Association of epileptiform abnormalities and seizures in Alzheimer disease.
To examine the relationship between scalp EEG biomarkers of hyperexcitability in Alzheimer disease (AD) and to determine how these electric biomarkers relate to the clinical expression of seizures in AD. In this cross-sectional study, we performed 24-hour ambulatory scalp EEGs on 43 cognitively normal elderly healthy controls (HC), 41 participants with early-stage AD with no history or risk factors for epilepsy (AD-NoEp), and 15 participants with early-stage AD with late-onset epilepsy related to AD (AD-Ep). Two epileptologists blinded to diagnosis visually reviewed all EEGs and annotated all potential epileptiform abnormalities. A panel of 9 epileptologists blinded to diagnosis was then surveyed to generate a consensus interpretation of epileptiform abnormalities in each EEG. Epileptiform abnormalities were seen in 53% of AD-Ep, 22% of AD-NoEp, and 4.7% of HC. Specific features of epileptiform discharges, including high frequency, robust morphology, right temporal location, and occurrence during wakefulness and REM, were associated with clinical seizures in AD. Multiple EEG biomarkers concordantly demonstrated a pattern of left temporal lobe hyperexcitability in early stages of AD, whereas clinical seizures in AD were often associated with bitemporal hyperexcitability. Frequent small sharp spikes were specifically associated with epileptiform EEGs and thus identified as a potential biomarker of hyperexcitability in AD. Epileptiform abnormalities are common in AD but not all equivalent. Specific features of epileptiform discharges are associated with clinical seizures in AD. Given the difficulty recognizing clinical seizures in AD, these EEG features could provide guidance on which patients with AD are at high risk for clinical seizures.


The individual experience of ageing prisoners: systematic review and meta-synthesis through a Good Lives Model framework.
The existing literature on ageing prisoners tends to focus on such aspects as diagnosis and physical ill-health. In contrast, the experience of imprisonment from the perspective of ageing prisoners has received less attention. Grounded in a Good Lives Model theoretical framework, we reviewed and meta-synthesised literature around their experience of life in prison, its impact on their wellbeing and how prison services are currently addressing their complex needs. We further identify potential areas of improvement. 1. Systematic search on Assia, PsycInfo, MedLine, Embase, Web of Science, Google and Gov.uk. 2. Extraction and categorisation of data on NVivo. 3. Development of themes through thematic analysis and meta-synthesis. 4. Identification of potential areas of improvement. We selected 25 studies for our review, of which 13 were from the USA, seven from the UK, two from Australia and one each from Ireland, Switzerland and Israel. We identified three themes: The hardship of imprisonment, addressing health and social care needs, and the route out of prison. Ageing prisoners have unique and complex health and social care needs which, to varying degree across different countries, are mostly unmet. Promising initiatives to address their needs are emerging, but, at present time, the overall experience of incarceration for the ageing prisoner is quite poor, given the inconsistent physical, emotional and social care support offered from prison intake to release and beyond. Copyright © 2017 John Wiley & Sons, Ltd.


HIF-1: a key mediator in hypoxia.
The transcription factor HIF-1 is one of the principal mediators of homeostasis in human tissues exposed to hypoxia. It is implicated in virtually every process of rapid gene expression in response to low oxygen levels. The most common causes of tissue hypoxia are inflammation and/or insufficient circulation or a combination of both. Inflamed tissues and the areas surrounding malignant tumors are characterized by hypoxia and low concentrations of glucose. Serious and generalized inflammation can lead to sepsis and circulatory collapse resulting in acute or chronic tissue hypoxia in various vital organs which induces a rapid homeostatic process in all nucleated cells of affected organs in the human body. Under hypoxic conditions the alpha and beta subunits of HIF-1 make an active heterodimer and drive the transcription of over 60 genes important for cell survival, adaptation, anaerobic metabolism, immune reaction, cytokine production, vascularization and general tissue homeostasis. In addition, HIF-1 plays a key role in the development of physiological systems in fetal and postnatal life. It is also a critical mediator of cancer, lung and cardiovascular diseases. The better understanding of the functions of HIF-1 and the pharmacological modulation of its activity could mean a successful therapeutic approach to these diseases.


A structured review of patient-reported outcome measures for patients with skin cancer, 2013.
The collection of patient-reported outcome measures (PROMs) within the national PROMs programme for elective procedures is now established mandatory practice in the NHS with high response rates and completion. This review examines the evidence of PROMs for people with skin cancer. Comprehensive searches were conducted using several sources and databases, using a detailed search strategy developed by the University of Oxford's PROM Group. Articles were assessed for eligibility. Data were extracted per PROM for each measurement property and appraised using an appraisal framework. A total of 3517 articles were identified in the searches, and 28 were included in the final review after assessment by two independent reviewers. Two generic instruments (SF-36 and Sickness Impact Profile) and nine condition-specific PROMs were identified. Overall, there is a limited volume of published evidence for the application of generic PROMs for people with skin cancer. Evaluation of the EQ-5D may be particularly important given its widespread use in many other healthcare contexts in the U.K. The Skin Cancer Index could be considered for piloting in the NHS. For patients with nonmelanoma skin cancers, the Skindex measures may also be considered. The SCQOLIT has some evidence of applicability across both skin cancer types but more evaluations are needed. The FACT-M does have more promising characteristics for patients with malignant melanomas although no evidence of testing in the U.K. was found. The forthcoming EORTC-M may prove a useful measure given the expertise and track record of this European collaboration in cancer and quality of life.


Immune response of cattle to Haemophilus somnus lipid A-protein conjugate vaccine and efficacy in a mouse abortion model.
Immunogenicity of the lipid A component of Haemophilus somnus lipooligosaccharide in cattle and mice was examined after purification, detoxification, and covalent conjugation to a protein carrier. After 2 inoculations, a substantial antibody response was induced in most cattle to lipid A and the protein carrier. To determine whether antibodies to lipid A would be protective, 5 x 10(7) colony-forming units of H somnus strain 649 were administered IV to endotoxin-responsive (C3H/HeN) mice. In one study, 8 of 13 C3H/HeN mice aborted when inoculated. In contrast, abortion did not result when mice were inoculated with the same dose of an isolate of H somnus normally found in the prepuce or with the rough mutant Escherichia coli J5. In addition, endotoxin-nonresponsive (C3H/HeJ) mice were significantly (P = 0.03) more resistant to abortion by strain 649 than were C3H/HeN mice, but inoculated C3H/HeN mice were only slightly more resistant to H somnus abortion, compared with control mice. Although a large antibody response to lipid A was detected, there was no significant difference in the immunized group between mice that aborted and mice that delivered normally. Thus, lipooligosaccharide and other properties of virulent H somnus strains may contribute to abortion in mice.


Ceacam1 separates graft-versus-host-disease from graft-versus-tumor activity after experimental allogeneic bone marrow transplantation.
Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models. We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin α(4)β(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells. We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation.


Requirement for Serratia marcescens cytolysin in a murine model of hemorrhagic pneumonia.
Serratia marcescens, a member of the carbapenem-resistant Enterobacteriaceae, is an important emerging pathogen that causes a wide variety of nosocomial infections, spreads rapidly within hospitals, and has a systemic mortality rate of ≤41%. Despite multiple clinical descriptions of S. marcescens nosocomial pneumonia, little is known regarding the mechanisms of bacterial pathogenesis and the host immune response. To address this gap, we developed an oropharyngeal aspiration model of lethal and sublethal S. marcescens pneumonia in BALB/c mice and extensively characterized the latter. Lethal challenge (>4.0 × 10(6) CFU) was characterized by fulminate hemorrhagic pneumonia with rapid loss of lung function and death. Mice challenged with a sublethal dose (<2.0 × 10(6) CFU) rapidly lost weight, had diminished lung compliance, experienced lung hemorrhage, and responded to the infection with extensive neutrophil infiltration and histopathological changes in tissue architecture. Neutrophil extracellular trap formation and the expression of inflammatory cytokines occurred early after infection. Mice depleted of neutrophils were exquisitely susceptible to an otherwise nonlethal inoculum, thereby demonstrating the requirement for neutrophils in host protection. Mutation of the genes encoding the cytolysin ShlA and its transporter ShlB resulted in attenuated S. marcescens strains that failed to cause profound weight loss, extended illness, hemorrhage, and prolonged lung pathology in mice. This study describes a model of S. marcescens pneumonia that mimics known clinical features of human illness, identifies neutrophils and the toxin ShlA as a key factors important for defense and infection, respectively, and provides a solid foundation for future studies of novel therapeutics for this important opportunistic pathogen.


Identification of a new membrane-associated protein that influences transport/maturation of gingipains and adhesins of Porphyromonas gingivalis.
The dual membrane envelopes of Gram-negative bacteria provide two barriers of unlike nature that regulate the transport of molecules into and out of organisms. Organisms have developed several systems for transport across the inner and outer membranes. The Gram-negative periodontopathogenic bacterium Porphyromonas gingivalis produces proteinase and adhesin complexes, gingipains/adhesins, on the cell surface and in the extracellular milieu as one of the major virulence factors. Gingipains and/or adhesins are encoded by kgp, rgpA, rgpB, and hagA on the chromosome. In this study, we isolated a P. gingivalis mutant (porT), which showed very weak activities of gingipains in the cell lysates and culture supernatants. Subcellular fractionation and immunoblot analysis demonstrated that precursor forms of gingipains and adhesins were accumulated in the periplasmic space of the porT mutant cells. Peptide mass fingerprinting and N-terminal amino acid sequencing of the precursor proteins and the kgp'-'rgpB chimera gene product in the porT mutant indicated that these proteins lacked the signal peptide regions, consistent with their accumulation in the periplasm. The PorT protein seemed to be membrane-associated and exposed to the periplasmic space, as revealed by subcellular fractionation and immunoblot analysis using anti-PorT antiserum. These results suggest that the membrane-associated protein PorT is essential for transport of the kgp, rgpA, rgpB, and hagA gene products across the outer membrane from the periplasm to the cell surface, where they are processed and matured.


Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years.
To assess risk factors for liver-related death, we re-evaluated, after a median follow-up of 25 years, a cohort of 70 Caucasian patients with hepatitis B e antigen (HBeAg) positive chronic hepatitis (CH) at presentation. Follow-up studies included clinical and ultrasound examinations, biochemical and virological tests, and cause of death. Sixty-one (87%) patients underwent spontaneous HBeAg seroconversion. During a median period of 22.8 years after HBeAg seroclearance, 40 (66%) patients became inactive carriers, whereas the remaining 21 (34%) showed alanine aminotransferase elevation: one (1%) had HBeAg reversion, nine (15%) detectable serum HBV DNA but were negative for HBeAg, eight (13%) concurrent virus(es) infection and three (5%) concurrent non-alcoholic fatty liver disease. Liver-related death occurred in 11 (15.7%) patients, caused by hepatocellular carcinoma in five and liver failure in six. The 25-year survival probability was 40% in patients persistently HBeAg positive, 50% in patients with HBeAg negative CH or HBeAg reversion and 95% in inactive carriers. Older age, male sex, cirrhosis at entry and absence of sustained remission predicted liver-related death independently. The adjusted hazard ratios (95% CI) for liver related death were 33 (3.01-363) for persistently HBeAg positive patients and 38.73 (4.65-322) for those with HBeAg negative CH or HBeAg reversion relative to inactive carriers. Most patients with HBeAg seroconversion became inactive carriers with very good prognosis. The risk of liver-related mortality in Caucasian adults with CH is strongly related with sustained disease activity and ongoing high level of HBV replication independently of HBeAg status.


Deep Learning Preoperatively Predicts Value Metrics for Primary Total Knee Arthroplasty: Development and Validation of an Artificial Neural Network Model.
The objective is to develop and validate an artificial neural network (ANN) that learns and predicts length of stay (LOS), inpatient charges, and discharge disposition before primary total knee arthroplasty (TKA). The secondary objective applied the ANN to propose a risk-based, patient-specific payment model (PSPM) commensurate with case complexity. Using data from 175,042 primary TKAs from the National Inpatient Sample and an institutional database, an ANN was developed to predict LOS, charges, and disposition using 15 preoperative variables. Outcome metrics included accuracy and area under the curve for a receiver operating characteristic curve. Model uncertainty was stratified by All Patient Refined comorbidity indices in establishing a risk-based PSPM. The dynamic model demonstrated "learning" in the first 30 training rounds with areas under the curve of 74.8%, 82.8%, and 76.1% for LOS, charges, and discharge disposition, respectively. The PSPM demonstrated that as patient comorbidity increased, risk increased by 2.0%, 21.8%, and 82.6% for moderate, major, and severe comorbidities, respectively. Our deep learning model demonstrated "learning" with acceptable validity, reliability, and responsiveness in predicting value metrics, offering the ability to preoperatively plan for TKA episodes of care. This model may be applied to a PSPM proposing tiered reimbursements reflecting case complexity.


Cognitive and affective outcomes of genetic counselling in the Netherlands at group and individual level: a personalized approach seems necessary.
We performed a large outcome study at group and individual level in which the goals of genetic counselling were operationalized into cognitive and affective outcomes: empowerment, perceived personal control and anxiety. We then examined which socio-demographic and clinical variables were associated with changes in these outcomes. Data came from 1479 counselees who completed questionnaires (GCOS-18, PPC and STAI) at three time points: before the start of genetic counselling, after the first consultation and after the results of genetic counselling were disclosed. Results showed that at group level empowerment, perceived personal control and anxiety improved significantly after the whole genetic counselling process. Effect-sizes were medium for empowerment and small for the other outcomes. At individual level, 48% of counselees improved in empowerment, 21% in perceived personal control and 17% in anxiety. Around 10% of counselees worsened on all outcomes. Only 'reason for referral' and 'genetic test result' were significantly associated with changes in outcomes. This study demonstrated improvements among counselees in cognitive and affective outcomes after genetic counselling at group level. However, our results also suggest that there are opportunities for improvement at individual level, as many counselees remained stable and some even worsened on all outcomes. Routine outcome monitoring could help to explore the needs of counselees and could help to identify counselees who worsen.


Which factors most influence referral for restorative dental treatment under sedation and general anaesthesia in children with complex disabilities: caries severity, child functioning, or dental service organisation?
The UN Convention on the Rights of the Child gives all children right to the highest standard of services for treatment and rehabilitation. For children with disabilities, sedation and general anaesthesia (GA) are often indicated for dental treatment; however, accessibility to this varies. The International Classification of Functioning, Disability and Health - Child and Youth version (ICF-CY) enables a biopsychosocial description of children undergoing dental treatment. To investigate conscious sedation and GA in children with complex disabilities and manifest caries and analyse how caries, child functioning, and dental service organisation relate to dental GA (DGA), comparing Argentina, France, and Sweden using the ICF-CY. Quantitative, cross-sectional; data collected through structured interviews, observation, and dental records. Sedation and DGA were common. Children with limitations in interpersonal interactions and relationships were more likely to have had DGA (OR: 5.3, P = 0.015). Level of caries experience was strongly correlated with experience of DGA. There were significant differences between countries regarding caries prevalence, sedation, DGA, and functional and environmental factors. Although caries experience and child functioning are important, dental health service organisation had the most impact on the incidence of DGA, and for the use of conscious sedation, for children with complex disabilities.


Bubbling over: soda consumption and its link to obesity in California.
Background The prevalence of overweight and obesity has increased dramatically in both adults and children in the last three decades in the n California, 62% of adolescents ages 12-17 and 41% of children ages 2-11 drink at least one soda or other sweetened beverage every day. In addition, 24% of adults drink at least one soda or other sweetened beverage on an average day. Adults who drink soda occasionally (not every day) are 15% more likely to be overweight or obese, and adults who drink one or more sodas per day are 27% more likely to be overweight or obese than adults who do not drink soda, even when adjusting for poverty status and race/ethnicity. This policy brief, produced collaboratively by the California Center for Public Health Advocacy and the UCLA Center for Health Policy Research, examines soda consumption in California by cities and counties using data from the 2005 California Health Interview Survey (CHIS 2005). In addition, the brief investigates whether there is an association between soda consumption and the prevalence of overweight and obesity. There are major differences in soda consumption rates by geographic area in California, suggesting that social and environmental factors affect the consumption of soda. Also, the prevalence of overweight and obesity is higher among those who drink one or more sodas or other sweetened beverages every day than among those who do not consume these soft drinks. Establishing public policies that focus on reducing soda consumption could contribute to reversing California's increasing overweight and obesity problem.


Parkinsonisms and Glucocerebrosidase Deficiency: A Comprehensive Review for Molecular and Cellular Mechanism of Glucocerebrosidase Deficiency.
In the last years, lysosomal storage diseases appear as a bridge of knowledge between rare genetic inborn metabolic disorders and neurodegenerative diseases such as Parkinson's disease (PD) or frontotemporal dementia. Epidemiological studies helped promote research in the field that continues to improve our understanding of the link between mutations in the glucocerebrosidase (GBA) gene and PD. We conducted a review of this link, highlighting the association in GBA mutation carriers and in Gaucher disease type 1 patients (GD type 1). A comprehensive review of the literature from January 2008 to December 2018 was undertaken. Relevance findings include: (1) There is a bidirectional interaction between GBA and α- synuclein in protein homeostasis regulatory pathways involving the clearance of aggregated proteins. (2) The link between GBA deficiency and PD appears not to be restricted to α⁻synuclein aggregates but also involves Parkin and PINK1 mutations. (3) Other factors help explain this association, including early and later endosomes and the lysosomal-associated membrane protein 2A (LAMP-2A) involved in the chaperone-mediated autophagy (CMA). (4) The best knowledge allows researchers to explore new therapeutic pathways alongside substrate reduction or enzyme replacement therapies.


The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects.
Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions. Although genotype tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes.


Arthroscopic Transosseous Repair for both Proximal and Distal Components of Peripheral Triangular Fibrocartilage Complex Tear.
Tears of the triangular fibrocartilage complex (TFCC) can result in instability of the distal radioulnar joint (DRUJ) and ulnar-sided wrist pain. This study evaluates clinical results of arthroscopic transosseous repair for both proximal and distal components of TFCC tear with DRUJ instability. Ten patients who underwent both proximal component and distal component of TFCC repair were retrospectively reviewed. The proximal component of TFCC was repaired through arthroscopic one-tunnel transosseous suture technique, and the combined distal component tear was repaired to the ulnar capsule using same transosseous tunnel in all cases. Visual analog scale (VAS) score for pain, wrist range of motion, grip strength, and postoperative complications were evaluated after a mean followup period of 23.5 months, and each patient was rated according to modified Mayo wrist score and quick disabilities of the arm, shoulder, and hand (DASH) questionnaire. On arthroscopic findings, the hook test confirmed the proximal component of the TFCC tear and visible capsular detachment from TFCC confirmed combined distal component tear in all patients. At final followup, 7 patients had normal stability of DRUJ and 3 patients showed mild laxity compared with the contralateral side. The mean VAS for pain perception decreased from 4.1 to 0.7, and grip strength was increased significantly. The modified Mayo wrist score and Quick DASH score showed significant functional improvement. No surgery-related complications occurred. Arthroscopic one-tunnel transosseous TFCC foveal repair and simulatneous transosseous capsular repair of distal component can be a safe and effective strategy for repair of complete TFCC tear combined with DRUJ instability.


