and from a public health perspective. Research suggests that Stop Smoking Services often fail to ask clients about underlying mental health problems and thus fail to put in place the treatment adaptations and liaison procedures often required to meet the needs of clients with a mental health condition who want to stop smoking. This study assesses the recording of mental health problems in a large NHS stop smoking service in England and examines the effect of implementing a short screening procedure on recording mental health conditions. Treatment records from the Stop Smoking Service covering a period of 13 months were audited. The prevalence of reported mental health problems in the six month period before the implementation of the mental health screening procedure was compared with that of the six month period following implementation. The screening procedure was only implemented in the support services directly provided by the Stop Smoking Service. Comparisons were also made with third-party sections of the service where no such screening procedure was introduced. The prevalence of reported mental health problems among a total of n = 4999 clients rose from less than 1% before implementation of the screening procedure to nearly 12% in the period following implementation, with the change being statistically significant. No significant rise was observed over the same period in the sections of the service where no screening procedure was implemented. The absence of standard procedures to record mental health problems among service users in many stop smoking services is currently likely to prevent the detection of co morbidity. Implementing a simple screening procedure appears suitable to increase the routine recording of mental health problems in a stop smoking service, which is an essential step to ensure services can be tailored and delivered appropriately to the client group.


Dose-dependent reduction of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by the aldose reductase inhibitor M79175.
The onset and progression of retinal vascular changes associated with early diabetic retinopathy has been delayed in beagles fed 30% galactose diet for 38 months by treatment with the aldose reductase inhibitor M79175 (2-methyl-6-fluoro-spirochroman-4-5'- imidazolidine-2',4'-dione). Forty 9-month old male beagles were fed a daily diet containing either 30% non-nutrient filler or 30% galactose. One group of galactose-fed dogs was untreated while the others received M79175 at an average group dose of either 10 or 16 mg/kg/day. After 38 months one eye from 4 dogs from each group was enucleated and the isolated retinal vasculatures were objectively evaluated using an Olympus Cue-3 color image analysis system. Measurements of endothelium/pericyte (E/P) ratios, pericyte ghosts/1000 cells, pericytes and endothelial densities, and % acellularity per area and % acellularity per capillary length were conducted on a 0.1 mm square area surrounding the midpoints of 12 previously defined subregions. With the exception of endothelial densities which were not changed in galactose-fed dogs, M79175 treatment resulted in smaller changes in all parameters examined with the E/P ratio in dogs treated with 16 mg/kg/day M79175 not significantly different from that of age-matched non-galactose-fed dogs. These studies indicate that aldose reductase inhibitors provide dose-dependent protection against pericyte degeneration and subsequent microaneurysms formation.


Home environment: association with hyperactivity/impulsivity in children with ADHD and their non-ADHD siblings.
We wished to ascertain if there is an association between symptoms of attention-deficit/hyperactivity disorder (ADHD) and home environment in children with ADHD and non-ADHD siblings, controlling for other environmental measures. 96 children with ADHD combined type (ADHD-CT) and their siblings participated in the study. Parent and teacher Conners' rating scales were completed and home environment was assessed using the middle childhood and early adolescent Home Observation for Measurement of the Environment (HOME). ADHD symptoms were assessed for correlation with HOME in children with ADHD-CT and non-ADHD siblings and multiple regression analysis was used to control for gender, socio-economic status, exposure to nicotine, exposure to alcohol in utero, birth weight, gestational age, pregnancy and perinatal risk factors. The presence of oppositional disorders was assessed for association with HOME score in those with ADHD-CT. The multiple regression analysis was repeated controlling for environmental factors and for oppositional disorders in those with ADHD-CT. Oppositional symptoms were assessed for correlation with HOME score in non-ADHD siblings. Teacher-rated hyperactive/impulsive scores correlated with HOME (r=-0.27, P < 0.01) in children with ADHD-CT. This association remained significant when other environmental factors and oppositional disorders were controlled for. Environmental factors and gender contributed to 30% of the variance of ADHD symptoms in ADHD-CT. Parent-rated hyperactive/impulsive scores also correlated with HOME (r=-0.28, P < 0.05) for non-ADHD siblings. An association between HOME and diagnosis of oppositional defiant disorder or conduct disorder was found for children with ADHD-CT and between HOME and oppositional symptoms in non-ADHD siblings. The home environment has a small but significant association with hyperactive/impulsive symptoms in children with ADHD-CT and non-ADHD siblings. This association remained when other environmental factors were taken into account. Oppositional symptoms are associated with home environment in ADHD-CT and in non-ADHD siblings.


Latent classes of posttraumatic stress and growth.
Potentially traumatic events may lead to different patterns of posttraumatic stress symptoms and posttraumatic growth. The objective of the present study was to identify subgroups with different patterns of posttraumatic reactions, and to determine whether these subgroups differed in terms of personal and social resources and indicators of adjustment. This study used survey data collected 10 months after the 2011 Oslo bombing attack to investigate patterns of reactions among ministerial employees (N=1970). We applied latent class analyses with covariates to extract subgroups of individuals. Three classes of individual reactions were extracted, and these were similar among those who were and those who were not physically proximate to the bombing attack: "High stress/high growth" (27% and 11%, respectively), "Low stress/high growth" (74% and 42%, respectively), and "Low stress/low growth" (only among the not physically proximate: 47%). The classes differed in terms of gender, neuroticism, and social support as well as life satisfaction and daily functioning. Heterogeneous patterns of posttraumatic reactions were found. Physical proximity is not necessary to experience posttraumatic stress or growth after political violence. Among individuals with low stress, posttraumatic growth may not encompass higher life satisfaction or functioning.


Poor insight into schizophrenia: contributing factors, consequences and emerging treatment approaches.
Poor insight or unawareness of illness has been commonly observed in schizophrenia and has been long recognized as a potent barrier to treatment adherence and a risk factor for a range of poorer outcomes. Paradoxically, the achievement of insight often poses a different set of problems including depression and low self-esteem. One barrier to the treatment of poor insight has been a lack of understanding of the phenomenon, which causes poor insight to develop and persist over time. Without knowing what promotes poor insight, treatment to date has had little to offer beyond the supportive provision of information. To explore these issues, this article reviews emerging literature on the correlates of poor insight in schizophrenia, and newly developing ways of conceptualizing insight. It then details a number of innovative integrative group and individual treatment approaches in the early stages of development, which take into account some of the potential causal forces behind poor insight, including deficits in neurocognition, social cognition, metacognition and heightened self-stigma. A plan for further research is presented to develop a model of the factors whose interaction influences insight, and to refine and test integrative treatments.


Fine-tuning the antigen sensitivity of CAR T cells: emerging strategies and current challenges.
Chimeric antigen receptor (CAR) T cells are "living drugs" that specifically recognize their target antigen through an antibody-derived binding domain resulting in T cell activation, expansion, and destruction of cognate target cells. The FDA/EMA approval of CAR T cells for the treatment of B cell malignancies established CAR T cell therapy as an emerging pillar of modern immunotherapy. However, nearly every second patient undergoing CAR T cell therapy is suffering from disease relapse within the first two years which is thought to be due to downregulation or loss of the CAR target antigen on cancer cells, along with decreased functional capacities known as T cell exhaustion. Antigen downregulation below CAR activation threshold leaves the T cell silent, rendering CAR T cell therapy ineffective. With the application of CAR T cells for the treatment of a growing number of malignant diseases, particularly solid tumors, there is a need for augmenting CAR sensitivity to target antigen present at low densities on cancer cells. Here, we discuss upcoming strategies and current challenges in designing CARs for recognition of antigen low cancer cells, aiming at augmenting sensitivity and finally therapeutic efficacy while reducing the risk of tumor relapse.


Addressing different biases in analysing drug use on cancer risk in diabetes in non-clinical trial settings--what, why and how?
Motivated by recent reports on associations between diabetes and cancer, many researchers have used administrative databases to examine risk association of cancer with drug use in patients with diabetes. Many of these studies suffered from major biases in study design and data analysis, which can lead to erroneous conclusions if these biases are not adjusted. This article discusses the sources and impacts of these biases and methods for correction of these biases. To avoid erroneous results, this article suggests performing sensitivity and specificity analysis as well as using a drug with a known effect on an outcome to ascertain the validity of the proposed methods. Using the Hong Kong Diabetes Registry, we illustrated the impacts of biases of drug use indication and prevalent user by examining the effects of statins on cardiovascular disease. We further showed that 'immortal time bias' may have a neutral impact on the estimated drug effect if the hazard is assumed to be constant over time. On the contrary, adjustment for 'immortal time bias' using time-dependent models may lead to misleading results biased towards against the treatment. However, artificial inclusion of immortal time in non-drug users to correct for immortal time bias may bias the result in favour of the therapy. In conclusion, drug use indication bias and prevalent user bias but not immortal time bias are major biases in the design and analysis of drug use effects among patients with diabetes in non-clinical trial settings.


Machine perfusion versus cold storage for the preservation of kidneys from donors ≥ 65 years allocated in the Eurotransplant Senior Programme.
In the Eurotransplant Senior Programme (ESP), kidneys from donors aged ≥ 65 years are preferentially allocated locally and transplanted into patients aged ≥ 65 years on dialysis. The purpose of this study was to analyse whether the results of transplantation in the ESP can be improved by preservation of organs by hypothermic machine perfusion (MP) compared with simple cold storage (CS). Overall, 85 deceased heart-beating donors ≥ 65 years of age were included in this analysis with follow-up until 1 year post-transplant. For each donor, one kidney was randomly assigned to preservation by CS and the contralateral kidney to MP from organ procurement until transplantation. Delayed graft function (DGF), primary non-function (PNF) and 1-year patient and graft survival rates were evaluated as primary and secondary endpoints. The median recipient age was 66 years in both groups and the median cold ischaemia time was 11 h for MP and 10.5 h for CS (P = 0.69). The DGF rate was 29.4% for MP and 34.1% for CS (P = 0.58). Only extended duration of cold ischaemia time was an independent risk factor for the development of DGF (odds ratio 1.2, P < 0.0001). PNF was significantly reduced (3.5% MP versus 12.9% CS, P = 0.02). The 1-year patient and graft survival rates were similar for MP and CS (94% versus 95% and 89 versus 81%, P > 0.05). The 1-year graft survival rate was significantly improved after MP in recipients who developed DGF (84% MP versus 48% CS, P = 0.01). Continuous pulsatile hypothermic MP for kidneys from donors aged ≥ 65 years can reduce the rate of never-functioning kidneys and improve the 1-year graft survival rate of kidneys with DGF. In this small cohort, the known advantage of MP for the reduction of DGF could not be confirmed, possibly due to relatively short cold ischaemia times.


