Stimulation of somatostatin expression in developing ciliary ganglion neurons by cells of the choroid layer.
An important component of neuronal development is the matching of neurotransmitter expression with the appropriate target cell. We have examined how peptide transmitter expression is controlled in a simple model system, the avian ciliary ganglion (CG). This parasympathetic ganglion contains 2 distinct types of neurons: choroid neurons, which project to vasculature in the eye's choroid layer and use somatostatin as a co-transmitter with ACh, and ciliary neurons, which innervate the ciliary body and iris and use ACh but no known peptide co-transmitter. We have found that the earliest developmental stage in which neurons with somatostatinlike immunoreactivity (SOM-IR) are consistently found in vivo is stage 30 (embryonic day 6.5), a time shortly after the extension of neurites to targets in the eye's choroid layer. In cell culture, CG neurons expressed SOM-IR in co-culture with choroid cells, but not when cultured with striated muscle myotubes or with ganglion non-neuronal cells. No significant differences in neuronal survival or in ChAT activity were observed under these different co-culture conditions, which suggests that somatostatin expression is independently regulated. The stimulation of somatostatin expression was also specific in that other neuropeptides commonly found in autonomic neurons [neuropeptide Y (NPY), substance P (SP), vasoactive intestinal polypeptide (VIP)] were not induced in the presence of choroid cells. The ability to stimulate SOM-IR was not contact dependent because a macromolecule of greater than or equal to 10 kDa in choroid-conditioned medium (ChCM) was found to stimulate somatostatin expression in a dosage-dependent fashion. The somatostatin-stimulating activity induced SOM-IR in more than 90% of CG neurons, as well as in retrogradely labeled ciliary neurons, which would not normally express SOM-IR. Thus, the expression of somatostatin in cultured CG neurons is regulated by a macromolecule produced by cells in the choroid layer, a target normally innervated in vivo by CG neurons expressing somatostatin.


Hedgehog, transmitted along retinal axons, triggers neurogenesis in the developing visual centers of the Drosophila brain.
The development of the visual centers of the Drosophila brain is tightly regulated by the ingrowth of retinal axons from the developing eye. In the first optic ganglion, the lamina, arriving retinal axons trigger the precursors of their synaptic partners to complete a final cell division and commence neural differentiation. The secreted product of the hedgehog gene regulates the temporal assembly of photoreceptor precursor cells into ommatidial clusters in the compound eye. Here, we show that Hedgehog is transmitted along the retinal axons to serve as the inductive signal in the brain. Hedgehog acts in the first of two retinal axon-mediated steps in the assembly of lamina synaptic cartridges. These observations provide a novel insight into the molecular interactions that orchestrate the assembly of neural precursor cells into precise synaptic circuits.


Population substructure and control selection in genome-wide association studies.
Determination of the relevance of both demanding classical epidemiologic criteria for control selection and robust handling of population stratification (PS) represents a major challenge in the design and analysis of genome-wide association studies (GWAS). Empirical data from two GWAS in European Americans of the Cancer Genetic Markers of Susceptibility (CGEMS) project were used to evaluate the impact of PS in studies with different control selection strategies. In each of the two original case-control studies nested in corresponding prospective cohorts, a minor confounding effect due to PS (inflation factor lambda of 1.025 and 1.005) was observed. In contrast, when the control groups were exchanged to mimic a cost-effective but theoretically less desirable control selection strategy, the confounding effects were larger (lambda of 1.090 and 1.062). A panel of 12,898 autosomal SNPs common to both the Illumina and Affymetrix commercial platforms and with low local background linkage disequilibrium (pair-wise r(2)<0.004) was selected to infer population substructure with principal component analysis. A novel permutation procedure was developed for the correction of PS that identified a smaller set of principal components and achieved a better control of type I error (to lambda of 1.032 and 1.006, respectively) than currently used methods. The overlap between sets of SNPs in the bottom 5% of p-values based on the new test and the test without PS correction was about 80%, with the majority of discordant SNPs having both ranks close to the threshold. Thus, for the CGEMS GWAS of prostate and breast cancer conducted in European Americans, PS does not appear to be a major problem in well-designed studies. A study using suboptimal controls can have acceptable type I error when an effective strategy for the correction of PS is employed.


Examining the impact of differential cultural adaptation with Latina/o immigrants exposed to adapted parent training interventions.
There is a dearth of empirical studies aimed at examining the impact of differential cultural adaptation of evidence-based clinical and prevention interventions. This prevention study consisted of a randomized controlled trial aimed at comparing the impact of 2 differentially culturally adapted versions of the evidence-based parenting intervention known as Parent Management Training, the Oregon Model (PMTOR). The sample consisted of 103 Latina/o immigrant families (190 individual parents). Each family was allocated to 1 of 3 conditions: (a) a culturally adapted PMTO (CA), (b) culturally adapted and enhanced PMTO (CE), and (c) a wait-list control. Measurements were implemented at baseline (T1), treatment completion (T2) and 6-month follow up (T3). Multilevel growth modeling analyses indicated statistically significant improvements on parenting skills for fathers and mothers (main effect) at 6-month follow-up in both adapted interventions, when compared with the control condition. With regard to parent-reported child behaviors, child internalizing behaviors were significantly lower for both parents in the CE intervention (main effect), compared with control at 6-month follow-up. No main effect was found for child externalizing behaviors. However, a Parent × Condition effect was found indicating a significant reduction of child externalizing behaviors for CE fathers compared with CA and control fathers at posttest and 6-month follow-up. Present findings indicate the value of differential cultural adaptation research designs and the importance of examining effects for both mothers and fathers, particularly when culturally focused and gender variables are considered for intervention design and implementation. (PsycINFO Database Record


(-)-Phenserine Ameliorates Contusion Volume, Neuroinflammation, and Behavioral Impairments Induced by Traumatic Brain Injury in Mice.
Traumatic brain injury (TBI), a major cause of mortality and morbidity, affects 10 million people worldwide, with limited treatment options. We have previously shown that (-)-phenserine (Phen), an acetylcholinesterase inhibitor originally designed and tested in clinical phase III trials for Alzheimer's disease, can reduce neurodegeneration after TBI and reduce cognitive impairments induced by mild TBI. In this study, we used a mouse model of moderate to severe TBI by controlled cortical impact to assess the effects of Phen on post-trauma histochemical and behavioral changes. Animals were treated with Phen (2.5 mg/kg, IP, BID) for 5 days started on the day of injury and the effects were evaluated by behavioral and histological examinations at 1 and 2 weeks after injury. Phen significantly attenuated TBI-induced contusion volume, enlargement of the lateral ventricle, and behavioral impairments in motor asymmetry, sensorimotor functions, motor coordination, and balance functions. The morphology of microglia was shifted to an active from a resting form after TBI, and Phen dramatically reduced the ratio of activated to resting microglia, suggesting that Phen also mitigates neuroinflammation after TBI. While Phen has potent anti-acetylcholinesterase activity, its (+) isomer Posiphen shares many neuroprotective properties but is almost completely devoid of anti-acetylcholinesterase activity. We evaluated Posiphen at a similar dose to Phen and found similar mitigation in lateral ventricular size increase, motor asymmetry, motor coordination, and balance function, suggesting the improvement of these histological and behavioral tests by Phen treatment occur via pathways other than anti-acetylcholinesterase inhibition. However, the reduction of lesion size and improvement of sensorimotor function by Posiphen were much smaller than with equivalent doses of Phen. Taken together, these results show that post-injury treatment with Phen over 5 days significantly ameliorates severity of TBI. These data suggest a potential development of this compound for clinical use in TBI therapy.


Abrogation of experimental colitis correlates with increased apoptosis in mice deficient for CD44 variant exon 7 (CD44v7).
Experimental colitis in mice is characterized by infiltration of activated T helper (Th) cells and macrophages into the lamina propria. Particularly, these cells expressed CD44 variant exon 7 (CD44v7)-containing isoforms. Upregulation of CD44v7 isoforms was induced by CD40 ligation, an inflammation-driving interaction between activated Th cells and macrophages. To define the role of CD44v7 in colitis, mice bearing a targeted deletion for exon v7 were generated. In trinitrobenzene sulfonic acid-induced colitis, wild-type mice developed severe signs of persistent inflammation. Mice lacking CD44v7 initially showed unspecific inflammation, then recovered completely. The pathogenic origin was shown to reside in bone marrow-derived CD44v7(+) cells, because adoptive transfer experiments demonstrated an absolute requirement for CD44v7 on hematopoietic cells for maintenance of colitis. Interleukin (IL)-10-deficient mice, which develop a chronic Th1-driven enterocolitis, were crossbred with CD44v6/v7 null mice. In IL-10 x CD44v6/v7 double deficient mice, intestinal inflammation developed only weakly and at an older age. Analysis of cell death in the inflamed lesions revealed that mononuclear cells in the CD44v7 null infiltrates had higher rates of apoptosis than those from wild-type mice. Thus, the region encoded by CD44v7 appears to be essential for survival of effector lymphocytes, resulting in persistence of inflammation.


Do "conditions contributing to the death" clarify the predictors of infant mortality in Texas?
Predictors of infant mortality are usually based on the underlying causes reported on infant death certificates. Death certificates also contain space for "Other significant conditions contributing to the death but not resulting in the underlying cause." We investigated whether these "contributing conditions" might clarify the predictors of infant death in Texas or interventions that might reduce deaths from the underlying causes. A "multiple cause of death" file converted the underlying causes and contributing conditions associated with each infant death in 1996 into International Classification of Diseases codes. We ranked the major underlying causes, the conditions contributing to those causes, the conditions contributing to all infant deaths, and the effect of combining the underlying causes with contributing conditions to determine the main predictors of infant mortality. We found that extreme immaturity was the most common condition, causing or contributing to 604 of the 2081 deaths in 1996. We conclude that the underlying causes provide a misleading perception of the major predictors of infant death in Texas; combining them with the conditions contributing to those deaths provides a clearer picture. Given the powerful predictive value of preterm birth for infant mortality, the limited current ability to prevent preterm birth, and the cost of its complications, expanded efforts to improve understanding of its causal processes and develop preventive strategies should be top national and state priorities.