Adverse Childhood Experiences and the Risk of Diabetes: Examining the Roles of Depressive Symptoms and Cardiometabolic Dysregulations in the Whitehall II Cohort Study.
Adverse childhood experiences (ACEs) are associated with an increased risk of diabetes in adulthood. However, the potential mediating roles of depression and cardiometabolic dysregulations in this association are not clear. Prospective data were from the Whitehall II cohort study, with the phase 5 assessment (1997-1999) serving as baseline (n = 5,093, age range = 44-68 years, 27.3% female). ACEs were retrospectively reported at phase 5. Depressive symptoms (Center for Epidemiologic Studies Depression Scale) and cardiometabolic dysregulations (inflammation, central obesity, HDL cholesterol, triglycerides, impaired fasting glucose, and hypertension) were examined at phase 7 (2002-2004). Incident diabetes was examined at phases 8-11 (2006-2013) via self-report and blood samples. Participants reporting diabetes prior to phase 8 were excluded. Statistical mediation was examined with path analysis using structural equation modeling. ACEs were modeled as an observed continuous variable, whereas depressive symptoms and cardiometabolic dysregulations were modeled as latent variables. Unstandardized probit regression coefficients with 95% CI are reported for mediation analysis. ACEs were associated with an increased likelihood of diabetes, with every addition of ACE associated with an ∼11% increase in odds of diabetes (odds ratio 1.11 [95% CI 1.00, 1.24], P = 0.048). In mediation analysis, ACEs were indirectly associated with diabetes via depressive symptoms (indirect effect 0.03 [95% CI 0.02, 0.04], P < 0.001) and cardiometabolic dysregulations (indirect effect 0.03 [95% CI 0.01, 0.05], P = 0.03). This study provides further evidence of the detrimental psychological and physiological effects of ACEs and suggests that depression and cardiometabolic dysregulations may be pathways linking ACEs with diabetes in adulthood.


In Vivo Imaging of Subretinal Bleb-Induced Outer Retinal Degeneration in the Rabbit.
To analyze the morphologic effects of subretinal blebs in rabbits using real-time imaging by spectral-domain optical coherence tomography (SD-OCT), infrared-confocal scanning laser ophthalmoscopy (IR-cSLO), and blue-light fundus autofluorescence (BAF). Subretinal blebs of PBS or balanced salt solution (BSS) were induced in albino or pigmented rabbits using a transvitreal pars plana technique. Spectral-domain optical coherence tomography, IR-cSLO, and BAF were done at multiple intervals for up to 12 weeks after subretinal bleb injection. The morphologic effects were compared with histologic analysis on hematoxylin-eosin-stained sections of the neurosensory retina and on flat-mounts of phalloidin-labeled RPE. Scans of SD-OCT of the normal rabbit posterior segment revealed 11 bands including six layers of the photoreceptors. Subretinal blebs of PBS or BSS caused acute swelling of the neurosensory retina followed by gradual atrophy. Outer retinal thickness was significantly reduced with pronounced degeneration of all the photoreceptor OCT layers. En face IR-cSLO showed a hyperreflective area corresponding to the progressive photoreceptor degeneration, whereas BAF revealed both hyper- and hypofluorescent changes in the RPE layer. The in vivo results were confirmed by histology and on subretinal flatmounts demonstrating extensive photoreceptor loss and disruption of the RPE mosaic. Subretinal blebs induce pronounced photoreceptor degeneration and RPE changes in the rabbit as demonstrated by in vivo imaging using SD-OCT, IR-cSLO, and BAF.


Phosphorus load estimation in the Saginaw River, MI using a Bayesian hierarchical/multilevel model.
We propose the use of Bayesian hierarchical/multilevel ratio approach to estimate the annual riverine phosphorus loads in the Saginaw River, Michigan, from 1968 to 2008. The ratio estimator is known to be an unbiased, precise approach for differing flow-concentration relationships and sampling schemes. A Bayesian model can explicitly address the uncertainty in prediction by using a posterior predictive distribution, while in comparison, a Bayesian hierarchical technique can overcome the limitation of interpreting the estimated annual loads inferred from small sample sizes by borrowing strength from the underlying population shared by the years of interest. Thus, by combining the ratio estimator with the Bayesian hierarchical modeling framework, long-term loads estimation can be addressed with explicit quantification of uncertainty. Our study results indicate a slight decrease in total phosphorus load early in the series. The estimated ratio parameter, which can be interpreted as flow-weighted concentration, shows a clearer decrease, damping the noise that yearly flow variation adds to the load. Despite the reductions, it is not likely that Saginaw Bay meets with its target phosphorus load, 440 tonnes/yr. Throughout the decades, the probabilities of the Saginaw Bay not complying with the target load are estimated as 1.00, 0.50, 0.57 and 0.36 in 1977, 1987, 1997, and 2007, respectively. We show that the Bayesian hierarchical model results in reasonable goodness-of-fits to the observations whether or not individual loads are aggregated. Also, this modeling approach can substantially reduce uncertainties associated with small sample sizes both in the estimated parameters and loads.


Macroautophagy is defective in mucolipin-1-deficient mouse neurons.
Mucolipidosis type IV is a neurodegenerative lysosomal disease clinically characterized by psychomotor retardation, visual impairment, and achlorhydria. In this study we report the development of a neuronal cell model generated from cerebrum of Mcoln1(-/-) embryos. Prior functional characterization of MLIV cells has been limited to fibroblast cultures gleaned from patients. The current availability of the mucolipin-1 knockout mouse model Mcoln1(-/-) allows the study of mucolipin-1-defective neurons, which is important since the disease is characterized by severe neurological impairment. Electron microscopy studies reveal significant membranous intracytoplasmic storage bodies, which correlate with the storage morphology observed in cerebral cortex of Mcoln1(-/-) P7 pups and E17 embryos. The Mcoln1(-/-) neuronal cultures show an increase in size of LysoTracker and Lamp1 positive vesicles. Using this neuronal model system, we show that macroautophagy is defective in mucolipin-1-deficient neurons and that LC3-II levels are significantly elevated. Treatment with rapamycin plus protease inhibitors did not increase levels of LC3-II in Mcoln1(-/-) neuronal cultures, indicating that the lack of mucolipin-1 affects LC3-II clearance. P62/SQSTM1 and ubiquitin levels were also increased in Mcoln1(-/-) neuronal cultures, suggesting an accumulation of protein aggregates and a defect in macroautophagy which could help explain the neurodegeneration observed in MLIV. This study describes, for the first time, a defect in macroautophagy in mucolipin-1-deficient neurons, which corroborates recent findings in MLIV fibroblasts and provides new insight into the neuronal pathogenesis of this disease.


Effect of body position on hamstring muscle group average torque.
The purpose of this investigation was to examine the effect of the supine and prone position on concentric and eccentric isokinetic strength of the hamstring muscle group. Twelve university female lacrosse players were tested for hamstring average torque on a Kinetic Communicator(R) dynamometer at 60 degrees /sec from the supine and prone positions. Analysis of variance indicated average torque generated from the prone was greater than the supine position. Greater torque was also generated during eccentric contraction than during concentric contraction. The influence of the tonic labyrinthine and the symmetrical tonic neck reflexes is proposed as the mechanism for the differences observed between the two test positions. The prone position facilitates optimal generation of torque while approximating a length-tension relationship observed during sprinting. These findings suggest consideration be given to assessment and strength training of the hamstring muscle group in the prone position. J Orthop Sports Phys Ther 1990;11(10):449-452.


The mathematical framework essential for magneto-therapy in the treatment of genomic and associated disorders, including cancer, AIDS, and CNS regeneration.
A new approach to the treatment of various viral, oncogenic and associated genetic and transmissible immunogenic, for example, infectious DNA or RNA, induced diseases is proposed utilizing amplitude and frequency modulated Jacobson resonance: mc2 = Bvl coulomb, a general expression of Zeeman and cyclotron resonance. Oncogenic and associated quantum genetic particles, such as oncogene associated proteins, viral nucleic acids and growth factors, may be induced electromagnetically into recrystallized and translocated states based upon various quantum phenomena affording new methodological techniques in magneto-therapy applicable to AIDS, cancer and CNS regeneration. A specific mathematical framework is presented by which to determine the appropriate physiologic amplitude (from about 4 x 10(-5) gauss to about 4 x 10(-11) gauss) and frequency (from about 10(-3) to 10(3) Hz) to subject biological systems therein reorienting atomic crystal lattice structures to congruent extensions of physiologic submolecular and atomic magnetic domains which are vital to homeostasis and health.


Nursing specialty certification and nursing-sensitive patient outcomes in the intensive care unit.
To the public and to individual nurses, certification usually means expert, high-quality, competent nursing care. Little research, however, has yielded results that support, or refute, any differences in clinical practice between certified and noncertified nurses. To determine whether the proportion of certified nurses on a unit is associated with the rate of nurse-sensitive patient outcomes. A nonexperimental, correlational, descriptive design was used to anonymously survey 866 nurses working in 25 intensive care units in Southeast Michigan. The Conditions for Work Effectiveness Questionnaire-II was used to measure workplace empowerment, and an additional question was asked about certification status. Outcome data were simultaneously collected on 3 nurse-sensitive patient outcomes: (1) rate of central line catheter-associated blood stream infection, (2) rate of ventilator-associated pneumonia, and (3) prevalence of pressure ulcers. Data were aggregated and analyzed at the unit level. No significant relationship was found between the proportion of certified nurses on a unit and patients' outcomes. The association between nurses' perception of overall work-place empowerment and certification, however, was positive and statistically significant (r=.397, P=.05). Although a link between certification and nurse-sensitive outcomes was not established, the association between workplace empowerment and the proportion of certified nurses on a unit underscores the importance of organizational factors in the promotion of nursing certification.