Intestinal glutathione: determinant of mucosal peroxide transport, metabolism, and oxidative susceptibility.
The intestine is a primary site of nutrient absorption and a critical defense barrier against dietary-derived mutagens, carcinogens, and oxidants. Accumulation of oxidants like peroxidized lipids in the gut lumen can contribute to impairment of mucosal metabolic pathways, enterocyte dysfunction independent of cell injury, and development of gut pathologies, such as inflammation and cancer. Despite this recognition, we know little of the pathways of intestinal transport, metabolism, and luminal disposition of dietary peroxides in vivo or of the underlying mechanisms of lipid peroxide-induced genesis of intestinal disease processes. This chapter summarizes our current understanding of the determinants of intestinal absorption and metabolism of peroxidized lipids. I will review experimental evidence from our laboratory and others (Table 1) supporting the pivotal role that glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) play in mucosal transport and metabolism of lipid hydroperoxides and how reductant availability can be compromised under chronic stress such as hypoxia, and the influence of GSH on oxidative susceptibility, and redox contribution to genesis of gut disorders. The discussion is pertinent to understanding dietary lipid peroxides and GSH redox balance in intestinal physiology and pathophysiology and the significance of luminal GSH in preserving the integrity of the intestinal epithelium.


Genetic counselling and testing of susceptibility genes for therapeutic decision-making in breast cancer-an European consensus statement and expert recommendations.
An international panel of experts representing 17 European countries and Israel convened to discuss current needs and future developments in BRCA testing and counselling and to issue consensus recommendations. The experts agreed that, with the increasing availability of high-throughput testing platforms and the registration of poly-ADP-ribose-polymerase inhibitors, the need for genetic counselling and testing will rapidly increase in the near future. Consequently, the already existing shortage of genetic counsellors is expected to worsen and to compromise the quality of care particularly in individuals and families with suspected or proven hereditary breast or ovarian cancer. Increasing educational efforts within the breast cancer caregiver community may alleviate this limitation by enabling all involved specialities to perform genetic counselling. In the therapeutic setting, for patients with a clinical suspicion of genetic susceptibility and if the results may have an immediate impact on the therapeutic strategy, the majority voted that BRCA1/2 testing should be performed after histological diagnosis of breast cancer, regardless of oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status. Experts also agreed that, in the predictive and therapeutic setting, genetic testing should be limited to individuals with a personal or family history suggestive of a BRCA1/2 pathogenic variant and should also include high-risk actionable genes beyond BRCA1/2. Of high-risk actionable genes, all pathological variants (i.e. class IV and V) should be reported; class III variants of unknown significance, should be reported provided that the current lack of clinical utility of the variant is expressly stated. Genetic counselling should always address the possibility that already tested individuals might be re-contacted in case new information on a particular variant results in a re-classification.


Hyaluronan and its potential role in periodontal healing.
Hyaluronan is a natural tissue component, which plays a vital role in the functioning of extracellular matrices, including those of the periodontium. This molecule is also important in relation to the mechanisms associated with inflammation and wound healing. The application of exogenous hyaluronan and hyaluronan-based biomaterials has been successful in manipulating and accelerating the wound healing process in a number of medical disciplines, as evident in ophthalmology, dermatology and rheumatology. It is conceivable that hyaluronan administration to periodontal sites could achieve comparable beneficial effects in periodontal healing and surgery, hence aiding treatment of periodontal disease.


Coordinate regulation of the alpha(2)-macroglobulin signaling receptor and the low density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor by insulin.
We have studied insulin-dependent regulation of macrophage alpha(2)-macroglobulin signaling receptors (alpha(2)MSR) and low density lipoprotein receptor-related protein/alpha(2)M receptors (LRP/alpha(2)MR) employing cell binding of (125)I-alpha(2)M*, inhibition of binding by receptor-associated protein (RAP) or Ni(2+), LRP/alpha(2)MR mRNA levels, and generation of second messengers. Insulin treatment increased the number of alpha(2)M* high (alpha(2)MSR) and low (LRP/alpha(2)MR) affinity binding sites from 1, 600 and 67,000 to 2,900 and 115,200 sites per cell, respectively. Neither RAP nor Ni(2+) blocked the binding of (125)I-alpha(2)M* to alpha(2)MSR on insulin- or buffer-treated cells, but they both blocked binding to LRP/alpha(2)MR. Insulin significantly increased LRP/alpha(2)MR mRNA levels in a dose- and time-dependent manner. Insulin-augmented (125)I-alpha(2)M* binding to macrophages was severely reduced by wortmannin, LY294002, PD98059, SB203580, or rapamycin. The increase in alpha(2)MSR receptor synthesis was reflected by augmented generation of IP(3) and increased [Ca(2+)](i) levels upon receptor ligation. Incubation of macrophages with wortmannin, LY294002, PD98059, SB203580, rapamycin, or antibodies against insulin receptors before insulin treatment and alpha(2)M* stimulation significantly reduced the insulin-augmented increase in IP(3) and [Ca(2+)](i) levels. Pretreatment of cells with actinomycin D or cycloheximide blocked the synthesis of new alpha(2)MSR. In conclusion, we show here that insulin coordinately regulates macrophage alpha(2)MSR and LRP/alpha(2)MR, utilizing both the PI 3-kinase and Ras signaling pathways to induce new synthesis of these receptors.


New quaternary arsenide oxides with square planar coordination of gold(I) - structure, (197)Au Mössbauer spectroscopic, XANES and XPS characterization of Nd10Au3As8O10 and Sm10Au3As8O10.
The quaternary gold(I) arsenide oxides Nd10Au3As8O10 and Sm10Au3As8O10 were synthesized in sealed quartz ampoules from the rare earth (RE) elements, their appropriate sesquioxides, arsenic, arsenic(III) oxide and finely dispersed gold at maximum annealing temperatures of 1223 K. Both structures were refined from X-ray single crystal diffractometer data at room temperature and at 90 K. Nd10Au3As8O10 and Sm10Au3As8O10 crystallize with a new structure type that derives from the BaAl4 structure through distortions and formation of ordered vacancies. The structures consist of stacked polycationic [RE10O10](10+) layers with oxygen in tetrahedral rare earth coordination and polyanionic [Au(I)3(As2)4](10-) layers with gold in square planar or rectangular planar coordination of four arsenic dumbbells (255 pm As1-As2). In contrast to the well known ionic rare earth oxide layers, the gold arsenide layers rather show covalent bonding and account for the metallic nature of these two new arsenide oxides. This is confirmed by electronic structure calculations and resistivity measurements. The oxidation state of gold was investigated by (197)Au Mössbauer, X-ray absorption near edge structure (XANES) and photoelectron (XPS) spectroscopy. Due to missing comparative gold arsenide compounds, the monovalent gold phosphide oxides RE2AuP2O were measured for comparison. The XANES measurements additionally comprise monovalent gold arsenides REAuAs2. The XPS study contains BaAuAs as reference compound instead. Combination of all data clearly indicates Au(I), which was not observed in square planar coordination up to now. Temperature dependent magnetic susceptibility data show Curie-Weiss paramagnetism for Nd10Au3As8O10 and no magnetic ordering down to 2.5 K. Sm10Au3As8O10 shows the typical Van Vleck type paramagnetism for samarium compounds along with a transition to an antiferromagnetically ordered state at TN = 8.6 K.


[Participation of synaptotagmin in release of catecholamines in rat adrenal chromaffin cells].
Exocytosis is known to provide such a vital processes as the release of neurotransmitters in synaptic transmission or release of hormones during secretion. The main mechanism of exocytotic process occurs through the specialized protein complex called the SNARE-complex. Due to its activity the fusion of vesicular and plasma membrane occurs and fusion pore is formed through which a content of vesicles is released outside. It is believed that just synaptotagmins which are Ca2+ dependent proteins, responsible for initiation of the process of Ca(2+)-dependent exocytosis. Synaptotagmins are located at the membrane of the vesicles and can bind two or three Ca2+ ions. In our research, we studied the role of one of the most common isoform of synaptotagmines--synaptotagmin-1. For this we used an injection of antibodies arised to synaptotagmin-1 (anti-STg-1) into isolated rat adrenal chromaffin cells to depress the function of this protein. Catecholamine secretion was measured by amperometric method. Our results showed that an exclusion of synaptotagmin-1 function in tested cells resulted in significant suppression of secretion. These data allow us to conclude that synaptotagmin-1 is a key protein which is needed for Ca(2+)-dependent exocytosis in chromaffin cells.


Implementation of a real-time multi-channel gateway server in ubiquitous integrated biotelemetry system for emergency care (UIBSEC).
We developed a gateway server to support various types of bio-signal monitoring devices for ubiquitous emergency healthcare in a reliable, effective, and scalable way. The server provides multiple channels supporting real-time N-to-N client connections. We applied our system to four types of health monitoring devices including a 12-channel electrocardiograph (ECG), oxygen saturation (SpO(2)), and medical imaging devices (a ultrasonograph and a digital skin microscope). Different types of telecommunication networks were tested: WIBRO, CDMA, wireless LAN, and wired internet. We measured the performance of our system in terms of the transmission rate and the number of simultaneous connections. The results show that the proposed network communication strategy can be successfully applied to the ubiquitous emergency healthcare service by providing a fast rate enough for real-time video transmission and multiple connections among patients and medical personnel.


Serologic diagnosis of canine and equine borreliosis: use of recombinant antigens in enzyme-linked immunosorbent assays.
Serum samples from dogs and equids suspected of having canine or equine borreliosis, respectively, were analyzed in polyvalent enzyme-linked immunosorbent assays (ELISAs) with whole-cell or recombinant antigens of Borrelia burgdorferi sensu stricto. Purified preparations of recombinant antigens included outer surface protein A (OspA), OspB, OspC, OspE, OspF, and p41-G (a fragment of flagellin). Of the 36 dog sera that reacted positively to whole-cell antigen, 32 (88.9%) contained antibodies to one or more recombinant antigens. Reactivities to OspF (88.9% positive) and p41-G (75% positive) were most prevalent. In analyses of 30 equid sera positive in an ELISA with whole cells, 24 (80%) contained antibodies to one or more recombinant antigens. Seropositivities in ELISAs with p41-G (50% positive) and OspF (46.7% positive) were more than twofold greater than in ELISAs with OspA, OspB, or OspC (10 to 20% positive). In parallel tests of eight canine and three equine sera, there was good agreement in results of Western blot (immunoblot) analyses and ELISAs. Although dog and equid sera with antibodies to whole-cell B. burgdorferi frequently reacted positively to one or more recombinant antigens, the inclusion of OspF and p41-G antigens in ELISAs was most useful in the serologic diagnosis of canine and equine borreliosis.