Breed-specific hematological phenotypes in the dog: a natural resource for the genetic dissection of hematological parameters in a mammalian species.
Remarkably little has been published on hematological phenotypes of the domestic dog, the most polymorphic species on the planet. Information on the signalment and complete blood cell count of all dogs with normal red and white blood cell parameters judged by existing reference intervals was extracted from a veterinary database. Normal hematological profiles were available for 6046 dogs, 5447 of which also had machine platelet concentrations within the reference interval. Seventy-five pure breeds plus a mixed breed control group were represented by 10 or more dogs. All measured parameters except mean corpuscular hemoglobin concentration (MCHC) varied with age. Concentrations of white blood cells (WBCs), neutrophils, monocytes, lymphocytes, eosinophils and platelets, but not red blood cell parameters, all varied with sex. Neutering status had an impact on hemoglobin concentration, mean corpuscular hemoglobin (MCH), MCHC, and concentrations of WBCs, neutrophils, monocytes, lymphocytes and platelets. Principal component analysis of hematological data revealed 37 pure breeds with distinctive phenotypes. Furthermore, all hematological parameters except MCHC showed significant differences between specific individual breeds and the mixed breed group. Twenty-nine breeds had distinctive phenotypes when assessed in this way, of which 19 had already been identified by principal component analysis. Tentative breed-specific reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis. This study represents the first large-scale analysis of hematological phenotypes in the dog and underlines the important potential of this species in the elucidation of genetic determinants of hematological traits, triangulating phenotype, breed and genetic predisposition.


A unified concept of idiopathic orofacial pain: clinical features.
The main features of atypical facial pain, stomatodynia, atypical odontalgia, and masticatory muscle and temporomandibular joint (TMJ) disorders are compared in this article, which included a search of articles indexed in MEDLINE. The fact that their terminology has been the subject of many debates can be considered a consequence of taxonomic difficulties and uncertainties. Epidemiologic studies indicate marked female predominance for all types of idiopathic orofacial pain. There is also a difference in the age of maximal prevalence between masticatory muscle and TMJ disorders and the other entities. The clinical presentations display several symptoms in common. Pain is oral, perioral, or facial and does not follow a nervous pathway. It has been present for the last 4 to 6 months or has returned periodically in the same form over a period of several months or years. The pain is continuous, has no major paroxysmal character, and is present throughout all or part of the day. It is generally absent during sleep. Clinical, radiographic, or laboratory examination does not reveal any obvious organic cause of pain. There is also a frequent presence of certain psychologic factors, personality traits, or life events. Based on these shared characteristics, a unified concept is proposed. Each of these entities belongs to a group of idiopathic orofacial pain and could be expressed in either the jaws, the buccal mucosa, the teeth, the masticatory muscles, or the TMJ.


Associations Between Pain, Current Tobacco Smoking, Depression, and Fibromyalgia Status Among Treatment-Seeking Chronic Pain Patients.
As smoking impacts physiological pathways in the central nervous system, it is important to consider the association between smoking and fibromyalgia, a pain condition caused predominantly by central nervous system dysfunction. The objectives were to assess the prevalence of current smoking among treatment-seeking chronic pain patients with (FM+) and without (FM-) a fibromyalgia-like phenotype; test the individual and combined influence of smoking and fibromyalgia on pain severity and interference; and examine depression as a mediator of these processes. Questionnaire data from 1566 patients evaluated for a range of conditions at an outpatient pain clinic were used. The 2011 Survey Criteria for Fibromyalgia were used to assess the presence of symptoms associated with fibromyalgia. Current smoking was reported by 38.7% of FM+ patients compared to 24.7% of FM- patients. FM+ smokers reported higher pain and greater interference compared to FM+ nonsmokers, FM- smokers, and FM- nonsmokers. There was no interaction between smoking and fibromyalgia. Significant indirect effects of fibromyalgia and smoking via greater depression were observed for pain severity and interference. Current smoking and positive fibromyalgia status were associated with greater pain and impairment among chronic pain patients, possibly as a function of depression. Although FM+ smokers report the most negative clinical symptomatology (i.e., high pain, greater interference) smoking does not appear to have a unique association with pain or functioning in FM+ patients, rather the effect is additive. The 38.7% smoking rate in FM+ patients is high, suggesting FM+ smokers present a significant clinical challenge.


Nutrition competencies in health professionals' education and training: a new paradigm.
Most health care professionals are not adequately trained to address diet and nutrition-related issues with their patients, thus missing important opportunities to ameliorate chronic diseases and improve outcomes in acute illness. In this symposium, the speakers reviewed the status of nutrition education for health care professionals in the United States, United Kingdom, and Australia. Nutrition education is not required for educating and training physicians in many countries. Nutrition education for the spectrum of health care professionals is uncoordinated, which runs contrary to the current theme of interprofessional education. The central role of competencies in guiding medical education was emphasized and the urgent need to establish competencies in nutrition-related patient care was presented. The importance of additional strategies to improve nutrition education of health care professionals was highlighted. Public health legislation such as the Patient Protection and Affordable Care Act recognizes the role of nutrition, however, to capitalize on this increasing momentum, health care professionals must be trained to deliver needed services. Thus, there is a pressing need to garner support from stakeholders to achieve this goal. Promoting a research agenda that provides outcome-based evidence on individual and public health levels is needed to improve and sustain effective interprofessional nutrition education.


Invasive pneumococcal disease in young children before licensure of 13-valent pneumococcal conjugate vaccine - United States, 2007.
Invasive pneumococcal disease (IPD), caused by Streptococcus pneumoniae (pneumococcus), remains a leading cause of serious illness in children and adults worldwide. After routine infant immunization with a 7-valent pneumococcal conjugate vaccine (PCV7) began in 2000, IPD among children aged <5 years in the United States decreased by 76%; however, IPD from non-PCV7 serotypes, particularly 19A, has increased. In February 2010, the Advisory Committee on Immunization Practices (ACIP) issued recommendations for use of a newly licensed 13-valent pneumococcal conjugate vaccine (PCV13). PCV13 contains the seven serotypes in PCV7 (4, 6B, 9V, 14, 18C, 19F, and 23F) and six additional serotypes (1, 3, 5, 6A, 7F, and 19A). To characterize the potentially vaccine-preventable IPD burden among children aged <5 years in the United States, CDC and investigators analyzed 2007 data from Active Bacterial Core surveillance (ABCs). This report summarizes the results of that analysis, which found that among 427 IPD cases with known serotype in children aged <5 years, 274 (64%) were caused by serotypes contained in PCV13. In 2007, an estimated 4,600 cases of IPD occurred in children in this age group in the United States, including approximately 2,900 cases caused by serotypes covered in PCV13 (versus 70 cases caused by PCV7 serotypes). PCV13 use has the potential to further reduce IPD in the United States. Post-licensure monitoring will help characterize the effectiveness of PCV13 in different populations and track the potential changes in disease burden caused by non-PCV13 serotypes.


Preliminary results on the atmospheres of io and jupiter from the pioneer 10 s-band occultation experiment.
The preliminary analysis of data from the Pioneer 10 S-band radio occultation experinment has revealed the presence of an ionosphere on the Jovian satellite Io (JI) having an electron density peak of about 6 x 10(4) electrons per cubic centimeter at an altitude of approximately 60 to 140 kilometers. This suggests the presence of an atmosphere having a surface number density of about 10(10) to 10(12) per cubic centimeter, corresponding to an atmospheric surface pressure of between 10(-8) and 10(-10) bar, at or below the detection threshold of the Beta Scorpii stellar occultation. A measurement of the atmosphere of Jupiter was obtained down to the level of about 80 millibars, indicating a large temperature increase at about the 20 millibar level, which cannot be explained by the absorption of solar radiation by methane alone and can possibly be due to absorption by particulate matter.


Exploring the potential for using results-based financing to address non-communicable diseases in low- and middle-income countries.
The burden of disease due to non-communicable diseases (NCDs) is rising in low- and middle-income countries (LMICs) and funding for global health is increasingly limited. As a large contributor of development assistance for health, the US government has the potential to influence overall trends in NCDs. Results-based financing (RBF) has been proposed as a strategy to increase aid effectiveness and efficiency through incentives for positive performance and results in health programs, but its potential for addressing NCDs has not been explored. Qualitative methods including literature review and key informant interviews were used to identify promising RBF mechanisms for addressing NCDs in resource-limited settings. Eight key informants identified by area of expertise participated in semi-structured interviews. The majority of RBF schemes to date have been applied to maternal and child health. Evidence from existing RBF programs suggests that RBF principles can be applied to health programs for NCDs. Several options were identified for US involvement with RBF for NCDs. There is potential for the US to have a significant impact on NCDs in LMICs through a comprehensive RBF strategy for global health. RBF mechanisms should be tested for use in NCD programs through pilot programs incorporating robust impact evaluations.