Melatonin increases the chemosensitivity of diffuse large B-cell lymphoma cells to epirubicin by inhibiting P-glycoprotein expression via the NF-κB pathway.
Epirubicin is a first-line chemotherapeutic drug for the clinical treatment of diffuse large B cell lymphoma (DLBCL), but the overexpression of multidrug resistance (MDR) transporter proteins, especially P-glycoprotein (P-gp), renders epirubicin ineffective. Some studies reveal the potential role of melatonin in chemotherapeutic synergy and MDR. The cell viability and apoptosis were determined by CCK-8 assay and acridine orange/ethidium bromide (AO/EB) fluorescence staining assay. Immunofluorescence and immunohistochemical staining were used to detect the expression of P-gp in DLBCL cells and tissues. Rhodamine-123 accumulation assay was used to evaluate the pump function of P-gp. The possible mechanisms of melatonin sensitize DLBCL cells to epirubicin were explored by western blotting, cytochrome C release, and pulldown assay. Melatonin significantly enhanced the epirubicin-induced cell proliferation suppression, epirubicin-induced apoptosis, and reduced the IC50 value of epirubicin. Further, melatonin synergized with epirubicin to promote the activation of the mitochondria-mediated apoptosis pathway and increased the accumulation of epirubicin in DLBCL cells by inhibiting the expression and function of P-gp. Immunohistochemical staining studies revealed that P-gp expression was positively correlated with P65 expression. Epirubicin was subsequently discovered to upregulate the expression of P-gp by activating the NF-κB pathway in the DLBCL cells. Melatonin reduced the amount of P65 protein in the nucleus and abrogated the ability of P65 to bind to the ABCB1 promoter, decisively suppressing P-gp expression. Our results demonstrated that melatonin inactivates the NF-κB pathway and downregulates the expression of P-gp, ultimately sensitizing DLBCL cells to the epirubicin that suppresses their growth.


Targeted disruption of a melanin biosynthesis gene affects conidial development and UV tolerance in the Japanese pear pathotype of Alternaria alternata.
Structural analysis of the BRM2 gene involved in melanin biosynthesis of the Japanese pear pathotype of Alternaria alternata suggested that this gene encodes 1,3,8-trihydroxynaphthalene reductase. Targeted disruption of the BRM2 gene did not affect pathogenicity, vegetative growth, or the number of conidia produced. Targeted disruption, however, did reduce conidial size and septal number, suggesting that melanin is associated with conidial development. The conidia of brm2 mutant transformants were more sensitive to UV light than those of the wild type, demonstrating that melanin confers UV tolerance.


The associations between low-level gaming, high-level gaming and problematic alcohol use.
The current study aimed to investigate associations between gaming and different patterns of problematic alcohol use, controlling for important demographics, personality and mental health covariates. Data was collected by an online survey during fall 2016 (N = 5217). Students who had participated in a survey among students in Bergen, Norway, one year earlier were invited to participate. Crude and adjusted binary logistic regression analyses were conducted in order to assess the relationship between different patterns of problematic alcohol use and gaming (i.e. low-level gaming and high-level gaming vs. no gaming) while controlling for important covariates. The different gaming groups were categorised based on the number of symptoms of "gaming addiction" (in total seven) that they endorsed: 4 > symptoms = low-level gaming, 4 ≤ symptoms = high-level gaming. Only 0.2% (n = 11) endorsed all seven symptoms. Low-level gaming was positively associated with patterns of problematic alcohol use in the crude analyses; these associations became non-significant when controlling for demographic variables. High-level gaming was inversely associated with patterns of problematic alcohol use when controlling for demographics, personality, and mental health covariates. The inverse relationship between high-level gaming and problematic alcohol use (when controlling for covariates) suggest that heavy investment in gaming may protect against excessive alcohol use and alcohol-related harm. Possible explanations discussed for the inverse associations include high-level gamers having less available time to drink, intoxication being incompatible with gaming, and/or high-level gamers experiencing sufficient satisfaction/escape and social bonding by gaming, hence having less need for alcohol.


The Y-chromosome C3* star-cluster attributed to Genghis Khan's descendants is present at high frequency in the Kerey clan from Kazakhstan.
To verify the possibility that the Y-chromosome C3* star-cluster attributed to Genghis Khan and his patrilineal descendants is relatively frequent in the Kereys, who are the dominant clan in Kazakhstan and in Central Asia as a whole, polymorphism of the Y-chromosome was studied in Kazakhs, represented mostly by members of the Kerey clan. The Kereys showed the highest frequency (76.5%) of individuals carrying the Y-chromosome variant known as C3* star-cluster ascribed to the descendants of Genghis Khan. C3* star-cluster haplotypes were found in two subclans, Abakh-Kereys and Ashmaily-Kereys, diverged about 20-22 generations ago according to the historical data. Median network of the Kerey star-cluster haplotypes at 17 STR loci displays a bipartite structure, with two subclusters defined by the only difference at the DYS448 locus. Noteworthy is a strong correspondence of these subclusters with the Kerey subclans affiliation. The data obtained suggest that the Kerey clan appears to be the largest known clan in the world descending from a common Y-chromosome ancestor. Possible ways of Genghis Khan's relationship to the Kereys are discussed.


Risperidone monotherapy for post-traumatic stress disorder related to sexual assault and domestic abuse in women.
Post-traumatic stress disorder is a common, chronic, and often disabling mental illness. Selective serotonin reuptake inhibitors are the usual first-line treatment for post-traumatic stress disorder, but many patients fail to respond adequately. Thus, other treatment options, including the atypical antipsychotics such as risperidone, need to be tested. Women between the ages of 19 and 64 years with post-traumatic stress disorder were enrolled. Symptom severity was rated at baseline using the Treatment Outcomes Post-traumatic Stress Disorder Scale-8, Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression, and Clinician Administered Post-traumatic Stress Disorder Scale. After washout from other psychotropic medications, 20 participants were randomized to either risperidone or placebo. Total score on the Treatment Outcomes Post-traumatic Stress Disorder Scale-8 served as the primary outcome measure. Repeated-measures analysis of variance was followed by Newman-Keuls tests. A significant main effect exists for visits using the Treatment Outcomes Post-traumatic Stress Disorder Scale-8 raw score. For the treatment group, the difference between baseline Treatment Outcomes Post-traumatic Stress Disorder Scale-8 scores and treatment visit scores was significant beginning at visit 6 and continued through visit 11. No significant difference observed between baseline and any treatment visit for the placebo group. The Clinician Administered Post-traumatic Stress Disorder Scale, Hamilton Rating Scale for Anxiety, and Hamilton Rating Scale for Depression data revealed a similar pattern. In this small pilot study, risperidone monotherapy was more effective than placebo in the treatment of post-traumatic stress disorder.


Avoidance of Majorana resonances in periodic topological superconductor-nanowire structures.
Semiconducting nanowires in proximity to superconductors are promising experimental systems for Majorana fermions which may ultimately be used as building blocks for topological quantum computers. A serious challenge in the experimental realization of the Majorana fermion in these semiconductor-superconductor-nanowire structures is tuning the semiconductor chemical potential in close proximity to the metallic superconductor. We show that presently realizable structures in experiments with tunable chemical potential lead to Majorana resonances, which are interesting in their own right, but do not manifest non-Abelian statistics. To resolve this crucial barrier to the solid state realization of Majorana fermions, we propose a new topological superconducting array structure where introducing the superconducting proximity effect from adjacent nanowires generates Majorana fermions with non-Abelian statistics.


Rest-related consolidation protects the fine detail of new memories.
Newly encoded memories are labile and consolidate over time. The importance of sleep in memory consolidation has been well known for almost a decade. However, recent research has shown that awake quiescence, too, can support consolidation: people remember more new memories if they quietly rest after encoding than if they engage in a task. It is not yet known how exactly this rest-related consolidation benefits new memories, and whether it affects the fine detail of new memories. Using a sensitive picture recognition task, we show that awake quiescence aids the fine detail of new memories. Young adults were significantly better at discriminating recently encoded target pictures from similar lure pictures when the initial encoding of target pictures had been followed immediately by 10 minutes of awake quiescence than an unrelated perceptual task. This novel finding indicates that, in addition to influencing how much we remember, our behavioural state during wakeful consolidation determines, at least in part, the level of fine detail of our new memories. Thus, our results suggest that rest-related consolidation protects the fine detail of new memories, allowing us to retain detailed memories.


Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.
Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time-dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG-related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG-related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans, finding deleterious mutations can provide an unequivocal diagnosis of the disease.


The role for HNF-1beta-targeted collectrin in maintenance of primary cilia and cell polarity in collecting duct cells.
Collectrin, a homologue of angiotensin converting enzyme 2 (ACE2), is a type I transmembrane protein, and we originally reported its localization to the cytoplasm and apical membrane of collecting duct cells. Recently, two independent studies of targeted disruption of collectrin in mice resulted in severe and general defects in renal amino acid uptake. Collectrin has been reported to be under the transcriptional regulation by HNF-1alpha, which is exclusively expressed in proximal tubules and localized at the luminal side of brush border membranes. The deficiency of collectrin was associated with reduction of multiple amino acid transporters on luminal membranes. In the current study, we describe that collectrin is a target of HNF-1beta and heavily expressed in the primary cilium of renal collecting duct cells. Collectrin is also localized in the vesicles near the peri-basal body region and binds to gamma-actin-myosin II-A, SNARE, and polycystin-2-polaris complexes, and all of these are involved in intracellular and ciliary movement of vesicles and membrane proteins. Treatment of mIMCD3 cells with collectrin siRNA resulted in defective cilium formation, increased cell proliferation and apoptosis, and disappearance of polycystin-2 in the primary cilium. Suppression of collectrin mRNA in metanephric culture resulted in the formation of multiple longitudinal cysts in ureteric bud branches. Taken together, the cystic change and formation of defective cilium with the interference in the collectrin functions would suggest that it is necessary for recycling of the primary cilia-specific membrane proteins, the maintenance of the primary cilia and cell polarity of collecting duct cells. The transcriptional hierarchy between HNF-1beta and PKD (polycystic kidney disease) genes expressed in the primary cilia of collecting duct cells has been suggested, and collectrin is one of such HNF-1beta regulated genes.