Tea catechins prevent the development of atherosclerosis in apoprotein E-deficient mice.
Green tea contains various antioxidative flavan-3ols (tea catechins), such as (-)-epigallocatechin gallate (EGCg, the major catechin), which exert potent inhibitory effects on LDL oxidation in vitro and ex vivo in humans. In this study, the antiatherogenic effects of tea catechins were examined in atherosclerosis-susceptible C57BL/6J, apoprotein (apo)E-deficient mice. Male apoE-deficient mice (10 wk old) were fed an atherogenic diet for 14 wk; during that time, one group (tea) was supplied drinking water supplemented with green tea extract (0.8 g/L), and another group (control) was offered the vehicle only. The tea extract consisted of the following (g/100 g): EGCg, 58.4; (-)-epigallocatechin (EGC), 11.7; (-)-epicatechin (EC), 6.6; (-)-gallocatechingallate (GCg), 1.6; (-)-epicatechin gallate (ECg), 0.5; and caffeine, 0.4. The estimated actual intake of tea catechin was 1.7 mg/(d. mouse). Tea ingestion did not influence plasma cholesterol or triglyceride concentrations. Plasma lipid peroxides were reduced in the tea group at wk 8, suggesting that the in vivo oxidative state is improved by tea ingestion. Atheromatous areas in the aorta from the arch to the femoral bifurcation and aortic weights were both significantly attenuated by 23% in the tea group compared with the control group. Aortic cholesterol and triglyceride contents were 27 and 50% lower, respectively, in the tea group than in the control group. These results suggest that chronic ingestion of tea extract prevents the development of atherosclerosis without changing the plasma lipid level in apoE-deficient mice, probably through the potent antioxidative activity of the tea.


How important is health status in defining quality of life for older people? An exploratory study of the views of older South Australians.
Cost-effectiveness analyses of interventions for older adults have traditionally focused on health status. However, there is increasing recognition of the need to develop new instruments to capture quality of life in a broader sense in the face of age-associated increasing frailty and declining health status, particularly in the economic evaluation of aged and social care interventions that may have positive benefits beyond health. To explore the relative importance of health and broader quality of life domains for defining quality of life from the perspective of older South Australians. Older adults (n=21) from a day rehabilitation facility in Southern Adelaide, South Australia attended one of two audio-recorded focus groups. A mixed methods (qualitative and quantitative) study design was adopted. The study included three main components. First was a general group discussion on quality of life and the factors of importance in defining quality of life. Second was a structured ranking exercise in which individuals were asked to rank domains from the brief Older People's Quality of Life (OPQOL-brief) questionnaire and Adult Social Care Outcomes Toolkit (ASCOT) in order of importance. Third, participants were asked to self-complete the EuroQol five-dimension (EQ-5D), a measure of health status, and two broader quality-of-life measures: the OPQOL-brief and ASCOT. Mean scores on the EQ-5D, OPQOL-brief and ASCOT were 0.71 (standard deviation [SD] 0.20, range 0.06-1.00), 54.6 (SD 5.5, range 38-61) and 0.87 (SD 0.13, range 0.59-1.00), respectively, with higher scores reflecting better ratings. EQ-5D scores were positively associated with OPQOL-brief (Spearman's Rho: 0.730; p<0.01), but not ASCOT. Approximately half (52.4%) of the participants ranked either 'health' or 'psychological and emotional well-being' as the domain most important to their quality of life. However, one-third (33.3%) of the total sample ranked a non-health domain from the ASCOT or OPQOL-brief (safety, dignity, independence) as the most important contributing factor to their overall quality of life. Qualitative analysis of focus group transcripts supported the high value of both health-related (health, psychological well-being) and social (independence, safety) domains to quality of life. Older adults value both health and social domains as important to their overall quality of life. Future economic evaluations of health, community and aged-care services for older adults should include assessment of both health-related and broader aspects of quality of life.


Brief cognitive behavioral therapy in primary care: a hybrid type 2 patient-randomized effectiveness-implementation design.
Despite the availability of evidence-based psychotherapies for depression and anxiety, they are underused in non-mental health specialty settings such as primary care. Hybrid effectiveness-implementation designs have the potential to evaluate clinical and implementation outcomes of evidence-based psychotherapies to improve their translation into routine clinical care practices. This protocol article discusses the study methodology and implementation strategies employed in an ongoing, hybrid, type 2 randomized controlled trial with two primary aims: (1) to determine whether a brief, manualized cognitive behavioral therapy administered by Veterans Affairs Primary Care Mental Health Integration program clinicians is effective in treating depression and anxiety in a sample of medically ill (chronic cardiopulmonary diseases) primary care patients and (2) to examine the acceptability, feasibility, and preliminary outcomes of a focused implementation strategy on improving adoption and fidelity of brief cognitive behavioral therapy at two Primary Care-Mental Health Integration clinics. The study uses a hybrid type 2 effectiveness/implementation design to simultaneously test clinical effectiveness and to collect pilot data on a multifaceted implementation strategy that includes an online training program, audit and feedback of session content, and internal and external facilitation. Additionally, the study engages the participation of an advisory council consisting of stakeholders from Primary Care-Mental Health Integration, as well as regional and national mental health leaders within the Veterans Administration. It targets recruitment of 320 participants randomized to brief cognitive behavioral therapy (n = 200) or usual care (n = 120). Both effectiveness and implementation outcomes are being assessed using mixed methods, including quantitative evaluation (e.g., intent-to-treat analyses across multiple time points) and qualitative methods (e.g., focus interviews and surveys from patients and providers). Patient-effectiveness outcomes include measures of depression, anxiety, and physical health functioning using blinded independent evaluators. Implementation outcomes include patient engagement and adherence and clinician brief cognitive behavioral therapy adoption and fidelity. Hybrid designs are needed to advance clinical effectiveness and implementation knowledge to improve healthcare practices. The current article describes the rationale and challenges associated with the use of a hybrid design for the study of brief cognitive behavioral therapy in primary care. Although trade-offs exist between scientific control and external validity, hybrid designs are part of an emerging approach that has the potential to rapidly advance both science and practice. NCT01149772 at http://www.clinicaltrials.gov/ct2/show/NCT01149772.


The effect of increasing methionine supply on the methionine conversion to cyst(e)ine in sheep.
The conversion of methionine to cyst(e)ine was determined in sheep infused with different amounts of methionine (0-5 g/d) into the duodenum by assaying the incorporation of 35S from intravenously-infused L-[35S]methionine into cyst(e)ine in wool, plasma albumin and the free plasma pool. The percentage of cystine-S in the plasma originating from methionine increased linearly from 4.5 to 18 with increasing supplemental methionine supply. The percentage of cysteine-S in albumin increased from 15 to 50; methionine supply increased to 3 g/d but then remained constant, indicating that the transsulphuration pathway of the liver was exceeded. The percentage of wool cysteine-S originating from methionine was high (approximately 70) at all methionine supplementation rates.


Neutrophil Extracellular Traps Are Induced by Coronavirus 2019 Disease-Positive Patient Plasma and Persist Longitudinally: A Possible Link to Endothelial Dysfunction as Measured by Syndecan-1.
Background: Neutrophil extracellular trap (NET) formation is a mechanism that neutrophils possess to respond to host infection or inflammation. However, dysregulation of NETosis has been implicated in many disease processes. Although the exact mechanisms of their involvement remain largely unknown, this study aimed to elucidate NET formation over the time course of coronavirus disease 2019 (COVID-19) infection and their possible role in endothelial injury. Patients and Methods: Plasma samples from COVID-19-positive patients were obtained at six timepoints during hospitalization. Neutrophils were extracted from healthy donors and treated with COVID-19-positive patient plasma. Myeloperoxidase (MPO) assay was used to assess for NETosis. Syndecan-1 (SDC-1) enzyme-linked immunosorbent assay (ELISA) was run using the same samples. Immunocytochemistry allowed for further quantification of NETosis byproducts MPO and citrullinated histone 3 (CitH3). The receiver operating characteristic (ROC) curve discriminated between admission levels of SDC-1 and MPO in predicting 30-day mortality and need for ventilator support. Results: Sixty-three patients with COVID-19 were analyzed. Myeloperoxidase was upregulated at day 3, 7, and 14 (p = 0.0087, p = 0.0144, p = 0.0421). Syndecan-1 levels were elevated at day 7 and 14 (p = 0.0188, p = 0.0026). Neutrophils treated with day 3, 7, and 14 plasma expressed increased levels of MPO (p < 0.001). Immunocytochemistry showed neutrophils treated with day 3, 7, and 14 plasma expressed higher levels of MPO (p < 0.001) and higher levels of CitH3 when treated with day 7 and 14 plasma (p < 0.01 and p < 0.05). Admission SDC-1 and MPO levels were found to be independent predictors of 30-day mortality and need for ventilator support. Conclusions: Neutrophil dysregulation can be detrimental to the host. Our study shows that COVID-19 plasma induces substantial amounts of NET formation that persists over the course of the disease. Patients also exhibit increased SDC-1 levels that implicate endothelial injury in the pathogenesis of COVID-19 infection. Furthermore, MPO and SDC-1 plasma levels are predictive of poor outcomes.


Porting and using PanGIA for Cytoscape 3: challenges and solutions.
Much of the biologically significant functionality in Cytoscape is contained within third-party add-ons, called plugins in Cytoscape 2 and apps in Cytoscape 3. In the transition from Cytoscape 2 to Cystoscape 3, some of the underlying assumptions upon which plugins relied changed, requiring a significant porting effort for plugins to work as Cytoscape 3 apps. PanGIA is a Cytoscape add-on (http://apps.cytoscape.org/apps/pangia) designed to analyze and visualize genetic interaction data in light of physical interaction data. In order to convert the PanGIA plugin to an app, various challenges, including those related to a transformed data model, concurrency, and randomization had to be overcome. In the process, the ability to control randomization was added to the GUI, a feature which was not only integral to the porting process, but which also ensures more easily reproducible scientific analysis for PanGIA users. Most authors of Cytoscape 2 plugins will face similar challenges porting their software to work with Cytoscape 3, and this paper gives details of how the PanGIA port addressed them.