From Negative Emotionality to Aggressive Behavior: Maternal and Paternal Parenting Stress as Intervening Factors.
Child temperament plays a key role in the development of psychopathology, notably through transactions with the family environment. In particular, temperamental negative emotionality is a documented antecedent of child aggressive behavior, with parenting stress sometimes proposed to play a mediating role in this association. However, research has mostly addressed bivariate associations and seldom considered the full chain linking child negative emotionality to aggression through parenting stress. In addition, most relevant studies have focused on mothers; therefore, possible combined contributions of maternal and paternal stress, such as interactive effects, are under-investigated. Addressing these gaps, this longitudinal multi-informant study aimed to examine the mediating role of maternal parenting stress, paternal parenting stress, and their interaction in the association between infant negative emotionality and child aggression. Among 186 mostly White middle-class families (98 boys), infant negative emotionality was reported by mothers and fathers at 15 months, both parents reported on their own parenting stress at 3 years, and child aggression was assessed by teachers in the first grade of elementary school. The results revealed a moderated mediated pathway, such that there was a significant indirect effect of child negative emotionality on aggression through paternal stress, however only when maternal stress was also high. These findings suggest that the risk of negative emotionality translating to aggressive behavior is magnified when both parents experience high levels of stress in their parenting role. The results also underscore that both parents play significant yet different roles in the process linking early negative emotionality to subsequent aggression.


Predicting psychological mindedness from personality style and attachment security.
The aim of this study was to increase the construct validity of the Psychological Mindedness Scale (PM Scale) by investigating its relationship to well-established measures of personality style (NEO Five-Factor Inventory) and attachment security (Inventory of Parent and Peer Attachment). Personality and attachment variables functioned as differential predictors of psychological mindedness (PM). Openness to Experience emerged as the best predictor of PM, followed by Extraversion, Neuroticism (inversely related to PM), and Attachment to Peers. Neither Attachment to Mother nor Attachment to Father predicted PM. The results of this study indicate that PM is related positively to healthy, rather than pathological, personal and interpersonal constructs.


The spatial extent of 20th-century warmth in the context of the past 1200 years.
Periods of widespread warmth or cold are identified by positive or negative deviations that are synchronous across a number of temperature-sensitive proxy records drawn from the Northern Hemisphere. The most significant and longest duration feature during the last 1200 years is the geographical extent of warmth in the middle to late 20th century. Positive anomalies during 890 to 1170 and negative anomalies during 1580 to 1850 are consistent with the concepts of a Medieval Warm Period and a Little Ice Age, but comparison with instrumental temperatures shows the spatial extent of recent warmth to be of greater significance than that during the medieval period.


Oxidation triggers guest dissociation during reorganization of an FeII 4L6 twisted parallelogram.
A three-dimensional FeII 4L6 parallelogram was prepared from ferrocene-containing ditopic ligands. The steric preference of the bulky ferrocene cores towards meridional vertex coordination brought about this new structure type, in which the ferrocene units adopt three distinct conformations. The structure possesses two distinct, bowl-like cavities that host anionic guests. Oxidation of the ferrocene FeII to ferrocenium FeIII causes rotation of the ferrocene hinges, converting the structure to an FeII 1L1 + species with release of anionic guests, even though the average charge per iron increases in a way that would ordinarily increase guest binding strength. The degrees of freedom exhibited by these new structures - derived from the different configurations of the three ligands surrounding a meridional FeII center and the rotation of ferrocene cores - thus underpin their ability to reconfigure and eject guests upon oxidation.


Lacto-N-fucopentaose III, a pentasaccharide, prolongs heart transplant survival.
Lacto-N-fucopentaose III (LNFPIII) is a pentasaccharide containing the Lewis(x) trisaccharide that is found on schistosome eggs and in breast milk. LNFPIII conjugates suppress host immune responses and have therapeutic efficacy in mouse models of psoriasis and type 1 diabetes. We used nonvascularized neonatal ear-heart transplantation and heterotopic vascularized heart transplantation models to evaluate immunosuppressive effects of LNFPIII and subsequently analyzed the mechanism. We found that administration of LNFPIII conjugates prolonged median graft survival by 80% when 1-day-old DBA/2 hearts were transplanted into ears of B6 mice. A similar graft prolongation was observed in a fully vascularized heterotopic heart transplantation model (DBA/2 into B6), No prolongation was observed with carrier protein (human serum albumin [HSA] or dextran) alone. We found increased programmed death ligand 1 (PD-L1) expression on F4/80 macrophages, CD4+ T cells, and CD11b+ CD11c+ (myeloid) dendritic cells, and increased arginase1 and Ym1 expression, typical of alternatively activated macrophages, in the draining (cervical) lymph node cells. We found accumulation of Foxp3+ regulatory T cells (Tregs) in the lymph nodes draining donor hearts, suggesting a possible role of Treg induction in graft prolongation. Anti-PD-L1 antibody treatment abrogated LNFPIII-mediated the graft survival benefit and Treg accumulation. LNFPIII-treated macrophages had increased PD-L1 expression and significantly prolonged DBA/2 allograft survival when injected intraperitoneally into B6 recipient mice. LNFPIII prolongs fully allogeneic graft survival in both vascularized and nonvascularized allograft transplantation models. The mechanism of graft prolongation seems to involve both alternatively activated PDL-1 macrophages and recruitment of Foxp3+ Treg cells.


Epidemiology of home enteral nutrition: an approximation to reality.
home enteral nutrition (HEN) has undergone an important development; however, there is a notable lack of information with regard to its incidence and characteristics. our aim was to assess the state of HEN in our area. an observational, prospective study, involving all patients who had initiated HEN in the Nutrition Unit during a year. Epidemiological, functional, and nutritional evolution of the patients was described and incidence of HEN was calculated. HEN incidences totalled 229/100,000 inhabitants/year. The HEN population in our area was characterized by the aged and a high frequency of comorbidity and functional limitations. Neurological and oncological diseases accounted for 50% of indications. The remaining cases were malnourished patients who had received short periods of HEN after hospitalization or a hip fracture. Oral supplements (60%) with standard and hypercaloric formulas were used the most. At baseline, 75% of the patients suffered from malnutrition. During the follow-up, patients showed weight gain (1.6%), an increase in the percentage of normal weight and overweight (from 74% to 82.7%, p = 0.001) and a reduction in pressure ulcers (15.7% vs10.3%, p < 0.001). The median duration of HEN was 8.5 months. Only a quarter of the patients experienced complications (mostly mild gastrointestinal complications); 43.1% had died at the end of the follow-up. in our area, the HEN incidence was much higher than those described in the literature. HEN appears to be a safe therapy with few complications that improves the nutritional status of the patients, even with short periods of administration.


Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus.
BMS-200475 is a novel carbocyclic 2'-deoxyguanosine analog found to possess potent and selective anti-hepatitis B virus (anti-HBV) activity. BMS-200475 is distinguished from guanosine by replacement of the natural furanose oxygen on the sugar moiety with an exo carbon-carbon double bond. In the HepG2 stably transfected cell line 2.2.15, BMS-200475 had a 50% effective concentration (EC50) of 3.75 nM against HBV, as determined by analysis of secreted HBV DNA. Structurally related compounds with adenine, iodouracil, or thymine base substitutions were significantly less potent or were inactive. Direct comparison of the antiviral activities of BMS-200475 with those of a variety of other nucleoside analogs, including lamivudine (EC50 = 116.26 nM), demonstrated the clearly superior in vitro potency of BMS-200475 in 2.2.15 cells. Intracellular HBV replicative intermediates were uniformly reduced when cells were treated with BMS-200475, but rebounded after treatment was terminated. The concentration of BMS-200475 causing 50% cytotoxicity in 2.2.15 cell cultures was 30 microM, approximately 8,000-fold greater than the concentration required to inhibit HBV replication in the same cell line. Treatment with BMS-200475 resulted in no apparent inhibitory effects on mitochondrial DNA content.


Analysis of Prophylactic Salpingo-oophorectomy at the Time of Hysterectomy for Benign Lesions.
Prophylactic salpingo-oophorectomy refers to the removal of clinically normal ovaries at the time of hysterectomy for benign lesions, to reduce the risk of ovarian and breast cancer in future. This risk reduction holds true for high-risk women, i.e., those with strong family history of breast or/and ovarian cancer and those who carry germline mutations (BRCA-1 and BRCA-2). However, it is still one of the commonly performed surgeries in low-risk women and has fallen into controversy. It is said that the number needed to treat is 300. The aim of the study was to analyze and understand the reasons behind women opting for prophylactic oophorectomy in spite of the available evidence. We also aimed to study the histopathology reports of the ovaries and tubes removed prophylactically. This was a prospective study carried out at a tertiary care center which serves both rural and urban population. Of the 252 patients counseled, 86 patients who opted for prophylactic salpingo-oophorectomy were included in the study. A detailed history, clinical examination, relevant investigations (ultrasonography and CA 125 levels), indications for hysterectomy, reasons for prophylactic oophorectomy, intraoperative findings, and the histopathology findings were noted. Main reasons for opting for prophylactic oophorectomy were lack of understanding and thus dependent on their treating doctor for the decision-making, fear of ovarian malignancy in future, inability to follow-up, and previous one or more abdominal surgeries. We as gynecologists need to reconsider the age at which we recommend prophylactic oophorectomy. Too much negative counseling should be deferred.


Genetic Diversity in Lens Species Revealed by EST and Genomic Simple Sequence Repeat Analysis.
Low productivity of pilosae type lentils grown in South Asia is attributed to narrow genetic base of the released cultivars which results in susceptibility to biotic and abiotic stresses. For enhancement of productivity and production, broadening of genetic base is essentially required. The genetic base of released cultivars can be broadened by using diverse types including bold seeded and early maturing lentils from Mediterranean region and related wild species. Genetic diversity in eighty six accessions of three species of genus Lens was assessed based on twelve genomic and thirty one EST-SSR markers. The evaluated set of genotypes included diverse lentil varieties and advanced breeding lines from Indian programme, two early maturing ICARDA lines and five related wild subspecies/species endemic to the Mediterranean region. Genomic SSRs exhibited higher polymorphism in comparison to EST SSRs. GLLC 598 produced 5 alleles with highest gene diversity value of 0.80. Among the studied subspecies/species 43 SSRs detected maximum number of alleles in L. orientalis. Based on Nei's genetic distance cultivated lentil L. culinaris subsp. culinaris was found to be close to its wild progenitor L. culinaris subsp. orientalis. The Prichard's structure of 86 genotypes distinguished different subspecies/species. Higher variability was recorded among individuals within population than among populations.