Broadband NIR photoluminescence from Bi-doped Ba2P2O7 crystals: insights into the nature of NIR-emitting Bismuth centers.
We report on a novel type of Bi-doped crystal that exhibits ultrabroadband photoluminescence in the near infrared (NIR). Emission centers can be generated and degenerated reversibly by annealing the material in CO atmosphere and air, respectively, indicating that emission is related to the presence of Bi-species in low valence states. Correlating static and dynamic excitation and emission data with the size and charge of available lattice sites suggests that two types of Bi(0)-species, each located on one of the two available Ba(2+) lattice sites, are responsible for NIR photoemission. This is further confirmed by the absence of NIR emission in polycrystalline Ca(2)P(2)O(7):Bi and Sr(2)P(2)O(7):Bi. Excitation is assigned to transitions between the doubly degenerated ground state (4)S(3/2) and the degenerated excited levels (2)D(3/2), (2)D(5/2) and (2)P(1/2), respectively. NIR emission is attributed to (2)D(3/2)?(4)S(3/2). The NIR emission center can coexist with Bi(2+) species. Then, also Bi(2+) is accommodated on one of the two Ba(2+)-sites. Energy transfer between Bi(2+) ions occurs within a critical distance of 25.9 A.


Methane contamination of drinking water accompanying gas-well drilling and hydraulic fracturing.
Directional drilling and hydraulic-fracturing technologies are dramatically increasing natural-gas extraction. In aquifers overlying the Marcellus and Utica shale formations of northeastern Pennsylvania and upstate New York, we document systematic evidence for methane contamination of drinking water associated with shale-gas extraction. In active gas-extraction areas (one or more gas wells within 1 km), average and maximum methane concentrations in drinking-water wells increased with proximity to the nearest gas well and were 19.2 and 64 mg CH(4) L(-1) (n = 26), a potential explosion hazard; in contrast, dissolved methane samples in neighboring nonextraction sites (no gas wells within 1 km) within similar geologic formations and hydrogeologic regimes averaged only 1.1 mg L(-1) (P < 0.05; n = 34). Average δ(13)C-CH(4) values of dissolved methane in shallow groundwater were significantly less negative for active than for nonactive sites (-37 ± 7‰ and -54 ± 11‰, respectively; P < 0.0001). These δ(13)C-CH(4) data, coupled with the ratios of methane-to-higher-chain hydrocarbons, and δ(2)H-CH(4) values, are consistent with deeper thermogenic methane sources such as the Marcellus and Utica shales at the active sites and matched gas geochemistry from gas wells nearby. In contrast, lower-concentration samples from shallow groundwater at nonactive sites had isotopic signatures reflecting a more biogenic or mixed biogenic/thermogenic methane source. We found no evidence for contamination of drinking-water samples with deep saline brines or fracturing fluids. We conclude that greater stewardship, data, and-possibly-regulation are needed to ensure the sustainable future of shale-gas extraction and to improve public confidence in its use.


Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation.
Cdc42 is a Ras-related protein that has been implicated in the control of normal cell growth, and when improperly regulated, in cellular transformation and invasiveness. A variety of extracellular stimuli, including epidermal growth factor (EGF), activate Cdc42. Here, we show that activation of Cdc42 protects the EGF receptor from the negative regulatory activity of the c-Cbl ubiquitin ligase. Activated Cdc42 binds to p85Cool-1 (for cloned-out-of-library)/beta-Pix (for Pak-interactive exchange factor), a protein that directly associates with c-Cbl. This inhibits the binding of Cbl by the EGF receptor and thus prevents Cbl from catalyzing receptor ubiquitination. The role played by Cdc42 in regulating the timing of EGF receptor-Cbl interactions is underscored by the fact that constitutively active Cdc42(F28L), by persistently blocking the binding of Cbl to these receptors, leads to their aberrant accumulation and sustained EGF-stimulated ERK activation, thus resulting in cellular transformation.


Effects of cycling and rigor crossbridges on the conformation of cardiac troponin C.
The results of work by several investigators indicate that crossbridge attachment serves as a positive feedback mechanism that transiently increases the Ca2+ affinity of troponin C (TnC) during each normal heartbeat. To monitor structural changes in the cardiac isoform of TnC (cTnC) associated with Ca2+ binding and crossbridge attachment in muscle, we labeled cTnC with the sulfhydryl-specific fluorescent probe 2-(4'-iodoacetamidoanilino)naphthalene-6-sulfonic acid (IAANS). When IAANS-labeled cTnC (cTnCIAANS) was substituted for endogenous TnC, the fluorescence intensity of cardiac and skeletal muscle preparations increased substantially during rigor crossbridge attachment in the absence of Ca2+ (pCa 9.2). In cardiac muscle, the fluorescence signal increased the same amount in rigor and maximal activation, whereas in skeletal muscle, it was higher in rigor (rigor: cardiac and skeletal = 1; pCa 4.0: cardiac = 0.98 +/- 0.13, skeletal = 0.59 +/- 0.05). This indicates that crossbridge attachment alone is capable of influencing the structure of cTnCIAANS. Because the relative fluorescence intensity of cTnCIAANS was more sensitive to Ca2+ than was force in both preparations (cardiac: pCa50 fluorescence = 6.05 +/- 0.05, pCa50 force = 5.51 +/- 0.11; skeletal: pCa50 fluorescence = 5.94 +/- 0.13, pCa50 force = 5.65 +/- 0.14), we measured the Ca2+ sensitivity of the strong crossbridge attachment (sinusoidal stiffness was measured by imposing 1 kHz at 0.1-0.2% muscle length) in rat trabeculae.(ABSTRACT TRUNCATED AT 250 WORDS)


Congenital Heart Defects and Receipt of Special Education Services.
We investigated the prevalence of receipt of special education services among children with congenital heart defects (CHDs) compared with children without birth defects. Children born from 1982 to 2004 in metropolitan Atlanta with CHDs (n = 3744) were identified from a population-based birth defect surveillance program; children without birth defects (n = 860 715) were identified from birth certificates. Cohorts were linked to special education files for the 1992-2012 school years to identify special education services. Children with noncardiac defects or genetic syndromes were excluded; children with CHDs were classified by presence or absence of critical CHDs (ie, CHDs requiring intervention by age one year). We evaluated the prevalence of receipt of special education services and prevalence rate ratios using children without birth defects as a reference. Compared with children without birth defects, children with CHDs were 50% more likely to receive special education services overall (adjusted prevalence rate ratio [aPRR] = 1.5; 95% confidence interval [CI]: 1.4-1.7). Specifically, they had higher prevalence of several special education categories including: intellectual disability (aPRR = 3.8; 95% CI: 2.8-5.1), sensory impairment (aPRR = 3.0; 95% CI: 1.8-5.0), other health impairment (aPRR = 2.8; 95% CI: 2.2-3.5), significant developmental delay (aPRR = 1.9; 95% CI: 1.3-2.8), and specific learning disability (aPRR = 1.4; 95% CI: 1.1-1.7). For most special education services, the excess prevalence did not vary by presence of critical CHDs. Children with CHDs received special education services more often than children without birth defects. These findings highlight the need for special education services and the importance of developmental screening for all children with CHDs.


Engagement of people with multiple sclerosis to enhance research into the physiological effect of hyperbaric oxygen therapy.
Thousands of people with multiple sclerosis (MS) have used self-administered oxygen therapy in the UK. Clinical trials have been performed, with scant evidence that people with MS have been consulted to explore how they benefit from or how to optimize this treatment. The conventional MS disease disability scores used in trials seldom reflect the effects individuals report when using oxygen therapy to treat their symptoms. Three people with MS and the manager of an MS Centre formed a public involvement group and collaborated with clinicians and scientists to inform a lab-based study to investigate the physiological effects of oxygen therapy on microvascular brain endothelial cells. People with MS often use oxygen therapy at a later stage when their symptoms worsen and only after using other treatments. The frequency of oxygen therapy sessions and hyperbaric pressure is individualized and varies for people with MS. Despite direct comparisons of efficacy proving difficult, most individuals are exposed to 100% O2 at 1.5 atmosphere absolute (ATA; 1140 mmHg absolute) for 60 min. In a laboratory-based study human brain endothelial cells were exposed in vitro to 152 mmHg O2 for 60 min with and without pressure, as this equates to 20% O2 achievable via hyperbarics, which was then replicated at atmospheric pressure. A significant reduction in endothelial cells ICAM-1 (CD54) implicated in inflammatory cell margination across the blood brain barrier was observed under oxygen treatment. By collaborating with people living with MS, we were able to design laboratory-based experimental protocols that replicate their treatment regimens to advance our understanding of the physiological effects of hyperbaric oxygen treatment on brain cells and their role in neuroinflammation.


