The development of an implementation framework for service-learning during the undergraduate nursing programme in the Western Cape Province.
Service-learning (SL) is a contested field of knowledge and issues of sustainability and scholarship have been raised about it. The South African Higher Education Quality Committee (HEQC) has provided policy documents to guide higher education institutions (HEIs) in the facilitation of SL institutionalisation in their academic programmes. An implementation framework was therefore needed to institutionalise the necessary epistemological shifts advocated in the national SL policy guidelines. This article is based on the findings of a doctoral thesis that aimed at developing an SL implementation framework for the School of Nursing (SoN) at the University of the Western Cape (UWC). Mixed methods were used during the first four phases of the design and developmenti ntervention research model developed by Rothman and Thomas. The SL implementation framework that was developed during Phase 3 specified the intervention elements to address the gaps that had been identified by the core findings of Phases 1 and 2. Four intervention elements were specified for the SL implementation framework. The first intervention element focused on the assessment of readiness for SL institutionalisation. The development of SL capacity and SL scholarship was regarded as the pivotal intervention element for three of the elements: the development of a contextual SL definition, an SL pedagogical model, and a monitoring and evaluation system for SL institutionalisation. The SL implementation framework satisfies the goals of SL institutionalisation, namely to develop a common language and a set of principles to guide practice, and to ensure the allocation of resources in order to facilitate the SL teaching methodology.The contextualised SL definition that was formulated for the SoN contributes to the SL operationalisation discourse at the HEI.


The return of the frogs: The importance of habitat refugia in maintaining diversity during a disease outbreak.
Recent decades have seen the emergence and spread of numerous infectious diseases, often with severe negative consequences for wildlife populations. Nevertheless, many populations survive the initial outbreaks, and even undergo recoveries. Unfortunately, the long-term effects of these outbreaks on host population genetics are poorly understood; to increase this understanding, we examined the population genetics of two species of rainforest frogs (Litoria nannotis and Litoria serrata) that have largely recovered from a chytridiomycosis outbreak at two national parks in the Wet Tropics of northern Australia. At the wetter, northern park there was little evidence of decreased genetic diversity in either species, and all of the sampled sites had high minor allele frequencies (mean MAF = 0.230-0.235), high heterozygosity (0.318-0.325), and few monomorphic markers (1.4%-4.0%); however, some recovered L. nannotis populations had low Ne values (59.3-683.8) compared to populations that did not decline during the outbreak (1,537.4-1,756.5). At the drier, southern park, both species exhibited lower diversity (mean MAF = 0.084-0.180; heterozygosity = 0.126-0.257; monomorphic markers = 3.7%-43.5%; Ne = 18.4-676.1). The diversity patterns in this park matched habitat patterns, with both species having higher diversity levels and fewer closely related individuals at sites with higher quality habitat. These patterns were more pronounced for L. nannotis, which has lower dispersal rates than L. serrata. These results suggest that refugia with high quality habitat are important for retaining genetic diversity during disease outbreaks, and that gene flow following disease outbreaks is important for re-establishing diversity in populations where it was reduced.


Interactive effects of ethanol and nicotine on learning in C57BL/6J mice depend on both dose and duration of treatment.
Alcohol and nicotine are commonly co-abused; one possible explanation for co-abuse is that each drug ameliorates the aversive effects of the other. Both drugs have dose-dependent effects on learning and memory. Thus, this study examined the interactive effects of acute ethanol and acute, chronic, or withdrawal from chronic nicotine on fear conditioning in C57BL/6J mice. Conditioning consisted of auditory conditioned stimulus-foot-shock unconditioned stimulus pairings. For acute studies, saline or ethanol, then saline or nicotine was administered before training, and saline or nicotine was also administered before testing. For chronic and withdrawal studies, saline or nicotine was administered chronically, and ethanol or saline was administered before training. Acute nicotine (0.09 mg/kg) reversed ethanol-induced deficits (1.0 and 1.5 g/kg) in contextual and cued fear conditioning, whereas a low dose of ethanol (0.25 g/kg) reversed nicotine (6.3 mg kg(-1) day(-1)) withdrawal-induced deficits in contextual conditioning. Tolerance developed for the effects of nicotine on ethanol-induced deficits in conditioning and cross-tolerance between chronic nicotine and acute ethanol was seen for the enhancing effects of ethanol on conditioning. The complex and sometimes polar actions of ethanol and nicotine on behavior may contribute to co-abuse of these drugs. Specifically, smoking may initially reduce the aversive effects of ethanol, but tolerance develops for this effect. In addition, low doses of alcohol may lessen nicotine withdrawal symptoms.


Risk-taking coping style correlates with SERT SNP290 polymorphisms in free-living great tits.
The coping style of an individual in relation to potentially dangerous situations has been suggested to be inherited in a polygenic fashion, SERT being one of the candidate genes. In this study, we assessed in free-living great tits (Parus major) the association between SNP290 in the SERT promoter and three standard fear-related behaviors: the response of the birds to a black-and-white flag fixed to the top of the nest box, distress calling rate of the birds in the hand once captured and the hissing call of incubating females when approached by a predator. We found a strong association between SNP290 polymorphism and the three risk-taking behaviors, with birds with genotype CT entering the nest box with the flag faster and displaying more distress calls and fewer hissing calls. CT birds could therefore be described as more proactive than CC individuals. These results also suggest that hissing behavior should be regarded as a fear-induced shy behavior, and confirm that SERT has an important function in relation to risk aversion behaviors and coping style.