Immune and neurotrophin stimulation by electroconvulsive therapy: is some inflammation needed after all?
A low-grade inflammatory response is commonly seen in the peripheral blood of major depressive disorder (MDD) patients, especially those with refractory and chronic disease courses. However, electroconvulsive therapy (ECT), the most drastic intervention reserved for these patients, is closely associated with an enhanced haematogenous as well as neuroinflammatory immune response, as evidenced by both human and animal studies. A related line of experimental evidence further shows that inflammatory stimulation reinforces neurotrophin expression and may even mediate dramatic neurogenic and antidepressant-like effects following exposure to chronic stress. The current review therefore attempts a synthesis of our knowledge on the neurotrophic and immunological aspects of ECT and other electrically based treatments in psychiatry. Perhaps contrary to contemporary views, we conclude that targeted potentiation, rather than suppression, of inflammatory responses may be of therapeutic relevance to chronically depressed patients or a subgroup thereof.


Long-range depth imaging using a single-photon detector array and non-local data fusion.
The ability to measure and record high-resolution depth images at long stand-off distances is important for a wide range of applications, including connected and automotive vehicles, defense and security, and agriculture and mining. In LIDAR (light detection and ranging) applications, single-photon sensitive detection is an emerging approach, offering high sensitivity to light and picosecond temporal resolution, and consequently excellent surface-to-surface resolution. The use of large format CMOS (complementary metal-oxide semiconductor) single-photon detector arrays provides high spatial resolution and allows the timing information to be acquired simultaneously across many pixels. In this work, we combine state-of-the-art single-photon detector array technology with non-local data fusion to generate high resolution three-dimensional depth information of long-range targets. The system is based on a visible pulsed illumination system at a wavelength of 670 nm and a 240 × 320 array sensor, achieving sub-centimeter precision in all three spatial dimensions at a distance of 150 meters. The non-local data fusion combines information from an optical image with sparse sampling of the single-photon array data, providing accurate depth information at low signature regions of the target.


Influences on prescribing in non-fundholding general practices.
The experience from general practice fundholding suggests that financial incentives may influence prescribing; guidelines and hospital prescribing are two other suggested influences. A study was undertaken to establish general practitioners' attitudes to a financial prescribing incentive scheme, the presence and use of guidelines, and the influence of prescribing initiated within secondary care. A postal questionnaire survey of non-fundholding general practices in the former Northern Region was conducted. Practices' thinking and subsequent decisions about the incentive prescribing scheme were most often influenced by discussions within the practice (45%). Those practices that achieved their savings under the incentive scheme were less likely than those not achieving savings to feel that the target was not achievable, the time scale was unacceptable, and that the philosophy behind the scheme was unacceptable. Forty-five per cent of practices received advice from neither a medical nor a pharmaceutical adviser; 27% of practices received advice from both, 12% from a medical adviser only and 16% from a pharmaceutical adviser only. Of the practices that tried to make their target savings, 91% intended to increase generic prescribing; fewer than one-third of practices mentioned any other measure. Prescribing guidelines were reported by a minority of practices, although reported rates of use were high when these were present. Clinical guidelines for three conditions, asthma, diabetes and hypertension, were present in more than 50% of practices; 25% of practices had no clinical guidelines. Hospital prescribing was reported as 'always' or 'usually' influencing prescribing for diabetes by 57% of respondents, ischaemic heart disease by 55%, peptic ulceration by 49%, asthma by 42% and hypertension by 39%. General practitioner prescribing is influenced by a complex web of factors, with no single factor pre-eminent. To understand this area further, there is a need to take each of these areas and ascertain the match between doctors' perceptions and actual practice.


Muscle power and metabolism in maximal intermittent exercise.
Muscle power and the associated metabolic changes in muscle were investigated in eight male human subjects who performed four 30-s bouts of maximal isokinetic cycling at 100 rpm, with 4-min recovery intervals. In the first bout peak power and total work were (mean +/- SE) 1,626 +/- 102 W and 20.83 +/- 1.18 kJ, respectively; muscle glycogen decreased by 18.2 mmol/kg wet wt, lactate increased to 28.9 +/- 2.7 mmol/kg, and there were up to 10-fold increases in glycolytic intermediates. External power and work decreased by 20% in both the second and third exercise periods, but no further change occurred in the fourth bout. Muscle glycogen decreased by an additional 14.8 mmol/kg after the second exercise and thereafter remained constant. Muscle adenosine triphosphate (ATP) was reduced by 40% from resting after each exercise period; creatine phosphate (CP) decreased successively to less than 5% of resting; in the recovery periods ATP and CP increased to 76 and 95% of initial resting levels, respectively. Venous plasma glycerol increased linearly to 485% of resting; free fatty acids did not change. Changes in muscle glycogen, lactate, and glycolytic intermediates suggested rate limitation at phosphofructokinase during the first and second exercise periods, and phosphorylase in the third and fourth exercise periods. Despite minimal glycolytic flux in the third and fourth exercise periods, subjects generated 1,000 W peak power and sustained 400 W for 30 s, 60% of the values recorded in the first exercise period.(ABSTRACT TRUNCATED AT 250 WORDS)


Interferon β for secondary progressive multiple sclerosis: a systematic review.
It is unclear whether recombinant β interferons (IFNβ) can be effective in secondary progressive multiple sclerosis (SPMS). The aim was to determine whether IFNβ can reduce the risk of disability and cognitive impairment progression in SPMS. Using Cochrane methodology, we reviewed all randomised placebo controlled trials of IFNβ in SPMS patients (1995-March 2012). 5 trials (3082 patients) were included. After 3 years, interferons did not reduce disability progression, confirmed at 6 months (RR 0.98, 95% CI 0.82 to 1.16). A small reduction in the number of patients who had relapses during the first 3 years of treatment (RR 0.91, 0.84 to 0.97) was found. No analysis of cognitive data was possible. More treated than placebo patients dropped out for adverse events. 3 year treatment with IFNβ does not delay permanent disability in SPMS but reduces relapse risk, indicating that the anti-inflammatory effect of IFNβ is unable to prevent MS progression once it has become established.


Predicting poaching risk in marine protected areas for improved patrol efficiency.
Marine Protected Areas (MPAs) are effective resource management and conservation measures, but their success is often hindered by non-compliant activities such as poaching. Understanding the risk factors and spatial patterns of poaching is therefore crucial for efficient law enforcement. Here, we conducted explanatory and predictive modelling of poaching from recreational fishers within no-take zones of Australia's Great Barrier Reef Marine Park (GBRMP) using Boosted Regression Trees (BRT). Combining patrol effort data, observed distribution of reported incidents, and spatially-explicit environmental and human risk factors, we modeled the occurrence probability of poaching incidents and mapped poaching risk at fine-scale. Our results: (i) show that fishing attractiveness, accessibility and fishing capacity play a major role in shaping the spatial patterns of poaching; (ii) revealed key interactions among these factors as well as tipping points beyond which poaching risk increased or decreased markedly; and (iii) highlight gaps in patrol effort that could be filled for improved resource allocation. The approach developed through this study provide a novel way to quantify the relative influence of multiple interacting factors in shaping poaching risk, and hold promises for replication across a broad range of marine or terrestrial settings.


How Can Respectfulness in Medical Professionals Be Increased? A Complex But Important Question.
Respectfulness is demanded of doctors and predicts more positive patient health-related outcomes, but research is scarce on ways to promote it. This study explores two ways to conceptualize unconditional respect from medical students, defined as respect paid to people on the basis of their humanity, in order to inform strategies to increase it. Unconditional respect conceptualized as an attitude suggests that unconditional respect and conditional respect are additive, whereas unconditional respect conceptualized as a personality trait suggests that people who are high on unconditional respect afford equal respect to all humans regardless of their merits. One hundred and eighty-one medical students completed an unconditional respect measure then read a description of a respect-worthy or a non-respect-worthy man and indicated their respect towards him. The study found a main effect for unconditional respect and a main effect for target respect-worthiness but no interaction between the two when respect paid to the target was assessed, supporting the attitude-based conceptualization. This suggests that unconditional respect can be increased through relevant interventions aimed at increasing the relative salience to doctors of the human worth of individuals. Interventions to increase unconditional respect are discussed.


Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence.
Twist1 and Twist2 are major regulators of embryogenesis. Twist1 has been shown to favor the metastatic dissemination of cancer cells through its ability to induce an epithelial-mesenchymal transition (EMT). Here, we show that a large fraction of human cancers overexpress Twist1 and/or Twist2. Both proteins override oncogene-induced premature senescence by abrogating key regulators of the p53- and Rb-dependent pathways. Twist1 and Twist2 cooperate with Ras to transform mouse embryonic fibroblasts. Interestingly, in epithelial cells, the oncogenic cooperation between Twist proteins and activated mitogenic oncoproteins, such as Ras or ErbB2, leads to complete EMT. These findings suggest an unanticipated direct link between early escape from failsafe programs and the acquisition of invasive features by cancer cells.


Do chiropractic college faculty understand informed consent: a pilot study.
The purpose of this study was to survey full-time faculty at a single chiropractic college concerning their knowledge of Institutional Review Board (IRB) policies in their institution as they pertain to educational research. All full-time faculty were invited to participate in an anonymous survey. Four scenarios involving educational research were described and respondents were asked to select from three possible courses of action for each. In addition, respondents were queried about their knowledge of IRB policies, how they learned of these policies and about their years of service and departmental assignments. The response rate was 55%. In no scenario did the level of correct answers by all respondents score higher than 41% and in most, the scores were closer to just under 1 in 3. Sixty-five percent of respondents indicated they were unsure whether Palmer had any policies in place at all, while 4% felt that no such policies were in place. Just over one-quarter (27%) were correct in noting that students can decline consent, while more than half (54%) did not know whether there were any procedures governing student consent. Palmer faculty have only modest understanding about institutional policies regarding the IRB and human subject research, especially pertaining to educational research. The institution needs to develop methods to provide knowledge and training to faculty. The results from this pilot study will be instrumental in developing better protocols for a study designed to survey the entire chiropractic academic community.