Diagnosing pediatric asthma: validating the Easy Breathing Survey.
To determine the sensitivity, specificity, and predictive value of a simple, self-administered questionnaire for the diagnosis of asthma in children. A questionnaire specifically designed to assist primary care providers in making a diagnosis of asthma in children was developed and administered in 4 different primary care and subspecialty clinics, validated, and then used as part of an asthma management program called Easy Breathing. Asthma diagnoses were made according to recommended National Asthma Expert Panel Guidelines. Four questions on the survey were shown to be sensitive and specific for asthma. The sensitivity was greater for all levels (mild, moderate, and severe) of persistent asthma than for mild, intermittent asthma. A positive response to any 1 of the 4 questions was over 94% sensitive for asthma; a negative response to all 4 questions was 55% specific for ruling out asthma. Patient responses to 4 specific respiratory symptom questions can assist primary care providers in diagnosing asthma in children. Primary care providers serving pediatric populations at high risk for asthma should consider asking patients or their parents these 4 questions regarding asthma symptoms on a regular basis.


Inferior glenosphere placement reduces scapular notching in reverse total shoulder arthroplasty.
Scapular notching is a common complication after reverse shoulder arthroplasty and has been associated with poor clinical outcomes. Factors associated with notching include neck shaft angle and glenosphere position. The goal of this study was to evaluate the incidence of notching with an eccentric glenosphere that allows for inferior offset as well as its effect on clinical outcome. The charts of 82 patients who underwent reverse shoulder arthroplasty with this eccentric glenosphere were retrospectively reviewed. Scapular notching was assessed with standard anteroposterior radiographs of the glenohumeral joint according to the Nerot-Sirveaux classification system. Two experienced observers evaluated all radiographs. The presence of radiolucent lines was also evaluated. Both range of motion (ROM) and Constant-Murley scores were obtained. Average age was 74 years (range, 61-91 years), and follow-up was 26.3 months (range, 19-39 months). According to the Nerot-Sirveaux classification, 73 (89%) had no notching, 5 (6%) had grade I notching, 2 (2.5%) had grade II notching, and 2 (2.5%) had grade III notching. The overall presence of notching was 11% and correlated to the amount of inferior offset. No radiolucent lines were seen around the prosthesis. Both ROM and Constant-Murley scores (from 31.3 to 74.2) improved significantly in all patients from preoperative evaluation to final follow-up (P<.05). No significant differences in ROM and functional outcome were seen between the groups with and without notching. The inferior offset glenosphere created with this glenosphere base plate design reduced the incidence of scapular notching in reverse shoulder arthroplasty. This was particularly true when the glenosphere was maximally offset inferiorly. In the short term, notching does not affect ROM or functional outcome.


Association of Presalvage Radiotherapy PSA Levels After Prostatectomy With Outcomes of Long-term Antiandrogen Therapy in Men With Prostate Cancer.
In men with recurrent prostate cancer, addition of long-term antiandrogen therapy to salvage radiotherapy (SRT) was associated with overall survival (OS) in the NRG/RTOG 9601 study. However, hormone therapy has associated morbidity, and there are no validated predictive biomarkers to identify which patients derive most benefit from treatment. To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT. Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years. In this secondary analysis of the multicenter RTOG 9601 double-blind, placebo-controlled randomized clinical trial conducted from 1998 to 2003 by a multinational cooperative group, men with a positive surgical margin or pathologic T3 disease after radical prostatectomy with pre-SRT PSA of 0.2 to 4.0 ng/mL were included. Analysis was performed between March 4, 2019, and December 20, 2019. The primary outcome was overall survival (OS). Secondary end points included distant metastasis (DM), other-cause mortality (OCM), and grades 3 to 5 cardiac and neurologic toxic effects. Subgroup analyses were performed using the protocol-specified PSA stratification variable (1.5 ng/mL) and additional PSA cut points, including test for interaction. Competing risk analyses were performed for DM and other-cause mortality (OCM). Overall, 760 men with PSA elevation after radical prostatectomy for prostate cancer were included. The median (range) age of particpants was 65 (40-83) years. Antiandrogen assignment was associated with an OS benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (hazard ratio [HR], 0.45; 95% CI, 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR, 0.87; 95% CI, 0.66-1.16). In a subanalysis of men with PSA of 0.61 to 1.5 (n = 253), there was an OS benefit associated with antiandrogen assignment (HR, 0.61; 95% CI, 0.39-0.94). In those receiving early SRT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in OS (HR, 1.16; 95% CI, 0.79-1.70), an increased OCM hazard (subdistribution HR, 1.94; 95% CI, 1.17-3.20; P = .01), and an increased odds of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio, 3.57; 95% CI, 1.09-15.97; P = .05). These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA >0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤0.6 ng/mL), long-term antiandrogen treatment was not associated with improved OS. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population. ClinicalTrials.gov Identifier: NCT00002874.


Oxygen(es) and the hypoxia-inducible factor-1.
The hypoxia-inducible factor-1 (HIF-1) is a basic-helix-loop-helix (bHLH) heterodimeric transcription factor activated by reductions in oxygen concentration (hypoxia). Activated HIF-1 upregulates expression of genes involved in the adaptation of higher organisms to hypoxic conditions, caused by e.g. high altitude, anemia, wound healing or during development. Examples of these oxy-genes include erythropoietin, a hormone regulating erythropoiesis and hence the oxygen transport capacity, and vascular endothelial growth factor, a potent inducer of angiogenesis leading to increased blood capillary density. The HIF-1 heterodimer is composed of a HIF-1alpha and an ARNT subunit, both belonging to the explosively growing PAS subfamily of bHLH transcription factors. Closely related, but differentially expressed, factors have recently been cloned, at least one of which can also be activated by hypoxia. In this review, we present a survey of the bH LH-PAS family as well as of the genes regulated by HIF-1, and we summarize our current knowledge on the oxygen-dependent activation of this fascinating transcription factor.


Effects of sodium hypochlorite (Dakin's solution) on cells of the wound module.
This study investigates the effects of sodium hypochlorite, or Dakin's solution (DS), on the function and viability of cells of the wound module (neutrophils, fibroblasts, and endothelial cells). For functional studies, the influence of DS on the in vitro migration of neutrophils was evaluated. Our data indicate that DS (2.5 x 10(-2)% to 2.5 x 10(-4)%) results in greater than 90% inhibition of the migration of both stimulated and nonstimulated neutrophils. Electron microscopy and trypan blue evaluation of neutrophils exposed to DS at these concentrations revealed normal structural features, which indicates that the observed reduction in neutrophil migration is not a result of cell death. In contrast to neutrophils, cultured fibroblasts and endothelial cells exposed to DS (2.5 x 10(-2)% or 2.5 x 10(-3)%) for 30 minutes show marked cell injury characterized by convoluted nuclei, cytoplasmic vacuolization, dilated endoplasmic reticulum, and swollen mitochondria on electron microscopy. These data suggest that DS, even at very dilute concentrations, is toxic to cells of the wound module. We therefore recommend abandonment of the use of DS in open wounds.


Energetics of base flipping at a DNA mismatch site confined at the latch constriction of α-hemolysin.
Unique, two-state modulating current signatures are observed when a cytosine-cytosine mismatch pair is confined at the 2.4 nm latch constriction of the α-hemolysin (αHL) nanopore. We have previously speculated that the modulation is due to base flipping at the mismatch site. Base flipping is a biologically significant mechanism in which a single base is rotated out of the DNA helical stack by 180°. It is the mechanism by which enzymes are able to access bases for repair operations without disturbing the global structure of the helix. Here, temperature dependent ion channel recordings of individual double-stranded DNA duplexes inside αHL are used to derive thermodynamic (ΔH, ΔS) and kinetic (EA) parameters for base flipping of a cytosine at an unstable cytosine-cytosine mismatch site. The measured activation energy for flipping a cytosine located at the latch of αHL out of the helix (18 ± 1 kcal mol-1) is comparable to that previously reported for base flipping at mismatch sites from NMR measurements and potential mean force calculations. We propose that the αHL nanopore is a useful tool for measuring conformational changes in dsDNA at the single molecule level.


Failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients*.
To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU. Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial. Sixty-seven medical-surgical ICUs in six countries. Three thousand seven hundred forty-six medical-surgical critically ill patients. All patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses. Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism developing during critical illness were assessed. A total of 289 patients (7.7%) developed venous thromboembolism. Predictors of thromboprophylaxis failure as measured by development of venous thromboembolism included a personal or family history of venous thromboembolism (hazard ratio, 1.64; 95% CI, 1.03-2.59; p = 0.04) and body mass index (hazard ratio, 1.18 per 10-point increase; 95% CI, 1.04-1.35; p = 0.01). Increasing body mass index was also a predictor for developing proximal leg deep vein thrombosis (hazard ratio, 1.25; 95% CI, 1.06-1.46; p = 0.007), which occurred in 182 patients (4.9%). Pulmonary embolism occurred in 47 patients (1.3%) and was associated with body mass index (hazard ratio, 1.37; 95% CI, 1.02-1.83; p = 0.035) and vasopressor use (hazard ratio, 1.84; 95% CI, 1.01-3.35; p = 0.046). Low-molecular-weight heparin (in comparison to unfractionated heparin) thromboprophylaxis lowered pulmonary embolism risk (hazard ratio, 0.51; 95% CI, 0.27-0.95; p = 0.034) while statin use in the preceding week lowered the risk of proximal leg deep vein thrombosis (hazard ratio, 0.46; 95% CI, 0.27-0.77; p = 0.004). Failure of standard thromboprophylaxis using low-molecular-weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients.