Rationally designed transition metal hydroxide nanosheet arrays on graphene for artificial CO2 reduction.
The performance of transition metal hydroxides, as cocatalysts for CO2 photoreduction, is significantly limited by their inherent weaknesses of poor conductivity and stacked structure. Herein, we report the rational assembly of a series of transition metal hydroxides on graphene to act as a cocatalyst ensemble for efficient CO2 photoreduction. In particular, with the Ru-dye as visible light photosensitizer, hierarchical Ni(OH)2 nanosheet arrays-graphene (Ni(OH)2-GR) composites exhibit superior photoactivity and selectivity, which remarkably surpass other counterparts and most of analogous hybrid photocatalyst system. The origin of such superior performance of Ni(OH)2-GR is attributed to its appropriate synergy on the enhanced adsorption of CO2, increased active sites for CO2 reduction and improved charge carriers separation/transfer. This work is anticipated to spur rationally designing efficient earth-abundant transition metal hydroxides-based cocatalysts on graphene and other two-dimension platforms for artificial reduction of CO2 to solar chemicals and fuels.


Aortic Intima-Media Thickness in Newborns with Congenital Hypothyroidism.
Congenital hypothyroidism (CH) in neonates is associated with lipid alterations that might be a risk factor for early cardiovascular disease in adult life. The aim of this study was to investigate the effect of CH on lipid metabolism and aortic intima media thickness (aIMT) as a unique finding of the increased risk of atherogenic risk in neonatal age. The study group consisted of 15 newborns with CH who were identified by neonatal mass screening (patient group), and 25 healthy newborns (control group). Serum lipid profiles and aIMT obtained from abdominal aorta were measured in all subjects. The mean aIMT were higher in the patient group (0.46 ± 0.062 mm) compared with the control group (0.34 ± 0.035 mm; p = 0.006). The weight-adjusted aIMT of patients (0.13 ± 0.017 mm/kg) was also significantly greater than that of the controls (0.10 ± 0.019 mm/kg; p < 0.001). Total serum cholesterol levels were significantly higher in patients than those in healthy controls (130.80 ± 44.46 vs. 99.96 ± 18.87 mg/dl). The other lipid levels including triglyceride, low-density lipoprotein (LDL), high-density lipoprotein cholesterol and LDL cholesterol levels of the patients were slightly higher than those of the controls, without statistical significance. Neonates with CH have significantly higher aIMT with lipid alterations. Hypothyroidism might increase the risk of early atherosclerosis even in the neonatal period.


Universal health coverage in emerging economies: findings on health care utilization by older adults in China, Ghana, India, Mexico, the Russian Federation, and South Africa.
The achievement of universal health coverage (UHC) in emerging economies is a high priority within the global community. This timely study uses standardized national population data collected from adults aged 50 and older in China, Ghana, India, Mexico, the Russian Federation, and South Africa. The objective is to describe health care utilization and measure association between inpatient and outpatient service use and patient characteristics in these six low- and middle-income countries. Secondary analysis of data from the World Health Organization's Study on global AGEing and adult health Wave 1 was undertaken. Country samples are compared by socio-demographic characteristics, type of health care, and reasons for use. Logistic regressions describe association between socio-demographic and health factors and inpatient and outpatient service use. In the pooled multi-country sample of over 26,000 adults aged 50-plus, who reported getting health care the last time it was needed, almost 80% of men and women received inpatient or outpatient care, or both. Roughly 30% of men and women in the Russian Federation used inpatient services in the previous 3 years and 90% of men and women in India used outpatient services in the past year. In China, public hospitals were the most frequently used service type for 52% of men and 51% of women. Multivariable regression showed that, compared with men, women were less likely to use inpatient services and more likely to use outpatient services. Respondents with two or more chronic conditions were almost three times as likely to use inpatient services and twice as likely to use outpatient services compared with respondents with no reported chronic conditions. This study provides a basis for further investigation of country-specific responses to UHC.


Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial.
Moderate vitamin B-12 deficiency is relatively common in older people. However, there is little robust evidence on the effect of vitamin B-12 supplementation on neurologic and cognitive outcomes in later life. We investigated whether vitamin B-12 supplementation benefits neurologic and cognitive function in moderately vitamin B-12-deficient older people. We conducted a double-blind, randomized, placebo-controlled trial in 7 general practices in South East England, United Kingdom. Study participants were aged ≥75 y and had moderate vitamin B-12 deficiency (serum vitamin B-12 concentrations: 107-210 pmol/L) in the absence of anemia and received 1 mg crystalline vitamin B-12 or a matching placebo as a daily oral tablet for 12 mo. Peripheral motor and sensory nerve conduction, central motor conduction, a clinical neurologic examination, and cognitive function were assessed before and after treatment. A total of 201 participants were enrolled in the trial, and 191 subjects provided outcome data. Compared with baseline, allocation to vitamin B-12 was associated with a 177% increase in serum concentration of vitamin B-12 (641 compared with 231 pmol/L), a 331% increase in serum holotranscobalamin (240 compared with 56 pmol/L), and 17% lower serum homocysteine (14.2 compared with 17.1 μmol/L). In intention-to-treat analysis of covariance models, with adjustment for baseline neurologic function, there was no evidence of an effect of supplementation on the primary outcome of the posterior tibial compound muscle action potential amplitude at 12 mo (mean difference: -0.2 mV; 95% CI: -0.8, 0.3 mV). There was also no evidence of an effect on any secondary peripheral nerve or central motor function outcome, or on cognitive function or clinical examination. Results of the trial do not support the hypothesis that the correction of moderate vitamin B-12 deficiency, in the absence of anemia and of neurologic and cognitive signs or symptoms, has beneficial effects on neurologic or cognitive function in later life. This trial was registered at www.isrctn.com as ISRCTN54195799.