Center-Specific Modeling Predicts Cancer Trial Accrual More Accurately Than Investigators and Random Effects Modeling at 16 Cancer Centers.
Clinical trials often exceed their anticipated enrollment periods, and study sites often do not meet accrual goals. We previously reported the development and validation of a single-site accrual prediction model. Here, we describe the expansion of this methodology at 16 cancer centers (CCs) and compare an overall model versus site-specific models. This retrospective cohort study used data from treatment and supportive care intervention studies permanently closed to accrual between 2009 and 2015 at 16 United States-based CCs. Center and ClinicalTrials.gov data were used to generate both site-specific and random effects mixed models (random effect: institution). Accrual predictions were generated from each model and compared with the accrual prediction of the disease team (DT). Sixteen institutions submitted 5,787 eligible trials (range, 93 to 697 trials per institution). Local accrual ranged from 363 to 6,716 participants; 1,053 studies (18%) accrued no participants. Actual average accrual was 8.5 participants (median, four participants). Site-specific models predicted accrual at 99% of actual and correctly predicted whether a study would accrue four or more participants 73% of the time versus DT prediction of 58%. Correlation at the category level was 30%; model sensitivity and specificity were 83% and 62%, respectively. The overall model predicted accrual 93% of actual and correctly predicted accrual of four or more participants 66% of the time, with a correlation at the category level of 28%. Both regression models predicted clinical trial accrual at least as or more accurately than DT at all but one center. Site-specific models generally performed slightly better than the random effects model. This study confirms the previous finding that this method is an accurate and objective metric that can be easily implemented to improve clinical research resource allocation across multiple centers.


Protection against lethal viral infection by neutralizing and nonneutralizing monoclonal antibodies: distinct mechanisms of action in vivo.
Monoclonal antibodies (MAb) reactive with the glycoprotein of vesicular stomatitis virus (VSV) serotypes Indiana (VSV-Ind) and New Jersey (VSV-NJ) were used to protect mice against lethal infection. MAb which reacted with a number of distinct epitopes and which could neutralize the virus in vitro could also protect against infection in vivo. MAb which could not neutralize the virus in vitro but which were specific for the glycoprotein of a single serotype were also able to protect mice against lethal VSV challenge. Interestingly, a group of MAb which cross-reacted with the glycoproteins of VSV-Ind and VSV-NJ could passively protect against challenge with either serotype. It was shown that as early as 2 h after infection, neither neutralizing nor nonneutralizing MAb could protect. Nonneutralizing MAb were found to be less effective at in vivo protection than neutralizing MAb. Furthermore, nonneutralizing MAb demonstrated a much lower binding efficiency to intact virions than did neutralizing MAb. These observations, plus the fact that the nonneutralizing MAb could lyse virus-infected cells in the presence of complement, suggested that in vivo protection by these antibodies may involve cell-associated viral determinants. To compare the mechanisms by which neutralizing and nonneutralizing MAb protected in vivo, F(ab')2 fragments were used in protection experiments. Although the F(ab')2 of a neutralizing MAb was still able to protect animals lethal virus challenge, the F(ab')2 of a cross-reactive nonneutralizing MAb was unable to do so. The reactivity of nonneutralizing MAb with virions and the apparent necessity of an intact Fc portion for protection further distinguish these antibodies from those MAb that are able to neutralize VSV solely by binding to the glycoprotein.


Automated Construction of Molecular Active Spaces from Atomic Valence Orbitals.
We introduce the atomic valence active space (AVAS), a simple and well-defined automated technique for constructing active orbital spaces for use in multiconfiguration and multireference (MR) electronic structure calculations. Concretely, the technique constructs active molecular orbitals capable of describing all relevant electronic configurations emerging from a targeted set of atomic valence orbitals (e.g., the metal d orbitals in a coordination complex). This is achieved via a linear transformation of the occupied and unoccupied orbital spaces from an easily obtainable single-reference wave function (such as from a Hartree-Fock or Kohn-Sham calculations) based on projectors to targeted atomic valence orbitals. We discuss the premises, theory, and implementation of the idea, and several of its variations are tested. To investigate the performance and accuracy, we calculate the excitation energies for various transition-metal complexes in typical application scenarios. Additionally, we follow the homolytic bond breaking process of a Fenton reaction along its reaction coordinate. While the described AVAS technique is not a universal solution to the active space problem, its premises are fulfilled in many application scenarios of transition-metal chemistry and bond dissociation processes. In these cases the technique makes MR calculations easier to execute, easier to reproduce by any user, and simplifies the determination of the appropriate size of the active space required for accurate results.


Tart cherry anthocyanins inhibit tumor development in Apc(Min) mice and reduce proliferation of human colon cancer cells.
Anthocyanins, which are bioactive phytochemicals, are widely distributed in plants and especially enriched in tart cherries. Based on previous observations that tart cherry anthocyanins and their respective aglycone, cyanidin, can inhibit cyclooxygenase enzymes, we conducted experiments to test the potential of anthocyanins to inhibit intestinal tumor development in Apc(Min) mice and growth of human colon cancer cell lines. Mice consuming the cherry diet, anthocyanins, or cyanidin had significantly fewer and smaller cecal adenomas than mice consuming the control diet or sulindac. Colonic tumor numbers and volume were not significantly influenced by treatment. Anthocyanins and cyanidin also reduced cell growth of human colon cancer cell lines HT 29 and HCT 116. The IC(50) of anthocyanins and cyanidin was 780 and 63 microM for HT 29 cells, respectively and 285 and 85 microM for HCT 116 cells, respectively. These results suggest that tart cherry anthocyanins and cyanidin may reduce the risk of colon cancer.


Inherent biological variation and reference values.
There is a need for revisiting theoretical concepts and practical applications of conventional population-based reference values to make for better clinical use of laboratory data. Knowledge of the underlying biological variation of quantities examined in medical laboratories is vital to understanding the proper generation and application of traditional population-based reference values. Appreciation of the biological changes that occur over the span of life is a necessary prerequisite to deciding whether stratification of reference values according to age is likely to be necessary. Knowledge of the detail of predictable biological cyclical rhythms is required for correct clinical interpretation of laboratory data and appropriate collection of specimens at times relevant to the clinical purpose. Quantitative data on inherent within- and between-subject biological components of variation have shown the marked individuality of most quantities of interest in laboratory medicine. This individuality casts light on why examinations are not generally very successfully applied in population screening or case-finding. Consideration of individuality demonstrates why stratification of reference values is often very advantageous. Individuality provides an indisputable argument for better use of individual specific reference values.


Trinuclear ruthenium core-containing polyoxometalate-based hybrids: preparation, characterization and catalytic behavior.
Two ruthenium-containing polyoxometalate-based hybrids (Ru-POMs), KH8[Ru3O(Trz)6Cl3]2[(NaO6)W6(H2O)6(AsW9O33)4]·28H2O (1) and H3[Ru3O(Trz)6Cl3]2[(WO)2W(OH)(AsW9O33)2]·6H2O (2), (Trz = 1,2,4-triazole), were successfully isolated by a one-step hydrothermal method under different acidic conditions and further characterized by single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), IR spectroscopy, electrospray ionization and mass spectrometry (ESI-MS), thermogravimetric (TG) analyses and elemental analyses. Single-crystal X-ray diffraction analyses reveal two polyanions comprised of four/two identical trivacant Keggin-type polyanion building blocks, leading to the formation of tetrameric/dimeric assembly stabilized by additional metal-oxo cores, respectively. ESI-MS shows that the polyanion units [(NaO6)W6(H2O)6(AsW9O33)4]11- and [(WO)2W(OH)(AsW9O33)2]5- are intact in mixed solvent. Moreover, the two heterogeneous catalysts with trinuclear ruthenium cations were further investigated, and 1 was found to exhibit much higher yield (94.1%)/conversion (95.1%) and better selectivity (>99%) towards the oxidation of thioanisole to sulfoxide than 2.


Identification and characterization of a novel cyclic nucleotide phosphodiesterase gene (PDE9A) that maps to 21q22.3: alternative splicing of mRNA transcripts, genomic structure and sequence.
Cyclic nucleotide-specific phosphodiesterases (PDEs) play an essential role in signal transduction by regulating the intracellular concentration of second messengers (cAMP and cGMP). We have identified and made an initial characterization of a full-length cDNA encoding a novel human cyclic nucleotide phosphodiesterase, PDE9A. At least four different mRNA transcripts (PDE9A1, A2, A3, A4) are produced as a result of alternative splicing of 5' exons, potentially changing the N-terminal amino acid sequences of the encoded proteins. All these predicted proteins would contain a 3',5'-cyclic nucleotide phosphodiesterase signature motif (Prosite no. PDOC00116). Northern blot analysis revealed several mRNA species of approximately 2.4 kb with varying expression patterns and intensities in most tissues examined, except blood. We have also isolated the mouse homolog of the human PDE9A2 mRNA transcript, pde9A2. The human and mouse isoforms have 93 and 83% sequence identity at the amino acid and nucleotide levels, respectively. PDE9A was mapped to 21q22.3, between TFF1 and D21S360. Comparison of the PDE9A1 cDNA with the genomic sequence from the region revealed that the gene is split into 20 exons that extend over 122 kb. Comparison of the physical map of the region and the genomic sequence further refines the mapping, with D21S113 being derived from intron 15. Several genetic disorders map to 21q22.3, including one form of bipolar affective disorder. Since functional disturbances in intraneuronal signal transmission via second messengers play an important role in the pathophysiology of affective disorders, PDE9A is a strong candidate for such a role by position and function.


Orthogonal nanoarchitectonics of M13 phage for receptor targeted anticancer photodynamic therapy.
Photodynamic therapy (PDT) represents a promising therapeutic modality for cancer. Here we used an orthogonal nanoarchitectonics approach (genetic/chemical) to engineer M13 bacteriophages as targeted vectors for efficient photodynamic killing of cancer cells. M13 was genetically refactored to display on the phage tip a peptide (SYPIPDT) able to bind the epidermal growth factor receptor (EGFR). The refactored M13EGFR phages demonstrated EGFR-targeted tropism and were internalized by A431 cancer cells, that overexpress EGFR. Using an orthogonal approach to the genetic display, M13EGFR phages were then chemically modified, conjugating hundreds of Rose Bengal (RB) photosensitizing molecules on the capsid surface, without affecting the selective recognition of the SYPIPDT peptides. Upon internalization, the M13EGFR-RB derivatives generated intracellularly reactive oxygen species, activated by an ultralow intensity white light irradiation. The killing activity of cancer cells is observed at picomolar concentrations of the M13EGFR phage.