Molecular forms of acetylcholinesterases in Alzheimer's disease.
In this study, we examined 26 cases of Alzheimer's disease (AD) and 14 age-matched controls. In Brodmann area 21 cerebral cortex of the AD cases, there was no change in soluble G1 and G4 acetylcholinesterase (AChE) (EC 184.108.40.206), a significant 40% decrease in membrane-associated G4 AChE, significant 342 and 406% increases in A12 and A8 AChE, and a significant 71% decrease in choline acetyltransferase (ChAT) (EC 188.8.131.52). Our working hypothesis to account for these changes postulates that soluble globular forms are unchanged because they are primarily associated with intrinsic cortical neurons that are relatively unaffected by AD, that ChAT and membrane-associated G4 AChE decrease because they are primarily associated with incoming axons of cholinergic neurons that are abnormal in AD, and that asymmetric forms of AChE increase because of an acrylamide-type impairment of fast axonal transport in diseased incoming cholinergic axons. In the nucleus basalis of Meynert (nbM) of the 26 AD cases, there was a significant 61% decrease in the number of cholinergic neurons, an insignificant 23% decrease in nbM ChAT, a significant 298% increase in nbM ChAT per cholinergic neuron, and a significant 7% increase in the area of cholinergic perikarya. To account for the increased ChAT in cholinergic neurons and the enlargement of cholinergic perikarya, we propose that slow axonal transport may be impaired in nbM cholinergic neurons in AD.


Diagnostic Utility of Serum Ascites Lipid and Protein Gradients in Differentiation of Ascites.
Ability of SAAG to differentiate malignant ascites from other aetiologies like tubercular peritonitis is a major problem. Alternate screening test is needed for differentiating ascites due to malignancy from those due to tubercular peritonitis. To study the diagnostic utility of serum ascites lipid gradients and serum ascites protein gradients in pathophysiological differentiation of ascites. The present study is a prospective, descriptive, hospital-based, cross-sectional study. The study was conducted on patients with ascites who were admitted to General Medicine Department, Kasturba Hospital, Manipal. The study included 60 patients with ascites of different etiologies (liver cirrhosis, tubercular peritonitis, and malignant ascites). All of them had undergone clinical, laboratory, and imaging investigations and were treated as per standard of care. All patients underwent abdominal paracentesis, and fluid samples were sent for analysis. ANOVA, Kruskal-Wallis H test, and ROC curve analysis. Among the gradients, only SAPG and SAAG had over all statistical significance (<0.005) among the groups, but no significance between malignancy and tubercular peritonitis had been observed. Similarly all the ascitic fluid parameters measured had an overall statistical significance (<0.005), but there was no significant difference observed between malignancy and tubercular peritonitis groups. However, ascitic fluid and serum HDL cholesterol had a statistical significance (<0.05) between malignancy and tubercular peritonitis. With a cut-off value of 4, SAPG is one of best screening tests in differentiation of cirrhotic with noncirrhotic ascites when compared with SAAG, whereas it is a poor parameter with high sensitivity and very low specificity in differentiation of malignant with nonmalignant ascites. Also the present study reveals HDL cholesterol levels in ascitic fluid to be a valuable marker with higher sensitivity and specificity in differentiation of malignancy and tuberculosis peritonitis (i.e., differentiation of low SAAG ascites).


High-density lipoprotein receptor SCARB1 is required for carotenoid coloration in birds.
Yellow, orange, and red coloration is a fundamental aspect of avian diversity and serves as an important signal in mate choice and aggressive interactions. This coloration is often produced through the deposition of diet-derived carotenoid pigments, yet the mechanisms of carotenoid uptake and transport are not well-understood. The white recessive breed of the common canary (Serinus canaria), which carries an autosomal recessive mutation that renders its plumage pure white, provides a unique opportunity to investigate mechanisms of carotenoid coloration. We carried out detailed genomic and biochemical analyses comparing the white recessive with yellow and red breeds of canaries. Biochemical analysis revealed that carotenoids are absent or at very low concentrations in feathers and several tissues of white recessive canaries, consistent with a genetic defect in carotenoid uptake. Using a combination of genetic mapping approaches, we show that the white recessive allele is due to a splice donor site mutation in the scavenger receptor B1 (SCARB1; also known as SR-B1) gene. This mutation results in abnormal splicing, with the most abundant transcript lacking exon 4. Through functional assays, we further demonstrate that wild-type SCARB1 promotes cellular uptake of carotenoids but that this function is lost in the predominant mutant isoform in white recessive canaries. Our results indicate that SCARB1 is an essential mediator of the expression of carotenoid-based coloration in birds, and suggest a potential link between visual displays and lipid metabolism.


"Rules of Engagement" of Protein-Glycoconjugate Interactions: A Molecular View Achievable by using NMR Spectroscopy and Molecular Modeling.
Understanding the dynamics of protein-ligand interactions, which lie at the heart of host-pathogen recognition, represents a crucial step to clarify the molecular determinants implicated in binding events, as well as to optimize the design of new molecules with therapeutic aims. Over the last decade, advances in complementary biophysical and spectroscopic methods permitted us to deeply dissect the fine structural details of biologically relevant molecular recognition processes with high resolution. This Review focuses on the development and use of modern nuclear magnetic resonance (NMR) techniques to dissect binding events. These spectroscopic methods, complementing X-ray crystallography and molecular modeling methodologies, will be taken into account as indispensable tools to provide a complete picture of protein-glycoconjugate binding mechanisms related to biomedicine applications against infectious diseases.


Analysis of Hypo- and Hyperphosphatemia in an Intensive Care Unit Cohort.
Blood phosphate levels are vulnerable to fluctuations and changes in phosphate levels are often neglected. The aim of this study was to evaluate whether deviations in phosphate levels correlate to higher 180-day overall mortality or morbidity. Four thousand six hundred fifty-six patients with 19,467 phosphate values treated at the adult intensive care unit at Skåne University Hospital, Lund, Sweden during 2006-2014 were retrospectively divided into a control group and 3 study groups: hypophosphatemia, hyperphosphatemia, and a mixed group showing both hypo/hyperphosphatemia. Sex, age, disease severity represented by maximal organ system Sequential Organ Failure Assessment score, renal Sequential Organ Failure Assessment score, lowest ionized calcium value, and diagnoses classes were included in a Cox hazard model to adjust for confounding factors, with time to death in the first 180 days from the intensive care unit (ICU) admission as outcome. When compared to normophosphatemic controls, the hyperphosphatemic study group was associated with higher risk of death with a hazard ratio of 1.2 (98.3% confidence interval 1.0-1.5, P = .0089). Mortality in the hypophosphatemic or mixed study group did not differ from controls. The mixed group showed markedly longer ventilator times and ICU stays compared to all other groups. Phosphate alterations in ICU patients are common and associated with worse morbidity and mortality. Many underlying pathophysiologic mechanisms may play a role. A rapidly changing phosphate level or isolated hypo or hyperphosphatemia should be urgently corrected.


Individual differences reveal the basis of consonance.
Some combinations of musical notes are consonant (pleasant), whereas others are dissonant (unpleasant), a distinction central to music. Explanations of consonance in terms of acoustics, auditory neuroscience, and enculturation have been debated for centuries. We utilized individual differences to distinguish the candidate theories. We measured preferences for musical chords as well as nonmusical sounds that isolated particular acoustic factors--specifically, the beating and the harmonic relationships between frequency components, two factors that have long been thought to potentially underlie consonance. Listeners preferred stimuli without beats and with harmonic spectra, but across more than 250 subjects, only the preference for harmonic spectra was consistently correlated with preferences for consonant over dissonant chords. Harmonicity preferences were also correlated with the number of years subjects had spent playing a musical instrument, suggesting that exposure to music amplifies preferences for harmonic frequencies because of their musical importance. Harmonic spectra are prominent features of natural sounds, and our results indicate that they also underlie the perception of consonance.


Computerized clinical decision support systems for chronic disease management: a decision-maker-researcher partnership systematic review.
The use of computerized clinical decision support systems (CCDSSs) may improve chronic disease management, which requires recurrent visits to multiple health professionals, ongoing disease and treatment monitoring, and patient behavior modification. The objective of this review was to determine if CCDSSs improve the processes of chronic care (such as diagnosis, treatment, and monitoring of disease) and associated patient outcomes (such as effects on biomarkers and clinical exacerbations). We conducted a decision-maker-researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews database, Inspec, and reference lists for potentially eligible articles published up to January 2010. We included randomized controlled trials that compared the use of CCDSSs to usual practice or non-CCDSS controls. Trials were eligible if at least one component of the CCDSS was designed to support chronic disease management. We considered studies 'positive' if they showed a statistically significant improvement in at least 50% of relevant outcomes. Of 55 included trials, 87% (n = 48) measured system impact on the process of care and 52% (n = 25) of those demonstrated statistically significant improvements. Sixty-five percent (36/55) of trials measured impact on, typically, non-major (surrogate) patient outcomes, and 31% (n = 11) of those demonstrated benefits. Factors of interest to decision makers, such as cost, user satisfaction, system interface and feature sets, unique design and deployment characteristics, and effects on user workflow were rarely investigated or reported. A small majority (just over half) of CCDSSs improved care processes in chronic disease management and some improved patient health. Policy makers, healthcare administrators, and practitioners should be aware that the evidence of CCDSS effectiveness is limited, especially with respect to the small number and size of studies measuring patient outcomes.


A sensitive electrometer based on a Rydberg atom in a Schrödinger-cat state.
Fundamental quantum fluctuations caused by the Heisenberg principle limit measurement precision. If the uncertainty is distributed equally between conjugate variables of the meter system, the measurement precision cannot exceed the standard quantum limit. When the meter is a large angular momentum, going beyond the standard quantum limit requires non-classical states such as squeezed states or Schrödinger-cat-like states. However, the metrological use of the latter has been so far restricted to meters with a relatively small total angular momentum because the experimental preparation of these non-classical states is very challenging. Here we report a measurement of an electric field based on an electrometer consisting of a large angular momentum (quantum number J ≈ 25) carried by a single atom in a high-energy Rydberg state. We show that the fundamental Heisenberg limit can be approached when the Rydberg atom undergoes a non-classical evolution through Schrödinger-cat states. Using this method, we reach a single-shot sensitivity of 1.2 millivolts per centimetre for a 100-nanosecond interaction time, corresponding to 30 microvolts per centimetre per square root hertz at our 3 kilohertz repetition rate. This highly sensitive, non-invasive space- and time-resolved field measurement extends the realm of electrometric techniques and could have important practical applications: detection of individual electrons in mesoscopic devices at a distance of about 100 micrometres with a megahertz bandwidth is within reach.