Intradermal cytosine-phosphate-guanosine treatment reduces lung inflammation but induces IFN-γ-mediated airway hyperreactivity in a murine model of natural rubber latex allergy.
Asthma and other allergic diseases are continuously increasing, causing considerable economic and sociologic burden to society. The hygiene hypothesis proposes that lack of microbial T helper (Th) 1-like stimulation during early childhood leads to increased Th2-driven allergic disorders later in life. Immunostimulatory cytosine-phosphate-guanosine (CpG)-oligodeoxynucleotide motifs are candidate molecules for immunotherapeutic studies, as they have been shown to shift the Th2 response toward the Th1 direction and reduce allergic symptoms. Using natural rubber latex (NRL)-induced murine model of asthma, we demonstrated that intradermal CpG administration with allergen reduced pulmonary eosinophilia, mucus production, and Th2-type cytokines, but unexpectedly induced airway hyperreactivity (AHR) to inhaled methacholine, one of the hallmarks of asthma. We found that induction in AHR was dependent on STAT4, but independent of STAT6 signaling. CpG treatment increased production of IFN-γ in the airways and shifted the ratio of CD4(+):CD8(+) T cells toward CD8(+) dominance. By blocking soluble IFN-γ with neutralizing antibody, AHR diminished and the CD4(+):CD8(+) ratio returned to CD4(+) dominance. These results indicate that increased production of IFN-γ in the lungs may lead to severe side effects, such as enhancement of bronchial hyperreactivity to inhaled allergen. This finding should be taken into consideration when planning prophylaxis treatment of asthma with intradermal CpG injections.


Comparison of Campylobacter populations in wild geese with those in starlings and free-range poultry on the same farm.
Wild geese are a potential source of Campylobacter infection for humans and farm animals and have been implicated in at least two large waterborne disease outbreaks. There have been few investigations into the population biology of Campylobacter in geese, carriage rates are reported to vary (0 to 100%), and no genetic characterization of isolates has been performed. Fecal samples collected from wild geese in Oxfordshire, United Kingdom, were culture positive for C. jejuni (50.2%) and C. coli (0.3%). The C. jejuni (n = 166) isolates were characterized by using multilocus sequence typing and were compared with isolates collected from free-range broiler chickens and wild starlings sampled at the same location. A total of 38 STs, six clonal complexes, and 23 flaA SVR nucleotide STs were identified. The ST-21 and ST-45 complexes (5.4% of isolates) were the only complexes to be identified among isolates from the geese and the other bird species sampled in the same location. These clonal complexes were also identified among human disease isolates collected in the same health care region. The results indicate that large numbers of wild geese carry Campylobacter; however, there was limited mixing of Campylobacter populations among the different sources examined, and the host source could be predicted with high probability from the allelic profile of a C. jejuni isolate. In conclusion, genotypes of C. jejuni isolated from geese are highly host specific, and a comparison with isolates from Oxfordshire cases of human disease revealed that while geese cannot be excluded as a source of infection for humans and farm animals, their contribution is likely to be minor.


Redistribution of Mechanical Work at the Knee and Ankle Joints During Fast Running in Minimalist Shoes.
Minimalist shoes have been suggested as a way to alter running biomechanics to improve running performance and reduce injuries. However, to date, researchers have only considered the effect of minimalist shoes at slow running speeds. To determine if runners change foot-strike pattern and alter the distribution of mechanical work at the knee and ankle joints when running at a fast speed in minimalist shoes compared with conventional running shoes. Crossover study. Research laboratory. Twenty-six trained runners (age = 30.0 ± 7.9 years [age range, 18-40 years], height = 1.79 ± 0.06 m, mass = 75.3 ± 8.2 kg, weekly training distance = 27 ± 15 km) who ran with a habitual rearfoot foot-strike pattern and had no experience running in minimalist shoes. Participants completed overground running trials at 18 km/h in minimalist and conventional shoes. Sagittal-plane kinematics and joint work at the knee and ankle joints were computed using 3-dimensional kinematic and ground reaction force data. Foot-strike pattern was classified as rearfoot, midfoot, or forefoot strike based on strike index and ankle angle at initial contact. We observed no difference in foot-strike classification between shoes (χ21 = 2.29, P = .13). Ankle angle at initial contact was less (2.46° versus 7.43°; t25 = 3.34, P = .003) and strike index was greater (35.97% versus 29.04%; t25 = 2.38, P = .03) when running in minimalist shoes compared with conventional shoes. We observed greater negative (52.87 J versus 42.46 J; t24 = 2.29, P = .03) and positive work (68.91 J versus 59.08 J; t24 = 2.65, P = .01) at the ankle but less negative (59.01 J versus 67.02 J; t24 = 2.25, P = .03) and positive work (40.37 J versus 47.09 J; t24 = 2.11, P = .046) at the knee with minimalist shoes compared with conventional shoes. Running in minimalist shoes at a fast speed caused a redistribution of work from the knee to the ankle joint. This finding suggests that runners changing from conventional to minimalist shoes for short-distance races could be at an increased risk of ankle and calf injuries but a reduced risk of knee injuries.


Phylogeography of recently emerged DENV-2 in southern Viet Nam.
Revealing the dispersal of dengue viruses (DENV) in time and space is central to understanding their epidemiology. However, the processes that shape DENV transmission patterns at the scale of local populations are not well understood, particularly the impact of such factors as human population movement and urbanization. Herein, we investigated trends in the spatial dynamics of DENV-2 transmission in the highly endemic setting of southern Viet Nam. Through a phylogeographic analysis of 168 full-length DENV-2 genome sequences obtained from hospitalized dengue cases from 10 provinces in southern Viet Nam, we reveal substantial genetic diversity in both urban and rural areas, with multiple lineages identified in individual provinces within a single season, and indicative of frequent viral migration among communities. Focusing on the recently introduced Asian I genotype, we observed particularly high rates of viral exchange between adjacent geographic areas, and between Ho Chi Minh City, the primary urban center of this region, and populations across southern Viet Nam. Within Ho Chi Minh City, patterns of DENV movement appear consistent with a gravity model of virus dispersal, with viruses traveling across a gradient of population density. Overall, our analysis suggests that Ho Chi Minh City may act as a source population for the dispersal of DENV across southern Viet Nam, and provides further evidence that urban areas of Southeast Asia play a primary role in DENV transmission. However, these data also indicate that more rural areas are also capable of maintaining virus populations and hence fueling DENV evolution over multiple seasons.