Association of FAM167A-BLK rs2736340 Polymorphism with Susceptibility to Autoimmune Diseases: A Meta-Analysis.
The purpose of this study is to evaluate the correlation between family with sequence similarity 167A-B lymphoid tyrosine kinase (FAM167A-BLK) rs2736340 polymorphism and autoimmune diseases. Databases including PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature database (CBM) and Chinese database, Wan Fang database were used in searching eligible studies from January 1, 1966 to October 2, 2015. The odds ratios (ORs) and their 95% confidence intervals (CIs) were pooled to estimate the strength of the association. A total of 25 studies with 30,217 patients and 44,754 controls were included in the meta-analysis. The overall results showed FAM167A-BLK rs2736340 T allele was a risk allele for autoimmune diseases (OR 1.36, 95% CI 1.28-1.44, p < 0.001). In the subgroup by ethnicities, the results suggested T allele was an increased risk in North America, Europe, and Asia (OR 1.33, 95% CI 1.10-1.60, p = 0.004; OR 1.26, 95% CI 1.22-1.31, p < 0.001; and OR 1.46, 95% CI 1.40-1563, p < 0.001, respectively), but not in Africa. Subgroup analysis in different genetic models (recessive, dominant, and additive) revealed significant association between rs2736340 and autoimmune diseases in Asia and North America, but not the recessive model in Europe or Africa, or the additive model in Africa. Stratification analysis by diseases suggested FAM167A-BLK rs2736340 had a positive association with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Kawasaki disease, primary Sjogren's syndrome (pSS), primary antiphosholipid syndrome (APS), and myositis. The current meta-analysis suggested that FAM167A-BLK rs2736340 polymorphism is associated with several autoimmune diseases.


How does environment influence fighting? The effects of tidal flow on resource value and fighting costs in sea anemones.
An animal's decision to enter into a fight depends on the interaction between perceived resource value (V) and fighting costs (C). Both could be altered by predictable environmental fluctuations. For intertidal marine animals, such as the sea anemone Actinia equina, exposure to high flow during the tidal cycle may increase V by bringing more food. It may also increase C via energy expenditure needed to attach to the substrate. We asked whether simulated tidal cycles would alter decisions in fighting A. equina We exposed some individuals to still water and others to simulated tidal cycles. To gain insights into V, we measured their startle responses before and after exposure to the treatments, before staging dyadic fights. Individuals exposed to flow present shorter startle responses, suggesting that flowing water indicates high V compared with still water. A higher probability of winning against no-flow individuals and longer contests between flow individuals suggests that increased V increases persistence. However, encounters between flow individuals were less likely to escalate, suggesting that C is not directly related to V. Therefore, predictable environmental cycles alter V and C, but in complex ways.


[Effects of wenhua juanbi recipe on TNF-alpha and IL-1beta in peripheral blood of rheumatoid arthritis patients].
To observe the clinical effect of Wenhua Juanbi Recipe (WJR) in treating rheumatoid arthritis (RA), its effects in reducing the dosage of Western medicine used and stabilizing condition of disease, as well as its influences on peripheral blood levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and anti-cyclic citrullinated peptide antibody (anti-CCP), for the sake of exploring its preliminary acting mechanism. One hundred patients with RA were randomly assigned to 2 groups, the control group and the treated group, 50 in each group. All were treated with oral administration of methotrexate (MTX,7.5 mg per week), sulfasalazine (0.5 g, tid) and meloxicam (Mobic, 7.5 mg, bid), but to the treated group WJR was given additionally. The therapeutic course for both groups was 3 months. Clinical effect, changes of symptoms and physical signs, dosages of western medicines used, and laboratory indices in 2 groups after treatment were observed, and cases of relapse 3 months after treatment were figured out. The total effective rate in the treated group was higher than that in the control group (88.0% vs 76.0%, P<0.05). The improvements in scores of symptoms and signs [joint pain (0.61 +/- 0.59), swelling (1.49 +/- 1.20), tenderness (0.90 +/- 0.69), movement (0.68 +/- 0.62), griping strength (68.56 +/- 6.50) mm Hg, morning stiff time (23.26 +/- 9.26) min], and in levels of laboratory indices (TNF-alpha, IL-1beta, anti-CCP, RF, ESR, CRP, PLT and Ig) in the treated group after treatment were significantly superior to those in the control group (P<0.05 or P<0.01). The dosages of MTX [(82.11 +/- 11.35) mg vs (94.75 +/- 10.23) mg] and meloxicam [(108.85 +/- 16.13) mg vs (189.63 +/- 18.44) mg] used, and the relapse rate in the treated group were lower significantly (P<0.05, P<0.01) than those in the control group respectively. Effect of combined therapy of WJR and Western medicines is superior to that of using Western medicines alone in treating RA; WJR can reduce the dosages of Western medicines used and the relapse rate, as well as stabilize the condition of illness. It has the effects of immune regulating and anti-inflammatory reaction. Its mechanism for treating RA is possibly the inhibition on cytokines of TNF-alpha and IL-1beta.


Influence of behavioral symptoms on rates of institutionalization for persons with Alzheimer's disease.
Recent studies indicate that behavioral symptoms may play a key role in decisions to institutionalize persons with Alzheimer's disease (AD), but the specific types of behavior that contribute to this increased risk have not been reliably identified. The relationship between behavioral symptoms and time to institutionalization was evaluated in a 4-year longitudinal study. A total of 410 persons with the clinical diagnosis of AD completed annual clinical evaluations to assess cognitive impairment, functional limitations, delusions, hallucinations, depressive symptoms and physical aggression. Participation rates among survivors exceeded 90% for four follow-up evaluations with complete ascertainment of mortality and institutionalization. Time to institutionalization was evaluated using proportional hazards regression models in relation to time-varying clinical features. In multivariate models, adjusted for demographic and social variables, four clinical features emerged as the predominant predictors of institutionalization: cognitive impairment level, physical aggression, hallucinations and depressive symptoms. These associations were virtually unchanged in analyses controlling for mortality. Specific behavioral symptoms are important independent risk factors for institutionalization in persons with AD. Because behavioral symptoms are susceptible to therapy, efforts to modify or prevent these symptoms deserve careful consideration as a means to delay institutionalization for persons with this disease.


Salmonella serotypes encountered in animal feed additives in Lebanon.
Animal feed-additive samples (n = 300) were examined for the presence of salmonellae, using the selenite-F broth-enrichment method followed by subculturing on Salmonella-Shigella and brilliant green agar with sulfadiazine selective agar plates. Samples consisted of a variety of feed additives: 119 bone meal samples, 77 meat meal samples, 40 fish meal samples, and 64 miscellaneous meal samples. Results of examination found 49 (41.2%) of the bone meal samples, 6 (7.8%) of the meat meal samples and 2 (5%) of the fish meal samples contained salmonellae. Of 57 isolates representing 24 serotypes, 4 most frequently isolated serotypes were Salmonella meleagridis (35.1%), Salmonella tennessee (7%), Salmonella chester (5.2%), and Salmonella senftenberg (5.2%). This study shows a high Salmonella-contamination rate of bone meal compared with meat meal and fish meal samples. Of 12 known positive bone meal samples that were examined, 100% of 25-g samples, compared with 70% to 100% of 2.5-g samples and 30% to 90% of 0.25-g samples and 30% to 90% of 0.25-g samples, were positive for salmonellae.


Time trends in the epidemiology and outcome of perianal fistulizing Crohn's disease in a population-based cohort.
Perianal disease is a debilitating condition that frequently occurs in Crohn's disease (CD) patients. It is currently unknown whether its incidence has changed in the era of frequent immunomodulator use and biological availability. We studied the incidence and outcome of perianal and rectovaginal fistulas over the past two decades in our population-based Inflammatory Bowel Disease South-Limburg cohort. All 1162 CD patients registered in the Inflammatory Bowel Disease South-Limburg registry were included. The cumulative probabilities of developing a perianal and rectovaginal fistula were compared between three eras distinguished by the year of CD diagnosis: 1991-1998, 1999-2005 and 2006-2011. Second, clinical risk factors and the risk of fistula recurrence were determined. The cumulative 5-year perianal fistula rate was 14.1% in the 1991-1998 era, 10.4% in the 1999-2005 era and 10.3% in the 2006-2011 era, P=0.70. Colonic disease was associated with an increased risk of developing perianal disease, whereas older age was associated with a decreased risk (both P<0.01). Over time, more patients were exposed to immunomodulators or biologicals before fistula diagnosis (18.5 vs. 32.1 vs. 52.1%, respectively, P=0.02) and started biological therapy thereafter (18.6 vs. 34.1 vs. 54.0%, respectively, P<0.01). The cumulative 5-year perianal fistula recurrence rate was not significantly different between eras (19.5 vs. 25.5 vs. 33.1%, P=0.28). In contrast, the cumulative 5-year rectovaginal rate attenuated from 5.7% (the 1991-2005 era) to 1.7% (the 2006-2011 era), P=0.01. Over the past two decades, the risk of developing a perianal fistula was stable, as well as its recurrence rate, underlining the lasting need for improving treatment strategies for this invalidating condition.


Profiles of decline in activities of daily living in non-Alzheimer dementia.
Assessment of functional ability is an essential component in the clinical diagnosis of dementia. Most studies have primarily focused on disability due to Alzheimer disease (AD), and less is known about profiles of functional impairment in other dementia syndromes. Functional ability was assessed in individuals in the early stages of AD (N=100), the behavioral variant of frontotemporal dementia (FTD) (N=57), and primary progressive aphasia (PPA) (N=61), using the activities of daily living questionnaire (Johnson et al, 2004). The average duration of illness for the 3 groups ranged from 3.4 to 3.9 years. Overall level of functional impairment and the profile of abilities across subscales of Self-Care, Household Care, Employment and Recreation, Shopping and Money, Travel, and Communication were examined. Results showed that overall functional ability was moderately impaired in AD and FTD, and mildly impaired in PPA. For all groups, more complex ADLs were impaired early on, with relative preservation of self-care activities. The Communication score was the least impaired next to Self-Care for FTD and AD, and the most impaired for PPA patients. The activities of daily living questionnaire may capture aspects of preserved functioning that are not apparent from patients' scores on cognitive tests, especially for those with aphasia.