Sporadic inclusion body myositis: variability in prevalence and phenotype and influence of the MHC.
Sporadic inclusion body myositis (sIBM) is the most common myopathy presenting over the age of 40 years but its prevalence varies considerably in different populations. Genetic factors play a part in the pathogenesis of sIBM and in Caucasians susceptibility has been linked to the HLA-DR3 allele and the 8.1 MHC ancestral haplotype (AH) which is also associated with other autoimmune diseases. The variable prevalence of sIBM in different populations may be related to differences in the population frequency of this haplotype. Our recent observations indicate that the clinical phenotype at presentation is also quite variable and that the influence of the MHC is more complex than previously appreciated with HLA alleles also having modifying effects on the age-at-onset, severity and rate of progression of the disease. Recent recombinant mapping studies of polymorphisms in the Class II/III regions of the MHC by our group have further refined the susceptibility region and have identified a number of candidate genes warranting further investigation. The significance of these findings for the pathogenesis of the disease is discussed.


Ongoing niche differentiation under high gene flow in a polymorphic brackish water threespine stickleback (Gasterosteus aculeatus) population.
Marine threespine sticklebacks colonized and adapted to brackish and freshwater environments since the last Pleistocene glacial. Throughout the Holarctic, three lateral plate morphs are observed; the low, partial and completely plated morph. We test if the three plate morphs in the brackish water Lake Engervann, Norway, differ in body size, trophic morphology (gill raker number and length), niche (stable isotopes; δ15N, δ13C, and parasites (Theristina gasterostei, Trematoda spp.)), genetic structure (microsatellites) and the lateral-plate encoding Stn382 (Ectodysplasin) gene. We examine differences temporally (autumn 2006/spring 2007) and spatially (upper/lower sections of the lake - reflecting low versus high salinity). All morphs belonged to one gene pool. The complete morph was larger than the low plated, with the partial morph intermediate. The number of lateral plates ranged 8-71, with means of 64.2 for complete, 40.3 for partial, and 14.9 for low plated morph. Stickleback δ15N was higher in the lower lake section, while δ13C was higher in the upper section. Stickleback isotopic values were greater in autumn. The low plated morph had larger variances in δ15N and δ13C than the other morphs. Sticklebacks in the upper section had more T. gasterostei than in the lower section which had more Trematoda spp. Sticklebacks had less T. gasterostei, but more Trematoda spp. in autumn than spring. Sticklebacks with few and short rakers had more T. gasterostei, while sticklebacks with longer rakers had more Trematoda. spp. Stickleback with higher δ15N values had more T. gasterostei, while sticklebacks with higher δ15N and δ13C values had more Trematoda spp. The low plated morph had fewer Trematoda spp. than other morphs. Trait-ecology associations may imply that the three lateral plate morphs in the brackish water lagoon of Lake Engervann are experiencing ongoing divergent selection for niche and migratory life history strategies under high gene flow. As such, the brackish water zone may generally act as a generator of genomic diversity to be selected upon in the different environments where threespine sticklebacks can live.


Pallister Killian syndrome: unusual significant postnatal overgrowth in a girl with otherwise typical presentation.
Pallister Killian syndrome (PKS) is a rare genetic disorder caused by tetrasomy of the short arm of chromosome 12, revealed usually in mosaic distribution of an extra i (12) (p10) chromosome in fibroblasts. The syndrome presents with a recognizable pattern of findings including pigmentary skin changes, coarse face, high forehead, sparse anterior scalp hair, hypertelorism, seizures and progressive psychomotor developmental delay. It was first described independently by Pallister in 1977 and by Killian and Teschler-Nikola in 1981. We report a case of 21 month old girl with PKS and significant overgrowth. Cytogenetic analysis was performed using the GTG banding technique. The karyotype of cultured lymphocytes was normal. The karyotype from skin fibroblasts was established as mosaic tetrasomy of 12p 47,XX,+i (12) (p10)/46,XX. The origin of the extra marker chromosome was determinated by fluorescence in situ hybridization with chromosome 12 specific DNA probes confirming that supernumerary marker is chromosome i (12p) in 68% of cells. Despite the excessive postnatal growth we found low serum growth hormone levels and reduced response to pharmacological stimulation test. This is also the first report of a postnatal patient in our country.


IGFBP3 colocalizes with and regulates hypocretin (orexin).
The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression. We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals. Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy.


Access to conventional medical care and the use of complementary and alternative medicine.
The use of complementary and alternative medicine (CAM) in the United States has greatly increased during the past decade. Using survey data from the 2002 National Health Interview Survey (NHIS), we show that adults who did not get, or delayed, needed medical care because of cost in the prior twelve months were also more likely than all other adults to use CAM. Recent increases in CAM use could be the result of not only the desire for individual empowerment and patient dissatisfaction with conventional medicine, as has been claimed, but also of increases in the relative cost of conventional health care.


Quantitative neuropeptidomics of microwave-irradiated mouse brain and pituitary.
In neuropeptidomics, the degradation of a small fraction of abundant proteins overwhelms the low signals from neuropeptides, and many neuropeptides cannot be detected by mass spectrometry without extensive purification. Protein degradation was prevented when mice were sacrificed with focused microwave irradiation, permitting the detection of hypothalamic neuropeptides by mass spectrometry. Here we report an alternative and very simple method utilizing an ordinary microwave oven to inhibit enzymatic degradation. We used this technique to identify brain and pituitary neuropeptides. Quantitative analysis using mass spectrometry in combination with stable isotopic labeling was performed to determine the effect of microwave irradiation on relative levels of neuropeptides and protein degradation fragments. Microwave irradiation greatly reduced the levels of degradation fragments of proteins. In contrast, neuropeptide levels were increased about 2-3 times in hypothalamus by the microwave irradiation but not increased in pituitary. In a second experiment, three brain regions (hypothalamus, hippocampus, and striatum) from microwave-irradiated mice were analyzed. Altogether 41 neuropeptides or fragments of secretory pathway proteins were identified after microwave treatment; some of these are novel. These peptides were derived from 15 proteins: proopiomelanocortin, proSAAS, proenkephalin, preprotachykinins A and B, provasopressin, prooxytocin, melanin-concentrating hormone, proneurotensin, chromogranins A and B, secretogranin II, prohormone convertases 1 and 2, and peptidyl amidating monooxygenase. Although some protein degradation fragments were still found after microwave irradiation, these appear to result from protein breakdown during the extraction and not to an enzymatic reaction during the postmortem period. Two of the protein fragments corresponded to novel protein forms: VAP-33 with a 7-residue N-terminal extension and beta tubulin with a glutathione on the Cys near the N terminus. In conclusion, microwave irradiation with an ordinary microwave oven effectively inhibits enzymatic postmortem protein degradation, increases the recovery of neuropeptides, and makes it possible to conduct neuropeptidomic studies with mouse brain tissues.


Iron deposition is independent of cellular inflammation in a cerebral model of multiple sclerosis.
Perivenular inflammation is a common early pathological feature in multiple sclerosis (MS). A recent hypothesis stated that CNS inflammation is induced by perivenular iron deposits that occur in response to altered blood flow in MS subjects. In order to evaluate this hypothesis, an animal model was developed, called cerebral experimental autoimmune encephalomyelitis (cEAE), which presents with CNS perivascular iron deposits. This model was used to investigate the relationship of iron deposition to inflammation. In order to generate cEAE, mice were given an encephalitogen injection followed by a stereotactic intracerebral injection of TNF-α and IFN-γ. Control animals received encephalitogen followed by an intracerebral injection of saline, or no encephalitogen plus an intracerebral injection of saline or cytokines. Laser Doppler was used to measure cerebral blood flow. MRI and iron histochemistry were used to localize iron deposits. Additional histological procedures were used to localize inflammatory cell infiltrates, microgliosis and astrogliosis. Doppler analysis revealed that cEAE mice had a reduction in cerebral blood flow compared to controls. MRI revealed T2 hypointense areas in cEAE animals that spatially correlated with iron deposition around vessels and at some sites of inflammation as detected by iron histochemistry. Vessels with associated iron deposits were distributed across both hemispheres. Mice with cEAE had more iron-labeled vessels compared to controls, but these vessels were not commonly associated with inflammatory cell infiltrates. Some iron-laden vessels had associated microgliosis that was above the background microglial response, and iron deposits were observed within reactive microglia. Vessels with associated astrogliosis were more commonly observed without colocalization of iron deposits. The findings indicate that iron deposition around vessels can occur independently of inflammation providing evidence against the hypothesis that iron deposits account for inflammatory cell infiltrates observed in MS.


Repeated evolution of testis-specific new genes: the case of telomere-capping genes in Drosophila.
Comparative genome analysis has allowed the identification of various mechanisms involved in gene birth. However, understanding the evolutionary forces driving new gene origination still represents a major challenge. In particular, an intriguing and not yet fully understood trend has emerged from the study of new genes: many of them show a testis-specific expression pattern, which has remained poorly understood. Here we review the case of such a new gene, which involves a telomere-capping gene family in Drosophila. hiphop and its testis-specific paralog K81 are critical for the protection of chromosome ends in somatic cells and male gametes, respectively. Two independent functional studies recently proposed that these genes evolved under a reproductive-subfunctionalization regime. The 2011 release of new Drosophila genome sequences from the melanogaster group of species allowed us to deepen our phylogenetic analysis of the hiphop/K81 family. This work reveals an unsuspected dynamic of gene birth and death within the group, with recurrent duplication events through retroposition mechanisms. Finally, we discuss the plausibility of different evolutionary scenarios that could explain the diversification of this gene family.


Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline.
Cerebrovascular disease (CVD) and amyloid-β (Aβ) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aβ on neurodegenerative markers and cognition in patients without dementia. We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aβ1-42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aβ and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (-) of Aβ and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics. MTA and t-tau were elevated in the Aβ - WMH+, Aβ + WMH-, and Aβ + WMH+ groups. MTA was most severe in the Aβ + WMH+ group compared with the groups with a single pathology. Both WMH and Aβ were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline. In the present study, we found an additive association of Aβ and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up.


Consensus molecular subtype classification of colorectal adenomas.
Consensus molecular subtyping is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA expression. Only a minority of adenomas progress to malignancies, a transition that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined with polymerase chain reaction-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n = 30) or array-comparative genomic hybridisation (n = 32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 'metabolic subtype', which was least common among CRCs, was most prevalent among adenomas (n = 45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the 'MSI immune' subtype. Eight adenomas (13%) were classified as the 'canonical' CMS2. No adenomas were classified as the 'mesenchymal' CMS4, consistent with the fact that adenomas lack invasion-associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high-risk adenomas were observed in CMS2. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Trends in bilateral oophorectomy at the time of hysterectomy for benign disease.
To identify patient characteristics associated with bilateral oophorectomy or removal of remaining ovary at the time of benign hysterectomy, and to estimate trends in the performance of oophorectomy from 2001 to 2006. This was a cross-sectional analysis using the New York State Department of Health Statewide Planning and Research Cooperative System. Women aged 18 years or older undergoing hysterectomies for benign gynecologic conditions were included. We evaluated factors associated with oophorectomy on both univariable and multivariable analyses and assessed for changes in performance of oophorectomy over the course of the study. Forty-seven percent of 144,877 hysterectomies included oophorectomy. Women who underwent oophorectomy were older and were more likely to have a family history of breast or ovarian cancer, a personal history of breast cancer, ovarian cysts, or endometriosis. Women who underwent vaginal or laparoscopic hysterectomy or had uterine prolapse were less likely to undergo oophorectomy. Both race and insurance status were associated with performance of oophorectomy. From 2001 to 2006, there was an 8% absolute decrease in the performance of oophorectomy at the time of benign hysterectomy for women of all ages, with a 10.4% decrease in women aged younger than 55 (P for trend <.001). Age, route of hysterectomy, and concomitant gynecologic diagnoses influence oophorectomy rate. From 2001 to 2006, a significant decrease in the performance of oophorectomy at the time of benign hysterectomy was noted in women aged younger than 55 years. Recent studies of complications of hormone therapy and prophylactic oophorectomy may have influenced patients' and physicians' decision-making, leading to lower oophorectomy rates. II.


Phosphate buffers in capillary electrophoresis/mass spectrometry using atmospheric pressure photoionization and electrospray ionization.
Capillary electrophoresis (CE) has been combined with atmospheric pressure photoionization (APPI) and electrospray ionization (ESI) for mass spectrometric (MS) detection. Separation conditions using potassium phosphate buffer and ammonium formate buffer have been compared for analysis of eleven pharmaceutical bases. The results showed improvements in separation efficiency and peak symmetry when phosphate buffer was used. The low flow in CE may enable utilization of these advances with MS detection. Compared with ESI, the APPI technique provided a cluster-free background. The enhanced signal-to-noise ratio in the total ion current (TIC) and the reduced spectral background indicated that the APPI process is less affected by non-volatile salts in the CE buffers. This results in a wider range of choice of CE buffers in CE/MS analysis when APPI is the ionization method.


Ca2+-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse.
We report functional and structural evidence for GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs) at the mature hair cell ribbon synapse. By using the methodological advantages of three species (of either sex), we demonstrate that CP-AMPARs are present at the hair cell synapse in an evolutionarily conserved manner. Via a combination of in vivo electrophysiological and Ca2+ imaging approaches in the larval zebrafish, we show that hair cell stimulation leads to robust Ca2+ influx into afferent terminals. Prolonged application of AMPA caused loss of afferent terminal responsiveness, whereas blocking CP-AMPARs protects terminals from excitotoxic swelling. Immunohistochemical analysis of AMPAR subunits in mature rat cochlea show regions within synapses lacking the GluA2 subunit. Paired recordings from adult bullfrog auditory synapses demonstrate that CP-AMPARs mediate a major component of glutamatergic transmission. Together, our results support the importance of CP-AMPARs in mediating transmission at the hair cell ribbon synapse. Further, excess Ca2+ entry via CP-AMPARs may underlie afferent terminal damage following excitotoxic challenge, suggesting that limiting Ca2+ levels in the afferent terminal may protect against cochlear synaptopathy associated with hearing loss.SIGNIFICANCE STATEMENT A single incidence of noise overexposure causes damage at the hair cell synapse that later leads to neurodegeneration and exacerbates age-related hearing loss. A first step toward understanding cochlear neurodegeneration is to identify the cause of initial excitotoxic damage to the postsynaptic neuron. Using a combination of immunohistochemical, electrophysiological, and Ca2+ imaging approaches in evolutionarily divergent species, we demonstrate that Ca2+-permeable AMPARs (CP-AMPARs) mediate glutamatergic transmission at the adult auditory hair cell synapse. Overexcitation of the terminal causes Ca2+ accumulation and swelling that can be prevented by blocking CP-AMPARs. We demonstrate that CP-AMPARs mediate transmission at this first-order sensory synapse and that limiting Ca2+ accumulation in the terminal may protect against hearing loss.


Diagnostic Accuracy and Confidence of [18F] FDG PET/MRI in comparison with PET or MRI alone in Head and Neck Cancer.
The usefulness of PET/MRI in head and neck malignancy has not been fully elucidated. The purpose of our study was to evaluate the diagnostic accuracy and confidence of PET/MRI in comparison with PET or MRI alone. This study included 73 consecutive patients who underwent [18F] FDG PET/MRI in head and neck under the suspicion of malignancy. A neuroradiologist and a nuclear medicine specialist reviewed MRI and PET images, respectively and independently, followed by a consensus review of PET/MRI one month later. For 134 lesions, accuracy and confidence were compared among PET, MRI, and PET/MRI. For lesion base, PET/MRI had a sensitivity of 85.7%, a specificity of 89.1%, a PPV of 89.6%, a negative predictive value of 85.1%, and an accuracy of 87.3%. AUCs of PET/MRI per lesion (0.926) and per patient (0.934) for diagnosing malignancy were higher than PET (0.847 and 0.747, respectively) or MRI (0.836 and 0.798, respectively) alone (P < 0.05). More than 80% of the cases (111/134) showed diagnostic concordance between PET and MRI. PPV of PET/MRI was higher in malignant concordant cases (93.2%, 55/59) than in discordant cases (62.5%, 5/8) (p = 0.040). Confident scoring rate in malignant concordant cases was higher on PET/MRI (96.6%, 57/59) than on MRI (76.3%, 45/59) (p = 0.003). In conclusion, compared with PET or MRI alone, PET/MRI presents better diagnostic performance in accuracy and confidence for diagnosis of malignancy. PET/MRI is useful in patients with head and neck cancer.


Identification of cell-specific targets of sumoylation during mouse spermatogenesis.
Recent findings suggest diverse and potentially multiple roles of small ubiquitin-like modifier (SUMO) in testicular function and spermatogenesis. However, SUMO targets remain uncharacterized in the testis due to the complex multicellular nature of testicular tissue, the inability to maintain and manipulate spermatogenesis in vitro, and the technical challenges involved in identifying low-abundance endogenous SUMO targets. In this study, we performed cell-specific identification of sumoylated proteins using concentrated cell lysates prepared with de-sumoylation inhibitors from freshly purified spermatocytes and spermatids. One-hundred and twenty proteins were uniquely identified in the spermatocyte and/or spermatid fractions. The identified proteins are involved in the regulation of transcription, stress response, microRNA biogenesis, regulation of major enzymatic pathways, nuclear-cytoplasmic transport, cell-cycle control, acrosome biogenesis, and other processes. Several proteins with important roles during spermatogenesis were chosen for further characterization by co-immunoprecipitation, co-localization, and in vitro sumoylation studies. GPS-SUMO Software was used to identify consensus and non-consensus sumoylation sites within the amino acid sequences of the proteins. The analyses confirmed the cell-specific sumoylation and/or SUMO interaction of several novel, previously uncharacterized SUMO targets such as CDK1, RNAP II, CDC5, MILI, DDX4, TDP-43, and STK31. Furthermore, several proteins that were previously identified as SUMO targets in somatic cells (KAP1 and MDC1) were identified as SUMO targets in germ cells. Many of these proteins have a unique role in spermatogenesis and during meiotic progression. This research opens a novel avenue for further studies of SUMO at the level of individual targets.


A randomised crossover study investigating the effects of galacto-oligosaccharides on the faecal microbiota in men and women over 50 years of age.
Faecal microbial changes associated with ageing include reduced bifidobacteria numbers. These changes coincide with an increased risk of disease development. Prebiotics have been observed to increase bifidobacteria numbers within humans. The present study aimed to determine if prebiotic galacto-oligosaccharides (GOS) could benefit a population of men and women of 50 years and above, through modulation of faecal microbiota, fermentation characteristics and faecal water genotoxicity. A total of thirty-seven volunteers completed this randomised, double-blind, placebo-controlled crossover trial. The treatments - juice containing 4 g GOS and placebo - were consumed twice daily for 3 weeks, preceded by 3-week washout periods. To study the effect of GOS on different large bowel regions, three-stage continuous culture systems were conducted in parallel using faecal inocula from three volunteers. Faecal samples were microbially enumerated by quantitative PCR. In vivo, following GOS intervention, bifidobacteria were significantly more compared to post-placebo (P = 0·02). Accordingly, GOS supplementation had a bifidogenic effect in all in vitro system vessels. Furthermore, in vessel 1 (similar to the proximal colon), GOS fermentation led to more lactobacilli and increased butyrate. No changes in faecal water genotoxicity were observed. To conclude, GOS supplementation significantly increased bifidobacteria numbers in vivo and in vitro. Increased butyrate production and elevated bifidobacteria numbers may constitute beneficial modulation of the gut microbiota in a maturing population.