Temperature thresholds of physically dormant seeds and plant functional response to fire: variation among species and relative impact of climate change.
Variation in dormancy thresholds among species is rarely studied but may provide a basis to better understand the mechanisms controlling population persistence. Incorporating dormancy-breaking temperature thresholds into existing trait frameworks could improve predictions regarding seed bank persistence, and subsequently species resilience in response to fire, climate change and anthropogenic management. A key ecological strategy for many species from fire-prone ecosystems is the possession of a long-lived seed bank, ensuring recovery after fire. Physical dormancy is dominant in these ecosystems and maintaining this dormancy is directly linked to seed bank persistence. We identified a suite of seed-related factors relevant to maintaining populations in fire-prone regions for 14 co-occurring physically dormant species. We measured variation in initial levels of dormancy and then applied experimental heating treatments, based on current seasonal temperatures and those occurring during fires, to seeds of all study species. Additionally, higher seasonal temperature treatments were applied to assess response of seeds to temperatures projected under future climate scenarios. Levels of germination response and mortality were determined to assess how tightly germination response was bound to either fire or seasonal cues. Six species were found to have dormancy cues bound to temperatures that only occur during fires (80°C and above) and were grouped as having obligate pyrogenic dormancy release. The remaining species, classified as having facultative pyrogenic dormancy, had lower temperature dormancy thresholds and committed at least 30% of seeds to germinate after summer-temperature treatments. Evidence from this study supports including dormancy-breaking temperature thresholds as an attribute for identifying functional types. High temperature thresholds for breaking dormancy, found in our obligate pyrogenic group, appear to be a fire-adapted trait, while we predict that species in the facultative group are most at risk to increased seed bank decay resulting from elevated soil temperatures under projected climate change.


Observations on the fine structure of the developing spermatid in the domestic chicken.
The kinetic apparatus, the acrosome and associated structures, and the manchette of the spermatid of the domestic chicken have been studied with the electron microscope. The basic structural features of the two centrioles do not change during spermiogenesis, but there is a change in orientation and length. The proximal centriole is situated in a groove at the edge of the nucleus and oriented normal to the long axis of the nucleus and at right angles to the elongate distal centriole. The tail filaments appear to originate from the distal centriole. The plasma membrane is invaginated along the tail filaments. A dense structure which appears at the deep reflection of the plasma membrane is identified as the ring. The fine structure of the ring has no resemblance to that of a centriole and there is no evidence that it is derived from or related to the centrioles. The tail of the spermatid contains nine peripheral pairs and one central pair of tubular filaments. The two members of each pair of peripheral filaments differ in density and in shape: one is dense and circular, and the other is light and semilunar in cross-section. The dense filaments have processes. A manchette consisting of fine tubules appears in the cytoplasm of the older spermatid along the nucleus, neck region, and proximal segment of the tail. The acrosome is spherical in young spermatids and becomes crescentic and, finally, U-shaped as spermiogenesis proceeds. A dense granule is observed in the cytoplasm between acrosome and nucleus. This granule later becomes a dense rod which is interpreted as the perforatorium.


A review of the application of molecular genetics for fisheries management and conservation of sharks and rays.
Since the first investigation 25 years ago, the application of genetic tools to address ecological and evolutionary questions in elasmobranch studies has greatly expanded. Major developments in genetic theory as well as in the availability, cost effectiveness and resolution of genetic markers were instrumental for particularly rapid progress over the last 10 years. Genetic studies of elasmobranchs are of direct importance and have application to fisheries management and conservation issues such as the definition of management units and identification of species from fins. In the future, increased application of the most recent and emerging technologies will enable accelerated genetic data production and the development of new markers at reduced costs, paving the way for a paradigm shift from gene to genome-scale research, and more focus on adaptive rather than just neutral variation. Current literature is reviewed in six fields of elasmobranch molecular genetics relevant to fisheries and conservation management (species identification, phylogeography, philopatry, genetic effective population size, molecular evolutionary rate and emerging methods). Where possible, examples from the Indo-Pacific region, which has been underrepresented in previous reviews, are emphasized within a global perspective.


Divergent and synergistic regulation of matrix metalloprotease production by cytokines in combination with C-C chemokines.
The chemotactic effects of chemokines on cells has long been known, but it is now clear that chemokines also have much broader activities and are also involved in a number of disease pathologies, such as rheumatoid arthritis, cancer metastasis and other inflammatory processes. This study investigates the effects of four C-C chemokines, CCL2, CCL3, CCL4 and CCL5 either alone or in the presence of two regulatory cytokines TNF-alpha and TGF-beta and their effect on secretion of two matrix metalloproteases MMP, MMP-2 and MMP-9, and the expression of one membrane bound MMP, MMP-14, by a monocytic human cell line, MonoMac6. All four C-C chemokines were shown to be chemotactic, but only CCL2 and CCL4 had any significant stimulatory effect on MMP-9 and MMP-2, respectively. Both TNF-alpha and TGF-beta were found to divergently enhance MMP-9 and MMP-2 secretion respectively, with stimulation indexes of two and five respectively. Simultaneous treatment with TNF-alpha and chemokine resulted in up to a fifteen-fold stimulation of MMP-9 secretion and treatment with TGF-beta and chemokine resulted in up to a fifteen-fold stimulation of MMP-2 secretion, while TNF-alpha in combination with CCL4 stimulated MMP-14 expression five-fold. Chemokine receptor expression was also investigated using a calcium-sensitive dye and FACS analysis. CCL2, CCL3, and CCL5 all resulted in a detectable enhancement of cytoplasmic Ca2+concentration. CCL4 was unable to activate Ca2+ mobilization, despite the presence of CCR5, the receptor for CCL4. There appeared to be no correlation between MMP production and chemotaxis. The strong synergy between chemokines and cytokines and the enhanced production of MMP may signify the differential regulatory mechanisms of the two cytokines and chemokines in disease pathology.