The effects of soft drinks on etched and sealed enamel.
Decalcification around appliances is often a problem for orthodontic patients. This study was undertaken to determine the effects of cola soft drinks on enamel. Twenty-seven extracted teeth were soaked in nine test solutions (different cola drinks) for 72 hours. The scanning electron microscope revealed destruction of enamel in all specimens. Light-cured sealants offered little protection for enamel surfaces. Dark cola drinks containing phosphoric acid should be seen as a true hazard for patients with fixed appliances.


Replication of the deoxyribonucleic acid of multiple-drug-resistance factor in Escherichia coli.
1. It was shown that a system previously described for labelling R-factor DNA during transfer to an irradiated recipient strain of Escherichia coli did not allow high selectivity in the incorporation of thymine into R-factor DNA. 2. Lack of selectivity was shown to be due to cross-feeding from recipient to donor strain. 3. An improved system using a nalidixic acid-resistant recipient strain is described in which incorporation of thymine into the DNA of donor cells is minimized by addition of nalidixic acid after completion of transfer of the plasmid during conjugation.


Laparoscopic and robotic approach for hepatocellular carcinoma-state of the art.
Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and the most common primary liver cancer, in over 80% of cases HCC grown on a cirrhotic liver. Laparoscopic liver resection (LLR) is now worldwide accepted considering the excellent results shown. Minimally invasive surgical approach for HCC is increasing continuously and in specialized centers seems to become the first-line approach for those patients. The aim of this review presents and discusses state of the art in the laparoscopic and robotic surgical treatment of HCC. An electronic search was performed to identify all studies dealing with HCC resected with laparoscopy or robotic approach. Indications for laparoscopic resection, robotic assisted and totally robotic resection of HCC will be doubtless increased in future years. LLR and robotic approach for HCC is safe and feasible.


An intragenic suppressor of a calmodulin mutation in Paramecium: genetic and biochemical characterization.
We describe a suppressor of the calmodulin mutant cam1 in Paramecium tetraurelia. The cam1 mutant, which has a SER----PHE change at residue 101 of the third calcium-binding domain, inhibits the activity of the Ca(2+)-dependent K+ current and causes exaggerated behavioral responses to most stimuli. An enrichment scheme, based on an increased sensitivity to Ba2+ in cam1 cells, was used to isolate suppressors. One such suppressor, designated cam101, restores both the activity of the Ca(2+)-dependent K+ current and behavioral responses of the cells. We show that the cam101 mutant is an intragenic suppressor of cam1, based on genetic and microinjection data. The cam101 calmodulin is shown to be similar to wild-type calmodulin in terms of its ability to stimulate calmodulin-dependent phosphodiesterase at low concentrations of free calcium. However, the cam101 calmodulin has a reduced affinity for a monoclonal antibody to wild-type Paramecium calmodulin, as does the parental cam1 calmodulin, and a different mobility on acid-urea gels relative to both wild-type and cam1 calmodulin. We have been able to demonstrate that the isolation of intragenic suppressors of a calmodulin mutation is possible, which allows for the further genetic analysis of structure-function relationships in the calmodulin molecule.


Using imaging to identify psychogenic parkinsonism before deep brain stimulation surgery. Report of 2 cases.
The frequency with which patients with atypical parkinsonism and advanced motor symptoms undergo deep brain stimulation (DBS) procedures is unknown. However, the potential exposure of these patients to unnecessary surgical risks makes their identification critical. As many as 15% of patients enrolled in recent early Parkinson disease (PD) trials have been found to lack evidence of a dopaminergic deficit following PET or SPECT imaging. This suggests that a number of patients with parkinsonism who are referred for DBS may not have idiopathic PD. The authors report on 2 patients with probable psychogenic parkinsonism who presented for DBS surgery. They found that both patients had normal caudate and putamen [(18)F]-fluorodopa uptake on PET imaging, along with normal expression of specific disease-related metabolic networks for PD and multiple system atrophy, a common form of atypical neurodegenerative parkinsonism. The clinical and PET findings in these patients highlight the role of functional imaging in assisting clinical decision making when the diagnosis is uncertain.


A bioinformatics approach for precision medicine off-label drug drug selection among triple negative breast cancer patients.
Cancer has been extensively characterized on the basis of genomics. The integration of genetic information about cancers with data on how the cancers respond to target based therapy to help to optimum cancer treatment. The increasing usage of sequencing technology in cancer research and clinical practice has enormously advanced our understanding of cancer mechanisms. The cancer precision medicine is becoming a reality. Although off-label drug usage is a common practice in treating cancer, it suffers from the lack of knowledge base for proper cancer drug selections. This eminent need has become even more apparent considering the upcoming genomics data. In this paper, a personalized medicine knowledge base is constructed by integrating various cancer drugs, drug-target database, and knowledge sources for the proper cancer drugs and their target selections. Based on the knowledge base, a bioinformatics approach for cancer drugs selection in precision medicine is developed. It integrates personal molecular profile data, including copy number variation, mutation, and gene expression. By analyzing the 85 triple negative breast cancer (TNBC) patient data in the Cancer Genome Altar, we have shown that 71.7% of the TNBC patients have FDA approved drug targets, and 51.7% of the patients have more than one drug target. Sixty-five drug targets are identified as TNBC treatment targets and 85 candidate drugs are recommended. Many existing TNBC candidate targets, such as Poly (ADP-Ribose) Polymerase 1 (PARP1), Cell division protein kinase 6 (CDK6), epidermal growth factor receptor, etc., were identified. On the other hand, we found some additional targets that are not yet fully investigated in the TNBC, such as Gamma-Glutamyl Hydrolase (GGH), Thymidylate Synthetase (TYMS), Protein Tyrosine Kinase 6 (PTK6), Topoisomerase (DNA) I, Mitochondrial (TOP1MT), Smoothened, Frizzled Class Receptor (SMO), etc. Our additional analysis of target and drug selection strategy is also fully supported by the drug screening data on TNBC cell lines in the Cancer Cell Line Encyclopedia. The proposed bioinformatics approach lays a foundation for cancer precision medicine. It supplies much needed knowledge base for the off-label cancer drug usage in clinics.


Polymer-Induced Swelling of Solid-Supported Lipid Membranes.
In this paper, we study the interaction of charged polymers with solid-supported 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membranes by in-situ neutron reflectivity. We observe an enormous swelling of the oligolamellar lipid bilayer stacks after incubation in solutions of poly(allylamine hydrochloride) (PAH) in D₂O. The positively charged polyelectrolyte molecules interact with the lipid bilayers and induce a drastic increase in their d-spacing by a factor of ~4. Temperature, time, and pH influence the swollen interfacial lipid linings. From our study, we conclude that electrostatic interactions introduced by the adsorbed PAH are the main cause for the drastic swelling of the lipid coatings. The DMPC membrane stacks do not detach from their solid support at T > Tm. Steric interactions, also introduced by the PAH molecules, are held responsible for the stabilizing effect. We believe that this novel system offers great potential for fundamental studies of biomembrane properties, keeping the membrane's natural fluidity and freedom, decoupled from a solid support at physiological conditions.


Negative allosteric modulators of group II metabotropic glutamate receptors: A patent review (2015 - present).
Group II metabotropic glutamate (mGlu) receptors have emerged as an attractive potential target for the development of novel CNS therapeutics in areas such as Alzheimer's disease (AD), anxiety, cognitive disorders, depression, and others. Several small molecules that act as negative allosteric modulators (NAMs) on these receptors have demonstrated efficacy and/or target engagement in animal models, and one molecule (decoglurant) has been advanced into clinical trials. This review summarizes patent applications published between January 2015 and November 2020. It is divided into three sections: (1) small molecule nonselective mGlu2/3 NAMs, (2) small molecule selective mGlu2 NAMs, and (3) small molecule selective mGlu3 NAMs. Much progress has been made in the discovery of novel small molecule mGlu2 NAMs. Still, chemical diversity remains somewhat limited and room for expansion remains. Progress with mGlu3 NAMs has been more limited; however, some promising molecules have been disclosed. The process of elucidating the precise role of each receptor in the diseases associated with group II receptors has begun. Continued studies in animals with selective NAMs for both receptors will be critical in the coming years to inform researchers on the right compound profile and patient population for clinical development.


WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon.
Most cases of juvenile-onset diabetes (JOD) are diagnosed as type 1 diabetes (T1D), for which genetic studies conducted in outbred Caucasian populations support the concept of multifactorial inheritance. However, this view may be partly challenged in particular population settings. In view of the suggestive evidence for a high prevalence of Wolfram syndrome (WFS) in Lebanon, the phenotypic variability associated with WFS1 mutations, and the high consanguinity rate in Lebanon, we aimed to evaluate the contribution of WFS1 mutations as monogenic determinants to JOD in Lebanon. We performed a family-based genetic study, with linkage analysis followed by systematic mutation screening of WFS1 exons in all JOD probands. The study population consisted of an unbiased recruitment of all juvenile-onset insulin-dependent diabetic patients from a specialized diabetes pediatric clinic in Beirut, Lebanon. Homozygous or compound heterozygous WFS1 mutations were found in 22 of the 399 JOD probands (5.5%), resulting in WFS (17 probands) or in non-syndromic non-autoimmune diabetes mellitus (DM, five probands). These accounted for 12.1% (21/174) of probands in consanguineous families, compared with 0.4% (1/225) in non-consanguineous families. Of the 38 patients identified with homozygous or compound heterozygous WFS1 mutations, 11 (29%) had non-syndromic DM, all of whom carried a particular WFS1 mutation, WFS1(LIB), encoding a protein with an extended C-terminal domain. This mutation resulted in a delayed onset or absence of extrapancreatic features. These results underscore the major impact of population-specific factors, such as population-specific mutations and founder effects, and family structure in the genetic determinism of JOD.