The surgical management of recurrent stress urinary incontinence: a systematic review.
Despite a wide spectrum of interventions, surgical treatments of recurrent stress urinary incontinence (SUI) are associated with high failure rates. To systematically review current evidence on the effectiveness of surgical interventions for recurrent SUI. An electronic database search was undertaken (1980-2014). Keywords were: "stress urinary incontinence," "failure," "recurrence," "treatment." References of identified studies and abstracts from conferences were considered. We restricted the search to female patients and currently used surgical procedures, including studies with five or more cases. After the initial yield, studies were selected following title screening, abstract and full text scrutiny. The pooled objective cure rates of colposuspension for recurrent SUI are 76% (95% CI ±5.04), whereas rates for midurethral sling procedures are 68.5% (95% CI ±3.11). Repeat midurethral sling procedures have pooled success rates of 66.2% (95% CI ±4) but those of the transobturator approach appear lower than retropubic procedures. Pubovaginal slings for recurrent SUI have pooled success of 79.3% (95% CI ±6.54). Success rates for adjustable continence therapy and adjustable slings for recurrent SUI are 53.8% (95% CI ±5.28), whereas for midurethral sling fixation procedures the pooled success is 61% (95% CI ±10.56). Urethral bulking injections have success rates of 38% (95% CI ±10.7). Laparoscopic two-team sling procedures, salvage spiral slings, and artificial urinary sphincter have shown promising results, but there are limited data on recurrent cases. There is a wide spectrum of surgical interventions reported for secondary or tertiary treatment of SUI. A common characteristic for all recurrent procedures is a lower success rate compared with those reported following primary procedures.


Assessment of periprosthetic joint infection prevention methods amongst Turkish orthopedic surgeons in total joint replacement: A survey.
This study aims to assess the methods employed by Turkish orthopedic surgeons to prevent periprosthetic joint infection (PJI) in total joint arthroplasty (TJA). The data obtained for this study, conducted between January 2019 and February 2019, were gathered by sending out an online survey to Turkish Society of Orthopedics and Traumatology members (n=2,267). A total of 354 orthopedic surgeons responded and completed survey. The survey had 23 questions which include the experience, academic position, hospital where the physician works, monthly arthroplasty numbers, and infection prevention methods employed before, during, and after surgery. The period for antibiotics prophylaxis showed variability, with about 63% of surgeons using prophylaxis longer than 24 hours. In terms of academic position, 52.4% of professors and 52.8% of associate professors used prophylaxis for the first 24 hours whereas this rate was 31.3% in operators (p=0.01). Of surgeons, 50.7% who perform more than 10 arthroplasties per month and 33.6% of surgeons who perform less than 11 arthroplasties per month used 24-hour antibiotic prophylaxis (p=0.006). Blood glucose level assessment prior to surgery was performed by the majority of surgeons (94%). A total of 118 orthopedic surgeons (33.3%) performed methicillin- resistant Staphylococcus aureus (MRSA) decolonization with 54.7% of associate professors, 59.5% of professors, and 24.7% of operators (p=0.001). Only 60 surgeons (16.9%) checked vitamin D levels. Our study results demonstrated that the majority of orthopedic surgeons in Turkey do not follow the antibiotic prophylaxis recommendations and they use antibiotic prophylaxis for longer periods. Professors and associate professors, and surgeons with higher monthly arthroplasty numbers than surgeons with lower monthly arthroplasty numbers follow the recommended periods more than their counterparts. Most surgeons assess blood glucose levels whereas a small number of surgeons perform MRSA decolonization and check vitamin D levels.


A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression.
Insulin regulation of hepatic gene transcription is a vital component of glucose homeostasis. Understanding the molecular regulationof thisprocess aids the searchfor the defect(s) that promotesinsulin-resistant states, such asdiabetesmellitus. We havepreviously shownthat the insulin regulationof hepatic IGF-binding protein-1 (IGFBP1) expression requiresthe signalling proteins phosphatidylinositol 3-kinase (PI 3-kinase) and mammalian target of rapamycin (mTOR). In this report, we demonstrate that activation of the mTOR pathway, without activation of its upstream regulator PI 3-kinase, reduces IGFBP1 expression. Therefore, mTOR activation is sufficient to mimic insulin regulation of this gene. However, longer exposure (>3 h) of cells to insulin reduces the importance of this pathway in insulin regulation of the gene, suggesting a temporal switch in signalling mechanisms linking insulin action to the IGFBP1 gene promoter. In contrast, the activation of PI 3-kinase is required for insulin regulation of IGFBP1 under all conditions tested. Therefore, an mTOR-independent, PI 3-kinase-dependent pathway becomes more important in IGFBP1 regulation after long exposure to insulin. This is a novel concept in insulin regulation of gene expression and demonstrates the importance of temporal analysis of signalling processes.


Three combinations of manual therapy techniques within naprapathy in the treatment of neck and/or back pain: a randomized controlled trial.
Manual therapy as spinal manipulation, spinal mobilization, stretching and massage are common treatment methods for neck and back pain. The objective was to compare the treatment effect on pain intensity, pain related disability and perceived recovery from a) naprapathic manual therapy (spinal manipulation, spinal mobilization, stretching and massage) to b) naprapathic manual therapy without spinal manipulation and to c) naprapathic manual therapy without stretching for male and female patients seeking care for back and/or neck pain. Participants were recruited among patients, ages 18-65, seeking care at the educational clinic of Naprapathögskolan - the Scandinavian College of Naprapathic Manual Medicine in Stockholm. The patients (n = 1057) were randomized to one of three treatment arms a) manual therapy (i.e. spinal manipulation, spinal mobilization, stretching and massage), b) manual therapy excluding spinal manipulation and c) manual therapy excluding stretching. The primary outcomes were minimal clinically important improvement in pain intensity and pain related disability. Treatments were provided by naprapath students in the seventh semester of eight total semesters. Generalized estimating equations and logistic regression were used to examine the association between the treatments and the outcomes. At 12 weeks follow-up, 64% had a minimal clinically important improvement in pain intensity and 42% in pain related disability. The corresponding chances to be improved at the 52 weeks follow-up were 58% and 40% respectively. No systematic differences in effect when excluding spinal manipulation and stretching respectively from the treatment were found over 1 year follow-up, concerning minimal clinically important improvement in pain intensity (p = 0.41) and pain related disability (p = 0.85) and perceived recovery (p = 0.98). Neither were there disparities in effect when male and female patients were analyzed separately. The effect of manual therapy for male and female patients seeking care for neck and/or back pain at an educational clinic is similar regardless if spinal manipulation or if stretching is excluded from the treatment option. Current Controlled Trials ISRCTN92249294.


Exploring insecticide resistance mechanisms in three major malaria vectors from Bangui in Central African Republic.
Malaria remains the main cause of mortality and morbidity in the Central African Republic. However, the main malaria vectors remain poorly characterised, preventing the design of suitable control strategies. Here, we characterised the patterns and mechanisms of insecticide resistance in three important vectors from Bangui. Mosquitoes were collected indoors, using electrical aspirators in July 2016 in two neighborhoods at Bangui. WHO bioassays performed, using F2 An. gambiae sensu lato (s.l.), revealed a high level of resistance to type I (permethrin) and II (deltamethrin) pyrethroids and dichlorodiphenyltrichloroethane (< 3% mortality). Molecular analysis revealed the co-occurrence of Anopheles coluzzii (56.8 %) and An. gambiae s.s. (43.2%) within the An. gambiae complex. Anopheles funestus s.s. was the sole species belonging to An. funestus group. Both kdr-w (40% of homozygotes and 60% of heterozygotes/kdr-w/wild type) and kdr-e (37.5% of heterozygotes) mutations were found in An. gambiae. Contrariwise, only the kdr-w (9.5% homozygotes and 85.7% of heterozygotes) was detected in An. coluzzii. Quantitative RT-PCR showed that CYP6M2 and CYP6P3 are not upregulated in An. coluzzii from Bangui. Analysis of the sodium channel gene revealed a reduced diversity in An. coluzzii and An. gambiae s.s. In An. funestus s.s., the pyrethroid/DDT GSTe2 L119F resistance allele was detected at high frequency (54.7%) whereas a very low frequency for Rdl was observed. Polymorphism analysis of GSTe2 and GABA receptor gene in An. funestus revealed the presence of one resistant haplotype for each gene. This study provides baseline information to help guide current and future malaria vector control interventions in CAR.


Eye and Voice-Controlled Human Machine Interface System for Wheelchairs Using Image Gradient Approach.
Rehabilitative mobility aids are being used extensively for physically impaired people. Efforts are being made to develop human machine interfaces (HMIs), manipulating the biosignals to better control the electromechanical mobility aids, especially the wheelchairs. Creating precise control commands such as move forward, left, right, backward and stop, via biosignals, in an appropriate HMI is the actual challenge, as the people with a high level of disability (quadriplegia and paralysis, etc.) are unable to drive conventional wheelchairs. Therefore, a novel system driven by optical signals addressing the needs of such a physically impaired population is introduced in this paper. The present system is divided into two parts: the first part comprises of detection of eyeball movements together with the processing of the optical signal, and the second part encompasses the mechanical assembly module, i.e., control of the wheelchair through motor driving circuitry. A web camera is used to capture real-time images. The processor used is Raspberry-Pi with Linux operating system. In order to make the system more congenial and reliable, the voice-controlled mode is incorporated in the wheelchair. To appraise the system's performance, a basic wheelchair skill test (WST) is carried out. Basic skills like movement on plain and rough surfaces in forward, reverse direction and turning capability were analyzed for easier comparison with other existing wheelchair setups on the bases of controlling mechanisms, compatibility, design models, and usability in diverse conditions. System successfully operates with average response time of 3 s for eye and 3.4 s for voice control mode.