Can the Closed-Shell DFT Methods Describe the Thermolysis of 1,2-Dioxetanone?
The chemiluminescent decomposition of 1,2-dioxetanone has in the past been studied by state-of-the-art multireference quantum chemical calculations, and a stepwise biradical mechanism was established. Recently, this decomposition has been reinvestigated, and a concerted mechanism has been proposed based on calculations performed at the closed-shell density functional theory (DFT) level of theory. In order to solve this apparent mechanistic contradiction, the present paper presents restricted and unrestricted DFT results obtained using functionals including different amounts of Hartree-Fock (HF) exchange, repeating and complementing the above-mentioned DFT calculations. The calculated results clearly indicate that the closed-shell DFT methods cannot correctly describe the thermolysis of 1,2-dioxetanone. It is found that unrestricted Kohn-Sham reaction energies and barriers are always lower than the ones obtained using a restricted formalism. Hence, from energy principles, the biradical mechanism is found to be prevailing in the understanding of the 1,2-dioxetanone thermolysis.


Non-invasive Transcranial Magnetic Stimulation (TMS) of the Motor Cortex for Neuropathic Pain-At the Tipping Point?
The term "neuropathic pain" (NP) refers to chronic pain caused by illnesses or injuries that damage peripheral or central pain-sensing neural pathways to cause them to fire inappropriately and signal pain without cause. Neuropathic pain is common, complicating diabetes, shingles, HIV, and cancer. Medications are often ineffective or cause various adverse effects, so better approaches are needed. Half a century ago, electrical stimulation of specific brain regions (neuromodulation) was demonstrated to relieve refractory NP without distant effects, but the need for surgical electrode implantation limited use of deep brain stimulation. Next, electrodes applied to the dura outside the brain's surface to stimulate the motor cortex were shown to relieve NP less invasively. Now, electromagnetic induction permits cortical neurons to be stimulated entirely non-invasively using transcranial magnetic stimulation (TMS). Repeated sessions of many TMS pulses (rTMS) can trigger neuronal plasticity to produce long-lasting therapeutic benefit. Repeated TMS already has US and European regulatory approval for treating refractory depression, and multiple small studies report efficacy for neuropathic pain. Recent improvements include "frameless stereotactic" neuronavigation systems, in which patients' head MRIs allow TMS to be applied to precise underlying cortical targets, minimizing variability between sessions and patients, which may enhance efficacy. Transcranial magnetic stimulation appears poised for the larger trials necessary for regulatory approval of a NP indication. Since few clinicians are familiar with TMS, we review its theoretical basis and historical development, summarize the neuropathic pain trial results, and identify issues to resolve before large-scale clinical trials.


Intra-Articular Biocompatibility of Multistranded, Long-Chain Polyethylene Suture Tape in a Canine ACL Model.
The purpose of this study was to assess intra-articular use of a nonabsorbable braided suture tape for its biocompatibility when implanted adjacent to the native anterior cruciate ligament (ACL) in a canine model. Establishing biocompatibility of suture tape in the knee is an important foundational step for clinicians considering use of suture tape augmentation for ACL reconstruction or repair. The study hypothesis was that a nonabsorbable braided suture tape would be biocompatible in the knee with no resultant adverse functional consequences, and no significant intra-articular synovial reactions or articular cartilage degeneration attributable to direct exposure to the suture tape, whether intact or transected. Nonabsorbable braided suture tape was arthroscopically implanted adjacent to the native ACL of dogs (n = 6). The suture was intact in half of the dogs and was transected in the other half as a "worst-case" scenario. Dogs were assessed for postoperative complications and morbidity. Arthroscopic grading of synovium and cartilage was performed at 4 and 6 months. Histologic assessments were performed at the 6-month endpoint and compared with the ACL partial tear (n = 9) and ACL reconstruction (n = 5) cohorts as well as historical sham controls. No postoperative complications were noted. No animal developed lameness or clinical dysfunction, and there were no severe inflammatory or immune responses, cartilage erosions, or premature osteoarthritis noted. Arthroscopic assessments revealed no to mild synovitis and no apparent cartilage damage in either group. Histologically, both the intact and transected suture tape groups were associated with significantly (p ≤ 0.05) less synovial and articular cartilage pathology compared with the partial ACL transection and patellar bone-tendon-bone ACL autograft reconstruction cohorts, and matched historical sham controls. The hypothesis was accepted as study results support the biocompatibility of suture tape in the canine knee.


Relationship between perception of emotional home atmosphere and fruit and vegetable consumption in European adolescents: results from the I.Family survey.
Consumption of fruits and vegetables (F&V) among adolescents falls below recommendations in many Western countries. The impact of social and emotional aspects of family life on adolescent dietary behaviour may contribute to this, yet remains under-investigated. The present study examines the association between adolescents' perceptions of emotional home atmosphere (EHA) and their F&V consumption frequency. An FFQ was used to assess F&V consumption frequency. EHA was assessed by an eight-item measure with three subscales: perceived home warmth, strictness and relational tension. EHA subscales were used as binary variables: a score equal to or above the median value was considered as a higher perception, while a score below the median was considered as a lower perception of the EHA in question. Country differences in meeting the European 5-a-day recommendations were described. Further, the association between EHA and F&V consumption frequency was investigated using multiple linear regression. Regional examination centres in eight European countries. Adolescents (n 3196) aged 12-18 years. The mean F&V consumption frequency was 3·27 (sd 2·84) times/d. Only 16·1 % of boys and 18 % of girls in our study sample met the recommendation of five F&V daily. After controlling for age, sex, education level of the parents and country of origin, perceived home warmth was associated with a 16 (95 % CI 9, 22) % higher F&V consumption frequency (P < 0·001). F&V consumption frequency was suboptimal in the survey areas. Interventions targeting perceived warmth as a component of EHA could potentially have a positive effect on adolescents' dietary behaviour.