Slow components of potassium tail currents in rat skeletal muscle.
The kinetics of potassium tail currents have been studied in the omohyoid muscle of the rat using the three-microelectrode voltage-clamp technique. The currents were elicited by a two-pulse protocol in which a conditioning pulse to open channels was followed by a test step to varying levels. The tail currents reversed at a single well-defined potential (VK). At hyperpolarized test potentials (-100 mV and below), tail currents were inward and exhibited two clearly distinguishable phases of decay, a fast tail with a time constant of 2-3 ms and a slow tail with a time constant of approximately 150 ms. At depolarized potentials (-60 mV and above), tail currents were outward and did not show two such easily separable phases of decay, although a slow kinetic component was present. The slow kinetic phase of outward tail currents appeared to be functionally distinct from the slow inward tail since the channels responsible for the latter did not allow significant outward current. Substitution of Rb for extracellular K abolished current through the anomalous (inward-going) rectifier and at the same time eliminated the slow inward tail, which suggests that the slow inward tail current flows through anomalous rectifier channels. The amplitude of the slow inward tail was increased and VK was shifted in the depolarizing direction by longer conditioning pulses. The shift in VK implies that during outward currents potassium accumulates in a restricted extracellular space, and it is suggested that this excess K causes the slow inward tail by increasing the inward current through the anomalous rectifier. By this hypothesis, the tail current slowly decays as K diffuses from the restricted space. Consistent with such a hypothesis, the decay of the slow inward tail was not strongly affected by changing temperature. It is concluded that a single delayed K channel is present in the omohyoid. Substitution of Rb for K has little effect on the magnitude or time course of outward current tails, but reduces the magnitude and slows the decay of the fast component of inward tails. Both effects are consistent with a mechanism proposed for squid giant axon (Swenson and Armstrong, 1981): that (a) the delayed potassium channel cannot close while Rb is inside it, and (b) that Rb remains in the channel longer than K.


Scribes in an ambulatory urology practice: patient and physician satisfaction.
The increasing use of electronic medical records during the clinical encounter brings not only benefits but also barriers that may affect the doctor-patient relationship and increase the work burden of the physician. We evaluated whether the use of an electronic medical record scribe in an academic urology program would ameliorate these problems. We randomly assigned electronic medical record scribes to the office hours of 5 academic urologists, and using surveys we evaluated patient and physician acceptance and satisfaction. Patients were accepting of an electronic medical record scribe and satisfaction rates were high (93% vs 87% in the absence of a scribe, p = 0.36). Patients were comfortable disclosing urological information in the presence of the scribe. Physicians were dramatically more satisfied with office hours when a scribe was present (69% vs 19%, p <0.001). We were unable to determine whether the presence of a scribe improves productivity. Electronic medical record scribes in a urology practice may be a practical solution to provide documentation while maintaining or improving the doctor-patient relationship because they increase physician satisfaction and do not detract from patient satisfaction.


Immunofluorescence testing in a bullous skin disease of a dog.
A chronic skin disease in a dog, which resembled a pemphigus-like condition, was studied histologically and by direct immunofluorescence testing. Histologic examination revealed a bullous disorder and was a useful diagnostic tool; however, direct immunofluorescence testing showed the disease to be equivalent to bullous pemphigoid of man.


Spectral tuning of a circadian photopigment in a subterranean 'blind' mammal (Spalax ehrenbergi).
The atrophied subcutaneous eyes of Spalax ehrenbergi (the blind mole rat) express a long wavelength sensitive (LWS) cone opsin. Our data provide strong evidence that this photopigment is spectrally tuned to enhance photon capture in the red light environment of the eye. Furthermore, novel mechanisms appear partially responsible for this sensory fine-tuning. These data support the hypothesis that the LWS opsin of Spalax acts as a functional photopigment and that it is not a 'residue' of the pre-subterranean visual system. As the eye of Spalax has only one known function, the entrainment of circadian rhythms to environmental light, the LWS photopigment is implicated in this task. These results, together with our recent findings that rod and cone photopigments are not required for murine photoentrainment, suggest that multiple photopigments (classical and novel) mediate the effects of light on the mammalian circadian system.


Occurrence of adverse events in long-term intrathecal baclofen infusion: a 1-year follow-up study of 158 adults.
To assess the frequency and types of adverse events (AEs) related to intrathecal baclofen (ITB) therapy in adults, and associated risk factors. A prospective, observational cohort study of adults followed up from January 1 to December 31, 2010. A neurologic rehabilitation department in a university hospital. All consecutive adult subjects (N=158) receiving ITB via a pump, either implanted or followed up during the study period. Not applicable. Frequency and type of AEs. In 2010, 158 subjects were followed up for ITB therapy, of whom 128 were implanted before 2010 (nonsurgical subjects), and 30 underwent implantation in 2010 (surgical subjects). Of these 30 subjects, 20 were "newly implanted" and 10 were "replacements." The most frequent pathologic disorders were spinal cord injury (42%) and multiple sclerosis (28%). Twenty-eight subjects (18%) experienced a total of 38 AEs. The rate of AEs was .023 per month of ITB treatment. AEs were related to the surgical procedure in 53% of cases, to the device in 29% (predominantly catheter dysfunctions), and to adverse effects of baclofen in 18%. AEs related to the surgical incision (scar complications and collections) were more frequent in replacement than newly implanted subjects (P=.009). No significant association between occurrence of an AE and subject characteristics (age, gait capacity, spinal vs cerebral spasticity, duration of ITB therapy follow-up) was found. Nearly half of the AEs were serious, extending admission time by a mean of 16 days. No AE induced long-term morbidity or death. The AE rate was relatively low in this cohort. This has to be balanced against the clinical, functional, and quality-of-life improvements, which are expected from ITB therapy.


Visualization of anterior chamber angle dynamics using optical coherence tomography.
To describe the technology of optical coherence tomography (OCT) in imaging the anterior chamber angles and its impact on understanding the pathophysiology of angle-closure glaucoma (ACG). Observational case series. Three subjects with, respectively, impending angle-closure attack, plateau iris syndrome, and phacomorphic glaucoma were recruited. The anterior chamber angle in each patient was imaged with a commercially available OCT unit. The angle configurations were assessed and compared before and after laser peripheral iridotomy (LPI) and argon laser peripheral iridoplasty (ALPI). Visualization of the changes in the anterior chamber angle configurations and normalization of the intraocular pressure (IOP). A patient with impending angle-closure attack precipitated by a topical mydriatic agent was treated with LPI. Optical coherence tomography imaging of the anterior chamber angles was performed before and after the laser procedure. Conversion of anterior iris bowing and angle crowding to iris straightening and angle opening after LPI was demonstrated. Intraocular pressure became normalized with the change in angle configuration. The second patient presented with symptoms of intermittent angle-closure attacks and was initially diagnosed with primary ACG. Despite successful LPI, the angles remained occludable, and the IOP continued to be elevated. Optical coherence tomography was used to review the anterior chamber angle configuration and demonstrated a typical pattern compatible with the diagnosis of plateau iris syndrome. Subsequent ALPI converted the plateau configuration to open angle, with normalization of IOP and disappearance of symptoms. The third patient presented with an acute angle-closure attack and was diagnosed with phacomorphic glaucoma. Argon laser peripheral iridoplasty was performed successfully to open the angle, as evident by the OCT images, and the IOP was brought under control, together with relief of symptoms. The commercially available OCT unit can be practically employed for anterior chamber angle imaging. The different patterns of angle configurations are correlated with the underlying pathophysiology in different forms of ACG.


Pre-operative plasma levels of thrombin-antithrombin III complexes correlate with the development of venous thrombosis after major hip or knee surgery.
To determine whether levels of thrombin-antithrombin III (TAT) in plasma, taken two weeks pre-operatively, predict the development of deep vein thrombosis (DVT) in patients undergoing major hip or knee surgery. Prospective cohort. Tertiary-care referral centre, university-affiliated hospital. Ninety eight consecutive patients undergoing elective hip or knee surgery. All eligible consenting patients were seen in a preoperative clinic two weeks prior to surgery and had blood taken for measurement of plasma TAT level. After surgery, they received a combination of unfractionated heparin 5000 Units 12-hourly subcutaneously, and antiembolism stockings (TEDS), as prophylaxis against DVT. Contrast venography was performed prior to discharge, and according to the results, patients were classified as having proximal (popliteal and/or more proximal) DVT (n = 12), calf DVT (n = 7) or no DVT (n = 79). The mean TAT level was significantly higher in patients who developed DVT (5.7 micrograms/l) than in those who did not (4.1 micrograms/l), p = 0.035. Using cut-points of 3.5 and 5.5 micrograms/l for the TAT level, patients could be categorized as high, intermediate, and low risk for the development of DVT. The proportion of patients with TAT levels of > or = 3.5 micrograms/l who developed calf or proximal DVT was significantly higher than the proportion of patients with TAT levels of < 3.5 micrograms/l who developed calf or proximal DVT (p = 0.02). The proportion of patients with TAT levels > 5.5 micrograms/l who developed proximal DVT was significantly higher than the proportion of patients with TAT levels of < or = 5.5 micrograms/l who developed proximal DVT (p = 0.03). This study demonstrates that pre-operative TAT levels correlate with the risk of developing DVT after major orthopedic surgery. Further studies are needed to determine the reason(s) for this observation and whether rational recommendations about prophylaxis and screening for DVT can be made based on the results of a preoperative TAT level.


Functional differentiation of the glycosyltransferases that contribute to the chemical diversity of bioactive flavonol glycosides in grapevines (Vitis vinifera).
We identified two glycosyltransferases that contribute to the structural diversification of flavonol glycosides in grapevine (Vitis vinifera): glycosyltransferase 5 (Vv GT5) and Vv GT6. Biochemical analyses showed that Vv GT5 is a UDP-glucuronic acid:flavonol-3-O-glucuronosyltransferase (GAT), and Vv GT6 is a bifunctional UDP-glucose/UDP-galactose:flavonol-3-O-glucosyltransferase/galactosyltransferase. The Vv GT5 and Vv GT6 genes have very high sequence similarity (91%) and are located in tandem on chromosome 11, suggesting that one of these genes arose from the other by gene duplication. Both of these enzymes were expressed in accordance with flavonol synthase gene expression and flavonoid distribution patterns in this plant, corroborating their significance in flavonol glycoside biosynthesis. The determinant of the specificity of Vv GT5 for UDP-glucuronic acid was found to be Arg-140, which corresponded to none of the determinants previously identified for other plant GATs in primary structures, providing another example of convergent evolution of plant GAT. We also analyzed the determinants of the sugar donor specificity of Vv GT6. Gln-373 and Pro-19 were found to play important roles in the bifunctional specificity of the enzyme. The results presented here suggest that the sugar donor specificities of these Vv GTs could be determined by a limited number of amino acid substitutions in the primary structures of protein duplicates, illustrating the plasticity of plant glycosyltransferases in acquiring new sugar donor specificities.