Grape polyphenols decrease circulating branched chain amino acids in overfed adults.
Dietary polyphenols have long been associated with health benefits, including the prevention of obesity and related chronic diseases. Overfeeding was shown to rapidly induce weight gain and fat mass, associated with mild insulin resistance in humans, and thus represents a suitable model of the metabolic complications resulting from obesity. We studied the effects of a polyphenol-rich grape extract supplementation on the plasma metabolome during an overfeeding intervention in adults, in two randomized parallel controlled clinical trials. Blood plasma samples from 40 normal weight to overweight male adults, submitted to a 31-day overfeeding (additional 50% of energy requirement by a high calorie-high fructose diet), given either 2 g/day grape polyphenol extract or a placebo at 0, 15, 21, and 31 days were analyzed (Lyon study). Samples from a similarly designed trial on females (20 subjects) were collected in parallel (Lausanne study). Nuclear magnetic resonance (NMR)-based metabolomics was conducted to characterize metabolome changes induced by overfeeding and associated effects from polyphenol supplementation. The clinical trials are registered under the numbers NCT02145780 and NCT02225457 at ClinicalTrials.gov. Changes in plasma levels of many metabolic markers, including branched chain amino acids (BCAA), ketone bodies and glucose in both placebo as well as upon polyphenol intervention were identified in the Lyon study. Polyphenol supplementation counterbalanced levels of BCAA found to be induced by overfeeding. These results were further corroborated in the Lausanne female study. Administration of grape polyphenol-rich extract over 1 month period was associated with a protective metabolic effect against overfeeding in adults.


Restoration of LDL receptor activity in mutant cells by intercellular junctional communication.
Exchange of small molecules between cells through intercellular junctions is a widespread phenomenon implicated in many physiological and developmental processes. This type of intercellular communication can restore the activity of low-density lipoprotein (LDL) receptors in mammalian cells that are deficient in the enzyme UDP-Gal/UDP-GalNAc 4-epimerase. Pure cultures of the 4-epimerase mutant are unable to synthesize normal carbohydrate chains on LDL receptors and many other glycoproteins and therefore do not express LDL receptor activity. When these cells are cocultivated with cells expressing normal 4-epimerase activity, the structure and function of LDL receptors are restored to normal by the transfer of this enzyme's products through intercellular junctions. The formation of functional junctions does not require normal glycosylation of membrane proteins. Because many convenient assays and selections for LDL receptor activity are available, this mutant can provide a powerful new tool for biochemical and genetic studies of intercellular junctional communication.


Daytime napping and increased risk of incident respiratory diseases: symptom, marker, or risk factor?
We have identified a strong association between daytime napping and increased mortality risk from respiratory diseases, but little is known about the relationship between daytime napping and respiratory morbidity. Data were drawn from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort. Participants reported napping habits during 1998-2000 and were followed up for respiratory disease hospital admissions until March 2009. Cox proportional hazards regression was used to examine the association between daytime napping and respiratory disease incidence risk. The study sample included 10,978 men and women with a mean age of 61.9 years, and a total of 946 incident respiratory disease cases were recorded. After adjustment for age, sex, social class, education, marital status, employment status, nightshift work, body mass index, physical activity, smoking, alcohol intake, self-reported general health, hypnotic drug use, habitual sleep duration, and preexisting health conditions, daytime napping was associated with an increase in the overall respiratory disease incidence risk (hazard ratio (HR) = 1.32, 95% confidence interval (CI) 1.15, 1.52 for napping <1 h; HR = 1.54, 95% CI 1.14, 2.09 for napping ≥1 h). This association was more pronounced for lower respiratory diseases, especially for the risk of chronic lower respiratory diseases (HR = 1.52, 95% CI: 1.18, 1.96 for napping <1 h; HR = 1.72, 95% CI: 1.01, 2.92 for napping ≥1 h, overall p = 0.003). Excessive daytime napping might be a useful marker of future respiratory disease incidence risk. Further studies are required to confirm these findings and help understand potential mechanisms.


Effects of 6-month vitamin D supplementation on insulin sensitivity and secretion: a randomised, placebo-controlled trial.
To determine whether vitamin D3 supplementation improves insulin sensitivity, using the hyperinsulinemic-euglycemic clamp. This single-centre, double-blind, placebo-controlled trial randomised 96 participants at high risk of diabetes or with newly diagnosed type 2 diabetes to vitamin D3 5000 IU daily or placebo for 6 months. We assessed at baseline and 6 months: (1) primary aim: peripheral insulin sensitivity (M-value using a 2-h hyperinsulinemic-euglycemic clamp); (2) secondary aims: other insulin sensitivity (HOMA2%S, Matsuda) and insulin secretion (insulinogenic index, C-peptide area under the curve, HOMA2-B) indices using a 2-h oral glucose tolerance test (OGTT); β-cell function (disposition index: M-value × insulinogenic index); fasting and 2-h glucose post OGTT; HbA1c; anthropometry. Baseline characteristics were similar between groups (% or mean ± s.d.): women 38.5%; age 58.7 ± 9.4 years; BMI 32.2 ± 4.1 kg/m2; prediabetes 35.8%; diabetes 20.0%; 25-hydroxyvitamin D (25(OH)D) 51.1 ± 14.2 nmol/L. At 6 months, mean 25(OH)D reached 127.6 ± 26.3 nmol/L and 51.8 ± 16.5 nmol/L in the treatment and placebo groups, respectively (P < 0.001). A beneficial effect of vitamin D3 compared with placebo was observed on M-value (mean change (95% CI): 0.92 (0.24-1.59) vs -0.03 (-0.73 to 0.67); P = 0.009) and disposition index (mean change (95% CI): 267.0 (-343.4 to 877.4) vs -55.5 (-696.3 to 585.3); P = 0.039) after 6 months. No effect was seen on other outcomes. In individuals at high risk of diabetes or with newly diagnosed type 2 diabetes, vitamin D supplementation for 6 months significantly increased peripheral insulin sensitivity and β-cell function, suggesting that it may slow metabolic deterioration in this population.


Plant growth promotion and biological control of Pythium aphanidermatum, a pathogen of cucumber, by endophytic actinomycetes.
To evaluate the potential of Actinoplanes campanulatus, Micromonospora chalcea and Streptomyces spiralis endophytic in cucumber roots, to promote plant growth and to protect seedlings and mature plants of cucumber from diseases caused by Pythium aphanidermatum, under greenhouse conditions. Three endophytic isolates, out of 29, were selected through tests aimed at understanding their mechanisms of action as biocontrol agents and plant growth promoters. When applied individually or in combination, they significantly promoted plant growth and reduced damping-off and crown and root rot of cucumber. The combination of the three isolates resulted in significantly better suppression of diseases and plant growth promotion, than where the plants were exposed to individual strains. The three selected actinomycete isolates colonized cucumber roots endophytically for 8 weeks, promoted plant growth and suppressed pathogenic activities of P. aphanidermatum on seedling and mature cucumber plants. The results clearly show that the endophytic, glucanase-producing actinomycetes used, especially as a combined treatment, could replace metalaxyl, which is the currently recommended fungicide for Pythium diseases in the United Arab Emirates. These endophytic isolates also have the potential to perform as plant growth promoters, which is a useful attribute for crop production in nutrient impoverished soils.


Enhancing Self-Awareness: A Practical Strategy to Train Culturally Responsive Social Work Students.
A primary goal of social justice educators is to engage students in a process of self-discovery, with the goal of helping them recognize their own biases, develop empathy, and become better prepared for culturally responsive practice. While social work educators are mandated with the important task of training future social workers in culturally responsive practice with diverse populations, practical strategies on how to do so are scant. This article introduces a teaching exercise, the Ethnic Roots Assignment, which has been shown qualitatively to aid students in developing self-awareness, a key component of culturally competent social work practice. Practical suggestions for classroom utilization, common challenges, and past student responses to participating in the exercise are provided. The dissemination of such a teaching exercise can increase the field's resources for addressing the important goal of cultural competence training.


Discovery of Ibomycin, a Complex Macrolactone that Exerts Antifungal Activity by Impeding Endocytic Trafficking and Membrane Function.
Natural products are invaluable historic sources of drugs for infectious diseases; however, the discovery of novel antimicrobial chemical scaffolds has waned in recent years. Concurrently, there is a pressing need for improved therapeutics to treat fungal infections. We employed a co-culture screen to identify ibomycin, a large polyketide macrolactone that has preferential killing activity against Cryptococcus neoformans. Using chemical and genome methods, we determined the structure of ibomycin and identified the biosynthetic cluster responsible for its synthesis. Chemogenomic profiling coupled with cell biological assays link ibomycin bioactivity to membrane function. The preferential activity of ibomycin toward C. neoformans is due to the ability of the compound to selectively permeate its cell wall. These results delineate a novel antifungal agent that is produced by one of the largest documented biosynthetic clusters to date and underscore the fact that there remains significant untapped chemical diversity of natural products with application in antimicrobial research.


Siliceous urinary calculi in calves: prevention by addition of sodium chloride to the diet.
Urinary calculi were found in all but one of 14 calves given a ration associated with the formation of siliceous calculi. No calculi were found in a similar group of 14 calves given the same ration with sodium chloride added (4 percent). It is suggested that sodium chloride prevented calculus formation by in creasing water intake and urine volume, with a consequent reduction in the con-centration of silicic acid in the urine