Duplication of 111 bases in exon 1 of the CYP21 gene is combined with deletion of CYP21P-C4B genes in steroid 21-hydroxylase deficiency.
Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder mainly caused by defects in the steroid 21-hydroxylase (CYP21) gene. A 9.3-kb fragment generated by NdeI and AseI digestion by Southern blot analysis indicated that a consequence of deletion of the C4-CYP21 repeat module was the production of a distinct chimeric CYP21P/CYP21 molecule. In the present study, we report a novel CYP21 genotype in two CAH families in which the gene appeared as 9.4- and 3.3-kb fragments by TaqI digestion, rather than as a chimeric gene. From the analysis of PCR amplification patterns and DNA sequencing, we found that there was a duplication of 111 bases from codons 21 to 57 inserted at codon 58 in exon 1 of the CYP21 gene. In addition, codon 21 in the repeated sequence changed from TGG to AGG. Furthermore, this novel CYP21 gene present in both CAH families showed no mutations at IVS2-12A/C>G, 707-714delGAGACTAC, and P30L. Interestingly, the 5' end region of these two CYP21 genes showed the sequence of the CYP21P gene at nucleotides (nt) -103, -110, -123, and thereafter. Our data suggest that these two CYP21 genes are caused by deletion of the CYP21P, XA, RP2, and C4B genes. Possibly, the additional 111-base duplicated coding sequence may be generated by multiple intergenic recombinations, while there seems to be no relationship with deletion of the CYP21P-C4B regions.


Pre-embedding staining for GAD67 versus postembedding staining for GABA as markers for central GABAergic terminals.
Pre-embedding immunocytochemistry for the active form of glutamate decarboxylase (GAD67) and postembedding staining for gamma-aminobutyric acid (GABA) were compared as markers for central GABAergic terminals in the phrenic motor nucleus, in which phrenic motor neurons had been retrogradely labeled with cholera toxin B-horseradish peroxidase. Nerve terminals with or without GAD67 immunoreactivity were identified in one ultrathin section. GABA was localized with immunogold in an adjacent section after etching and bleaching. GABA labeling density was assessed over 519 GAD67-positive and GAD67-negative nerve terminals in the phrenic motor nucleus. Frequency histograms showed that statistically higher densities of gold particles occurred over most GAD67-positive terminals. However, some GAD67-negative terminals also showed high densities of gold particles, and some GAD67-positive terminals showed low densities. Preabsorption of the anti-GABA antibody with a GABA-protein conjugate, but not with other amino acid-protein conjugates, significantly reduced gold labeling over both GAD67-positive and GAD67-negative terminals. These results show that the presence of GAD67 immunoreactivity correlates strongly with high densities of immunogold labeling for GABA in nerve terminals in the phrenic motor nucleus. Preabsorption controls indicate that authentic GABA was localized in the postembedding labeling procedure. Only a small proportion of intensely GABA-immunoreactive terminals lack GAD67, suggesting that both GAD67 and GABA are reliable markers of GABAergic nerve terminals.


The STAT3-Ser/Hes3 signaling axis in cancer.
Disrupting the regenerative capacity of tumorigenic cells is a major focus in medicine. These regenerative properties are carried by a subpopulation of cells within the tumor, termed cancer stem cells. Current therapies don't effectively tackle the disease suggesting these cells employ yet unidentified molecular mechanisms allowing them to evade targeting. Recent observations in neural stem cells reveal an extraordinary plasticity in the signaling pathways they utilize to grow. These findings are being extended to the cancer stem cell field, illuminating conceptually novel treatment strategies. Tumorigenic cells can make use of distinct, even opposing pathways, including JAK/STAT and the non-canonical STAT3-Ser/Hes3 signaling axis. This plasticity may not be confined to the cancer stem cell population, but may be shared by various cell types within the tumor, blurring the line distinguishing cancer stem cells from other tumor cell types. The implications to anti-cancer medicine are highly significant, since these findings demonstrate that inhibiting one cell growth pathway may actually enhance the activity of alternative ones. Drug discovery programs will also benefit from these concepts.


Trait anxiety is associated with hidden state inference during aversive reversal learning.
Updating beliefs in changing environments can be driven by gradually adapting expectations or by relying on inferred hidden states (i.e. contexts), and changes therein. Previous work suggests that increased reliance on context could underly fear relapse phenomena that hinder clinical treatment of anxiety disorders. We test whether trait anxiety variations in a healthy population influence how much individuals rely on hidden-state inference. In a Pavlovian learning task, participants observed cues that predicted an upcoming electrical shock with repeatedly changing probability, and were asked to provide expectancy ratings on every trial. We show that trait anxiety is associated with steeper expectation switches after contingency reversals and reduced oddball learning. Furthermore, trait anxiety is related to better fit of a state inference, compared to a gradual learning, model when contingency changes are large. Our findings support previous work suggesting hidden-state inference as a mechanism behind anxiety-related to fear relapse phenomena.


Bringing host-cell takeover by pathogenic bacteria to center stage.
Intracellular pathogenic bacteria contrive processes in their host cell to create a niche for their own reproduction. One way that has emerged by which bacteria do that is delivery of secreted virulence factors, SVFs, to the cytoplasm of the host cells using the bacterial type IV secretion system, T4SS. These SVFs modulate the activity of their target host proteins, which in turn control key cellular processes. A major mechanism for the evolution of SVFs that modulate targets that do not exist in the bacterial kingdom is horizontal gene transfer. Recently, a number of bacterial SVFs were shown to act on two types of targets in host cells. First, a group of several SVFs modulate the activity and localization of one protein: Rab1 GTPase, a key regulator of intracellular trafficking. Second, ankyrin repeats-containing SVFs, referred to by microbiologists as Anks, interact with various binding proteins, which in turn regulate a myriad of cellular processes, including apoptosis. Modulation of trafficking and apoptosis are two examples of how invading bacteria takeover their host phagocyte, which instead of destroying the bacteria becomes a factory for its reproduction.