Predicted temperature-increase-induced global health burden and its regional variability.
An increase in the global health burden of temperature was projected for 459 locations in 28 countries worldwide under four representative concentration pathway scenarios until 2099. We determined that the amount of temperature increase for each 100 ppm increase in global CO2 concentrations is nearly constant, regardless of climate scenarios. The overall average temperature increase during 2010-2099 is largest in Canada (1.16 °C/100 ppm) and Finland (1.14 °C/100 ppm), while it is smallest in Ireland (0.62 °C/100 ppm) and Argentina (0.63 °C/100 ppm). In addition, for each 1 °C temperature increase, the amount of excess mortality is increased largely in tropical countries such as Vietnam (10.34%p/°C) and the Philippines (8.18%p/°C), while it is decreased in Ireland (-0.92%p/°C) and Australia (-0.32%p/°C). To understand the regional variability in temperature increase and mortality, we performed a regression-based modeling. We observed that the projected temperature increase is highly correlated with daily temperature range at the location and vulnerability to temperature increase is affected by health expenditure, and proportions of obese and elderly population.


Cbfa1 is required for epithelial-mesenchymal interactions regulating tooth development in mice.
Osteoblasts and odontoblasts, cells that are responsible for the formation of bone and dentin matrices respectively, share several molecular characteristics. Recently, Cbfa1 was shown to be a critical transcriptional regulator of osteoblast differentiation. Mutations in this gene cause cleidocranial dysplasia (CCD), an autosomal dominant disorder in humans and mice characterized by defective bone formation. CCD also results in dental defects that include supernumerary teeth and delayed eruption of permanent dentition. The dental abnormalities in CCD suggest an important role for this molecule in the formation of dentition. Here we describe results of studies aimed at understanding the functions of Cbfa1 in tooth formation. RT-PCR and in situ hybridization analyses show that Cbfa1 has a unique expression pattern in dental mesenchyme from the bud to early bell stages during active epithelial morphogenesis. Unlike that observed in osteoblast differentiation, Cbfa1 is downregulated in fully differentiated odontoblasts and is surprisingly expressed in ectodermally derived ameloblasts during the maturation phase of enamel formation. The role of Cbfa1 in tooth morphogenesis is further illustrated by the misshapen and severely hypoplastic tooth organs in Cbfa1-/- mice. These tooth organs lacked overt odontoblast and ameloblast differentiation and normal dentin and enamel matrices. Epithelial-mesenchymal recombinants demonstrate that dental epithelium regulates mesenchymal Cbfa1 expression during the bud and cap stages and that these effects are mimicked by the FGFs but not by the BMPs as shown by our bead implantation assays. We propose that Cbfa1 regulates the expression of molecules in mesenchyme that act reciprocally on dental epithelium to control its growth and differentiation. Taken together, our data indicate a non-redundant role for Cbfa1 in tooth development that may be distinct from that in bone formation. In odontogenesis, Cbfa1 is not involved in the early signaling networks regulating tooth initiation and early morphogenesis but regulates key epithelial-mesenchymal interactions that control advancing morphogenesis and histodifferentiation of the epithelial enamel organ.


Impact of substance use disorders on recovery from episodes of depression in bipolar disorder patients: prospective data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).
Bipolar disorder is highly comorbid with substance use disorders, and this comorbidity may be associated with a more severe course of illness, but the impact of comorbid substance abuse on recovery from major depressive episodes in these patients has not been adequately examined. The authors hypothesized that comorbid drug and alcohol use disorders would be associated with longer time to recovery in patients with bipolar disorder. Subjects (N=3,750) with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were followed prospectively for up to 2 years. Prospectively observed depressive episodes were identified for this analysis. Subjects with a past or current drug or alcohol use disorder were compared with those with no history of drug or alcohol use disorders on time to recovery from depression and time until switch to a manic, hypomanic, or mixed episode. During follow up, 2,154 subjects developed a new-onset major depressive episode; of these, 457 subjects switched to a manic, hypomanic, or mixed episode prior to recovery. Past or current substance use disorder did not predict time to recovery from a depressive episode relative to no substance use comorbidity. However, those with current or past substance use disorder were more likely to experience switch from depression directly to a manic, hypomanic, or mixed state. Current or past substance use disorders were not associated with longer time to recovery from depression but may contribute to greater risk of switch into manic, mixed, or hypomanic states. The mechanism conferring this increased risk merits further study.


Analgesic conopeptides targeting G protein-coupled receptors reduce excitability of sensory neurons.
Conotoxins (conopeptides) are a diverse group of peptides isolated from the venom of marine cone snails. Conus peptides modulate pain by interacting with voltage-gated ion channels and G protein-coupled receptors (GPCRs). Opiate drugs targeting GPCRs have long been used, nonetheless, many undesirable side effects associated with opiates have been observed including addiction. Consequently, alternative avenues to pain management are a largely unmet need. It has been shown that various voltage-gated calcium channels (VGCCs) respond to GPCR modulation. Thus, regulation of VGCCs by GPCRs has become a valuable alternative in the management of pain. In this review, we focus on analgesic conotoxins that exert their effects via GPCR-mediated inhibition of ion channels involved in nociception and pain transmission. Specifically, α-conotoxin Vc1.1 activation of GABAB receptors and inhibition of voltage-gated calcium channels as a novel mechanism for reducing the excitability of dorsal root ganglion neurons is described. Vc1.1 and other α-conotoxins have been shown to be analgesic in different animal models of chronic pain. This review will outline the functional effects of conopeptide modulation of GPCRs and how their signalling is translated to downstream components of the pain pathways. Where available we present the proposed signalling mechanisms that couples metabotropic receptor activation to their downstream effectors to produce analgesia. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'


Behavioral and Physiological Health-Related Risk Factors in College Students.
The purpose of this study was to assess the behavioral and physiological health-related risk factors in college students. A cross-sectional study was conducted in 1620 college students (21.3 ± 1.7 years, 897 males, and 723 females). Physical activity (PA), sitting time, body composition, cardiorespiratory fitness (CRF), muscular endurance (ME), and blood test were assessed. In the total sample, 15.2% were not meeting PA guidelines, 33% were sedentary, 13.3% were obese, 10.7% had low CRF, 36.8% had poor ME, 33.7% had dyslipidemia and 5.9% presented with prediabetes. Obesity and poor CRF were more prevalent in male students, whereas inactivity was more prevalent in female students. Individuals with poor CRF were more likely to be obese (odds ratio = 5.2, 95% CI = 3.5-7.8, P = .007 for male students, and 9.4, 95% CI = 1.5-57.8, P = .021 for female students). Sitting time positively correlated with fat percentage (fat%) and inversely with lean body mass (LBM) in male students, whereas ME inversely correlated with fat% and positively with LBM in female students. Although most students were active, significant prevalence of health-related risk factors were observed. Sedentary behavior and poor fitness were associated with a compromised body composition in both sexes. Improving fitness and reducing sedentary behavior in college students could be a public health strategy for health promotion and chronic diseases prevention.


Brucellosis of ruminants in Bosnia and Herzegovina: disease status, past experiences and initiation of a new surveillance strategy.
The current animal health situation in Bosnia and Herzegovina requires the prioritization of diseases for the application of control measures. One of the diseases requiring high priority is brucellosis of ruminants. Brucellosis is a zoonotic infectious disease and one of the most important zoonoses in the world. Brucellosis has been recognized during the past five decades as an important infectious disease in ruminants in Bosnia and Herzegovina. Control and eradication of brucellosis in animals is based on test and slaughter control policy. When the existing brucellosis control program was instituted, the veterinary and animal production sector was almost exclusively owned by the government, an arrangement that promoted compliance with the program and resulted in the successful control of the disease. This paper provides an overview of the current institutional and legislative framework for brucellosis control including the laboratory detection system and the epidemiological status of brucellosis in ruminants in Bosnia and Herzegovina. Relevant data were collected during the period spanning from the beginning of 2001 until the middle of 2007. Data we collected reveal an increase in the number of reported outbreaks in ruminants as well as a related increase in the number of human cases. This has brought serious consequences to public health, animal health and production and international trade.


The clinical management of hepatocellular carcinoma worldwide: A concise review and comparison of current guidelines from 2001 to 2017.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. In this review, we made a review on current guidelines published from January 2001 to June 2017 worldwide with a focus on the clinical management of HCC. The electronic databases MEDLINE, the Chinese SinoMed, and the Japanese CiNii were systematically searched. A total of 18 characteristic guidelines for HCC management were finally included, including 8 guidelines from Asia, 5 from Europe, and 5 from the United States of America (USA). If guidelines were published in multiple versions, the most recent update was included, and surveillance, diagnosis, and treatment were compared. The composition of and recommendations in current guidelines on HCC varied, so these guidelines were regrouped and diagnostic and treatment algorithms were summarized graphically to provide the latest information to clinicians. The diagnostic criteria were grouped into 2 categories of a "Size-based pathway" and a "Non-size-based pathway." The treatment criteria were divided into 4 categories: i) Criteria based on the Barcelona Clinic Liver Cancer staging system; ii) Criteria based on the modified Union of International Cancer Control staging system; iii) Criteria based on the Child-Pugh class of liver function; and iv) Criteria based on tumor resectability. Findings from comparison of current guidelines might help target and concentrate efforts to improve the clinical management of HCC. However, further studies are needed to improve the management and outcomes of HCC. More straightforward or refined guidelines would help guide doctors to make better decisions in the treatment of HCC in the future.