Efficacy of Anti-NaV1.7 Antibody on the Sensory Nervous System in a Rat Model of Lumbar Intervertebral Disc Injury.
The pathophysiology of discogenic low back pain is not fully understood. Tetrodotoxin-sensitive voltage-gated sodium (NaV) channels are associated with primary sensory nerve transmission, and the NaV1.7 channel has emerged as an analgesic target. Previously, we found increased NaV1.7 expression in dorsal root ganglion (DRG) neurons innervating injured discs. This study aimed to examine the effect of blocking NaV1.7 on sensory nerves after disc injury. Rat DRG neurons innervating the L5/6 disc were labeled with Fluoro-Gold (FG) neurotracer. Twenty-four rats underwent intervertebral disc puncture (puncture group) and 12 rats underwent sham surgery (non-puncture group). The injury group was divided into a saline infusion group (puncture+saline group) and a NaV1.7 inhibition group, injected with anti-NaV1.7 antibody (puncture+anti-NaV1.7 group); n=12 per group. Seven and 14 days post-surgery, L1 to L6 DRGs were harvested and immunostained for calcitonin gene-related peptide (CGRP) (an inflammatory pain marker), and the proportion of CGRP-immunoreactive (IR) DRG neurons of all FG-positive neurons was evaluated. The ratio of CGRP-IR DRG neurons to total FG-labeled neurons in the puncture+saline group significantly increased at 7 and 14 days, compared with the non-puncture group, respectively (p<0.05). Application of anti-NaV1.7 into the disc significantly decreased the ratio of CGRP-IR DRG neurons to total FG-labeled neurons after disc puncture at 7 and 14 days (40% and 37%, respectively; p<0.05). NaV1.7 antibody suppressed CGRP expression in disc DRG neurons. Anti-NaV1.7 antibody is a potential therapeutic target for pain control in patients with lumbar disc degeneration.


In situ radiometric and exposure age dating of the martian surface.
We determined radiogenic and cosmogenic noble gases in a mudstone on the floor of Gale Crater. A K-Ar age of 4.21 ± 0.35 billion years represents a mixture of detrital and authigenic components and confirms the expected antiquity of rocks comprising the crater rim. Cosmic-ray-produced (3)He, (21)Ne, and (36)Ar yield concordant surface exposure ages of 78 ± 30 million years. Surface exposure occurred mainly in the present geomorphic setting rather than during primary erosion and transport. Our observations are consistent with mudstone deposition shortly after the Gale impact or possibly in a later event of rapid erosion and deposition. The mudstone remained buried until recent exposure by wind-driven scarp retreat. Sedimentary rocks exposed by this mechanism may thus offer the best potential for organic biomarker preservation against destruction by cosmic radiation.


Joint hypermobility in children: a neglected sign needing more attention.
Joint hypermobility refers to the ability that a joint has to move beyond its normal range of motion. It is common in the general population, particularly in children. While many individuals manifesting joint hypermobility are healthy, this feature can accompany a wide range of symptoms and systemic disorders, whose management can be influenced by their prompt recognition. Given the increasing attention that joint hypermobility is attracting in various fields of medicine, many practitioners are asked to approach more carefully joint hypermobility, in order to avoid over- and under-diagnosis of related disorders. Among the most common conditions featuring joint hypermobility there are hypermobility spectrum disorders and hereditary connective tissue disorders, in particular, the Ehlers-Danlos syndromes. In children, joint hypermobility also accompany a variety of disorders affecting neurodevelopment. The nature of such an association is protean, as joint hypermobility may occur in selected congenital neuromuscular disorders, monogenic multiple malformation/intellectual disability syndromes, and well-known and emerging genomic syndromes. In addition, joint hypermobility seems strongly associated with developmental coordination disorders. This review offers an overview on definitions, assessment procedures, patterns of associated manifestations and disorders related to joint hypermobility, as well as treatment principles of associated musculoskeletal pain for practitioners that are not familial with this issue but encounter people featuring this physical attribute in their daily activity.


Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis.
We hypothesised that patients with acute respiratory distress syndrome (ARDS) can be clustered based on concentrations of plasma biomarkers and that the thereby identified biological phenotypes are associated with mortality. Consecutive patients with ARDS were included in this prospective observational cohort study. Cluster analysis of 20 biomarkers of inflammation, coagulation and endothelial activation provided the phenotypes in a training cohort, not taking any outcome data into account. Logistic regression with backward selection was used to select the most predictive biomarkers, and these predicted phenotypes were validated in a separate cohort. Multivariable logistic regression was used to quantify the independent association with mortality. Two phenotypes were identified in 454 patients, which we named 'uninflamed' (N=218) and 'reactive' (N=236). A selection of four biomarkers (interleukin-6, interferon gamma, angiopoietin 1/2 and plasminogen activator inhibitor-1) could be used to accurately predict the phenotype in the training cohort (area under the receiver operating characteristics curve: 0.98, 95% CI 0.97 to 0.99). Mortality rates were 15.6% and 36.4% (p<0.001) in the training cohort and 13.6% and 37.5% (p<0.001) in the validation cohort (N=207). The 'reactive phenotype' was independent from confounders associated with intensive care unit mortality (training cohort: OR 1.13, 95% CI 1.04 to 1.23; validation cohort: OR 1.18, 95% CI 1.06 to 1.31). Patients with ARDS can be clustered into two biological phenotypes, with different mortality rates. Four biomarkers can be used to predict the phenotype with high accuracy. The phenotypes were very similar to those found in cohorts derived from randomised controlled trials, and these results may improve patient selection for future clinical trials targeting host response in patients with ARDS.


Disasters in pediatric dentistry: a systematic review.
Disasters can harm many people, especially children, in unpredictable and public ways. One of the neglected aspects of children's health in disasters is oral and dental hygiene, which can affect their physical and mental well-being. This systematic review explores how dentistry can help children in disasters, focusing on two aspects: providing oral health care and identifying disaster victims. A thorough search of databases, such as PubMed, Cochrane Library, Scopus, Embase, ProQuest, and Web of Science, was done to find English-language publications from 1930 to August 31, 2023. The screening, data collection, and quality assessment followed the PRISMA guidelines. Out of 37,795 articles found in the databases, seven research articles were chosen. Five articles were retrospective, and two articles were prospective. The results showed that dentistry for children is very important in disasters by giving information about the oral and dental problems and identifying the victims. The results also showed some of the challenges and difficulties in giving dental care for children in disaster situations, such as changing control, referral systems, and parental fear of infection. Dentistry for children can improve the health and well-being of children affected by disasters.


Effect of amlodipine on echocardiographic variables in cats with systemic hypertension.
Left ventricular hypertrophy signals a poor prognosis in hypertensive humans. Cardiac disease is common in cats with systemic hypertension. The aims of this study were to characterize the echocardiographic findings of cats with systemic hypertension and to determine if reducing the degree of hypertension is associated with resolution of cardiac hypertrophy. Echocardiographic examinations were performed on 19 cats with naturally occurring systemic hypertension. Fourteen of these cats were subsequently studied after a minimum of 3 months of treatment with the antihypertensive agent amlodipine. Hypertensive cats had a significantly thicker interventricular septum in both systole and diastole, thicker left ventricular free wall in both systole and diastole, and larger left atrium compared to the published normal values and 74% (14/19) of the cats met criteria for left ventricular hypertrophy (diastolic septal or free-wall thickness > 0.60 cm). Systolic blood pressure was lower after treatment (217 +/- 25 mm Hg, range: 180-275 mm Hg; and 142 +/- 27 mm Hg, range: 90-200 mm Hg). No difference was found in any of the echocardiographic measurements between the untreated and treated cats, although more cats had ventricular hypertrophy before treatment (11/14) than after initiating amlodipine (6/14; P = .006). Ventricular hypertrophy is common in hypertensive cats and may resolve after the initiation of amlodipine.


Synergistic roles of oxidation and self-aggregation in efficient ultrafiltration membrane fouling alleviation using a flow-through Sb-SnO2 anode during wastewater reclamation.
The application of ultrafiltration (UF) in wastewater reclamation alleviates the demand for limited water supplies. However, the membrane fouling caused by the effluent organic matter (EfOM) becomes a major obstacle for UF application. In this study, a pre-oxidation strategy for UF using a Sb-SnO2 (ATO) anode in flow-through mode was proposed with the hopes to improve the performance of UF during wastewater reclamation. The results indicated that this flow-through ATO (FA) anode significantly outperformed a boron-doped diamond (BDD) anode in terms of EfOM degradation and membrane fouling control. It is noteworthy that apart from oxidation, the self-aggregation behavior of foulants was also involved in the mechanisms of membrane fouling mitigation. On the one hand, FA pre-oxidation relieved the burden of membrane fouling by decomposing the macromolecular EfOM into small molecular organic matter, and even mineralizing it. The effective destruction of unsaturated EfOM by FA pre-oxidation made a remarkable contribution to fouling mitigation due to the strong correlation between the total fouling index and UV254. On the other hand, the surface morphology of membrane and interface properties of foulants revealed the self-aggregation behavior of foulants. FA pre-oxidation made the foulants aggregate spontaneously and reduced the potential of forming a dense cake layer on the membrane surface, which was conductive for water permeation. Overall, FA pre-oxidation proved to be a feasible and chemical-free option for UF pretreatment to simultaneously produce high-quality reused water and alleviate membrane fouling during wastewater reclamation.


Concomitant downregulation of the imprinted genes DLK1 and MEG3 at 14q32.2 by epigenetic mechanisms in urothelial carcinoma.
The two oppositely imprinted and expressed genes, DLK1 and MEG3, are located in the same gene cluster at 14q32. Previous studies in bladder cancer have suggested that tumor suppressor genes are located in this region, but these have not been identified. We observed that both DLK1 and MEG3 are frequently silenced in urothelial cancer tissues and cell lines. The concomitant downregulation of the two genes is difficult to explain by known mechanisms for inactivating imprinted genes, namely deletion of active alleles or epitype switching. Indeed, quantitative PCR revealed more frequent copy number gains than losses in the gene cluster that were, moreover, consistent within each sample, excluding gene losses as the cause of downregulation. Instead, we observed distinctive epigenetic alterations at the three regions controlling DLK1 and MEG3 expression, namely the DLK1 promoter; the intergenic (IG) and MEG3 differentially methylated regions (DMRs). Bisulfite sequencing and pyrosequencing revealed novel patterns of DNA methylation in tumor cells, which were distinct from that of either paternal allele. Furthermore, chromatin immunoprecipitation demonstrated loss of active and gain of repressive histone modifications at all regulatory sequences. Our data support the idea that the main cause of the prevalent downregulation of DLK1 and MEG3 in urothelial carcinoma is epigenetic silencing across the 14q32 imprinted gene cluster, resulting in the unusual concomitant inactivation of oppositely expressed and imprinted genes.