Are we closing the Aboriginal child injury gap? A cohort study.
To assess if rates of hospitalised injury in Australian Aboriginal children, and differences in these rates between Aboriginal and non-Aboriginal children, have changed over time. We used linked hospital data for New South Wales (NSW), Australia, to construct cohorts of children born in NSW hospitals between 2003-2007 and 2008-2012. We calculated rates of hospitalised injuries per 10,000 person years for Aboriginal and non-Aboriginal children for both cohorts, and compared these using rate differences and rate ratios. Rates of unintentional injury hospitalisation were similar in Aboriginal children in both cohorts and Aboriginal children had 1.7 times higher rates of unintentional injury hospitalisation compared with non-Aboriginal children. Rate ratios between Aboriginal and non-Aboriginal children for leading injury mechanisms, burns, poisonings and transport were similar in both cohorts, with 2.5, 3.0 and 2.4 times higher rates in Aboriginal children in the 2008-2012 cohort, respectively. Conclusions and Implications for public health: Our findings suggest that current injury prevention measures have not been successful in reducing either rates of unintentional injury in Aboriginal children, or injury inequalities between Aboriginal and non-Aboriginal children. We recommend the implementation of targeted Aboriginal led injury prevention measures.


An individual-based versus group-based exercise and counselling intervention for improving quality of life in breast cancer survivors. A feasibility and efficacy study.
Cancer and its treatments produce lingering side-effects that undermine the quality of life (QOL) of survivors. Exercise and psycho-therapies increase QOL among survivors, however, research is needed to identify intervention characteristics most associated with such improvements. This research aimed to assess the feasibility of a 9 week individual or group based exercise and counselling program, and to examine if a group based intervention is as effective at improving the QOL of breast cancer survivors as an individual-based intervention. A three group design was implemented to compare the efficacy of a 9 week individual (IEC n = 12) and group based exercise and counselling (GEC n = 14) intervention to a usual care (UsC n = 10) group on QOL of thirty-six breast cancer survivors. Across all groups, 90% of participants completed the interventions, with no adverse effects documented. At the completion of the intervention, there was a significant difference between groups for change in global QOL across time (p < 0.023), with IEC improving significantly more (15.0 points) than the UsC group (1.8 points). The effect size was moderate (0.70). Although the GEC improved QOL by almost 10.0 points, this increase did not reach significance. Both increases were above the minimally important difference of 7-8 points. These preliminary results suggest a combined exercise and psychological counseling program is both a feasible and acceptable intervention for breast cancer survivors. Whilst both the individual and group interventions improved QOL above the clinically important difference, only the individual based intervention was significant when compared to UsC.


A pharmacological study on pegylated asparaginase used in front-line treatment of children with acute lymphoblastic leukemia.
Pegylated-asparaginase (PEG-ASP) has been traditionally used as a second-line preparation in children with acute lymphoblastic leukemia (ALL) presenting with clinical allergy to native asparaginase (ASP) products. The main goal of the present study was to investigate the pharmacological effects of the administration of PEG-ASP given as a first-line product in children with ALL. PEG-ASP serum enzymatic activity and serum and cerebrospinal fluid (CSF) levels of asparagine were investigated in 20 children with newly diagnosed ALL enrolled in the ongoing AIEOP ALL 2000 protocol and treated with PEG-ASP as a first-line ASP preparation. During induction the drug was administered at the dosage of 1,000 U/m2 i.v. on days 12 and 27. During reinduction the drug was administered only once at the same dosage. Among the 20 patients treated in induction serum PEG-ASP activity equalled or exceeded 100 U/L in 18/18, 11/11 and 15/18 of the samples available on days 22, 25 and 27, respectively, and in 16/16, 12/15 and 5/8 samples available on days 36, 39 and 45, respectively. In the 15 patients treated during reinduction serum PEG-ASP activity > or =100 U/L was observed in 14/15, 11/14, 6/10, and 0/12 samples available on days 11, 15, 18 and 23, respectively, after the administration of the drug. Serum asparagine levels were below the detection limit (< or =0.2 microM) in all patients/samples and at all time points evaluated during induction; during reinduction only one patient had detectable asparagine levels from day 11. CSF asparagine levels were below the detection limit of the method only in a few patients during both induction and reinduction. PEG-ASP given as a first-line ASP product in the context of an intensive chemotherapy protocol for pediatric ALL allowed adequate plasma enzymatic activity and asparagine depletion during both exposures to the drug. However, CSF asparagine depletion was inadequate.


Effects of exercise training on fasting insulin, insulin resistance, insulin-like growth factors, and insulin-like growth factor binding proteins in postmenopausal breast cancer survivors: a randomized controlled trial.
Insulin, insulin-like growth factors (IGFs) I and II, and IGF binding proteins (IGFBPs) 1 and 3 have been implicated in breast cancer outcomes. We conducted a randomized controlled trial to determine the physiological effects of exercise training on changes in these biological markers in postmenopausal breast cancer survivors. Fifty-three postmenopausal breast cancer survivors were randomly assigned to an exercise (n = 25) or control group (n = 28). The exercise group trained on cycle ergometers three times per week for 15 weeks. The control group did not train. End points included changes in fasting insulin, glucose, insulin resistance, IGF-I, IGF-II, IGFBP-1, IGFBP-3, and IGF-I:IGFBP-3 molar ratio between baseline and week 15. All of the statistical tests were two-sided (alpha = 0.05). Fifty-two participants completed the trial. The exercise group completed 44.3 of 45 (98.4%) prescribed exercise sessions. Baseline hormone concentrations did not differ between groups except that IGF-II was higher in the exercise group (P = 0.011). No significant differences between groups were observed for changes in fasting insulin (+6.3 pmol/liter; P = 0.941), glucose (+0.09 mmol/liter; P = 0.824), insulin resistance (+0.4; P = 0.247), IGF-II (-40.7 ng/ml; P = 0.101), or IGFBP-1 (+1.4 ng/ml; P = 0.774). However, significant differences between groups were observed for changes in IGF-I (-7.4 ng/ml; P = 0.045), IGFBP-3 (+180.5 ng/ml; P = 0.021), and IGF-I:IGFBP-3 molar ratio (-0.006; P = 0.017). Exercise training had significant physiological effects on IGF-I, IGFBP-3, and IGF-I:IGFBP-3 molar ratio in postmenopausal breast cancer survivors. The clinical implications of these findings remain to be defined.


Laboratory-confirmed cholera and rotavirus among patients with acute diarrhea in four hospitals in Haiti, 2012-2013.
An outbreak of cholera began in Haiti in October of 2010. To understand the progression of epidemic cholera in Haiti, in April of 2012, we initiated laboratory-enhanced surveillance for diarrheal disease in four Haitian hospitals in three departments. At each site, we sampled up to 10 hospitalized patients each week with acute watery diarrhea. We tested 1,616 specimens collected from April 2, 2012 to March 28, 2013; 1,030 (63.7%) specimens yielded Vibrio cholerae, 13 (0.8%) specimens yielded Shigella, 6 (0.4%) specimens yielded Salmonella, and 63 (3.9%) specimens tested positive for rotavirus. Additionally, 13.5% of children < 5 years old tested positive for rotavirus. Of 1,030 V. cholerae isolates, 1,020 (99.0%) isolates were serotype Ogawa, 9 (0.9%) isolates were serotype Inaba, and 1 isolate was non-toxigenic V. cholerae O139. During 1 year of surveillance, toxigenic cholera continued to be the main cause of acute diarrhea in hospitalized patients, and rotavirus was an important cause of diarrhea-related hospitalizations in children.


Assessment of biosafety precautions in Khartoum state diagnostic laboratories, Sudan.
This study was conducted to evaluate the biosafety precautions that applied by diagnostic laboratories in Khartoum state, 2009. A total number of 190 laboratories were surveyed about their compliance with standard biosafety precautions. These laboratories included 51 (27%) laboratories from government, 75 (39%) from private sectors and 64 (34%) laboratories belong to organization providing health care services. The study found that 32 (16.8%) of laboratories appointed biosafety officers. Only, ten (5.2%) participated in training about response to fire emergency, and 28 (14.7%) reported the laboratory accident occurred during work. 45 (23.7%) laboratories had a written standard operation procedures (SOPs), and 35 (18.4%) had written procedures for the lean-up of spills. Moreover, biosafety cabinet was found in 11 (5.8%) laboratories, autoclave in 28 (14.7%) and incinerator in only two (1.1%) laboratories. Sharp disposable containers were found in 84 (44.2%). Fire alarm system was found in 2 (1.1%) laboratories, fire extinguisher in 39 (20.5%) laboratories, and fire emergency exit found in 14 (7.4%) laboratories. Furthermore, 19 (10%) laboratories had a hepatitis B virus vaccination programme, 5 (6.2%) applied BCG vaccine, and 2 (1.1%0) vaccinated the staff against influenza. The study concluded that the standards biosafety precautions adopted by the diagnostic laboratories in Khartoum state was very low. Further, the laboratory personnel awareness towards biosafety principles implementation was very low too.


Cytogenetic studies of human breast cancer lines: MCF-7 and derived variant sublines.
Cytogenetic studies of the human breast cancer cell line MCF-7 and the sublines derived from it demonstrated extensive aneuploidy with both numerical and structural abnormalities and a wide range of heteroploidy. Detailed G-banding analyses showed that loss of marker chromosomes was a rare event, while formation of additional structural abnormalities was very common in these long-term cultures. All chromosomes were involved in these abnormalities. Loss of a morphologically normal X-chromosome may be related to the loss of estrogen receptors in these cell lines. With the exception of one subline, all cell lines had a short homogeneously staining region (HSR) on chromosome 7. Although the parent MCF-7 line had tetrahydrofolate dehydrogenase levels within the normal range, a lengthened HSR has been found in MCF-7 lines that are resistant to methotrexate. This observation strongly favors the association of an increased level of tetrahydrofolate dehydrogenase with HSR. In conclusion, the inherent genetic instability in this group of related cell lines may explain the heterogeneity found in this tumor. Continuous chromosomal rearrangements and numerical changes may reflect an ongoing process of selection and adaptation in these cell lines established from a breast carcinoma and may be characteristic of the aggressiveness of this neoplasm.


Amyotrophic lateral sclerosis patient iPSC-derived astrocytes impair autophagy via non-cell autonomous mechanisms.
Amyotrophic lateral sclerosis, a devastating neurodegenerative disease, is characterized by the progressive loss of motor neurons and the accumulation of misfolded protein aggregates. The latter suggests impaired proteostasis may be a key factor in disease pathogenesis, though the underlying mechanisms leading to the accumulation of aggregates is unclear. Further, recent studies have indicated that motor neuron cell death may be mediated by astrocytes. Herein we demonstrate that ALS patient iPSC-derived astrocytes modulate the autophagy pathway in a non-cell autonomous manner. We demonstrate cells treated with patient derived astrocyte conditioned medium demonstrate decreased expression of LC3-II, a key adapter protein required for the selective degradation of p62 and ubiquitinated proteins targeted for degradation. We observed an increased accumulation of p62 in cells treated with patient conditioned medium, with a concomitant increase in the expression of SOD1, a protein associated with the development of ALS. Activation of autophagic mechanisms with Rapamycin reduces the accumulation of p62 puncta in cells treated with patient conditioned medium. These data suggest that patient astrocytes may modulate motor neuron cell death by impairing autophagic mechanisms, and the autophagy pathway may be a useful target in the development of novel therapeutics.


Psychometric evaluation of depression measures with Northern Plains Indians.
Numerous psychometric measurements are used to assess for mental health problems in Native American and Alaskan Native (AI/AN) populations; however, few studies have been carried out to assess their validity and reliability within these populations. This study was designed to assess the validity and reliability of numerous measures among the Northern Plains Indians. This article is a partial report, focused on the psychometric measures directed at detecting depression, namely the Beck Depression Inventory (BDI) II, the Center for Epidemiologic Studies Depression (CES-D) Scale, the Tri-Ethnic Depression Scale (TEDS), the Beck Hopelessness Scale (BHS), the Beck Anxiety Inventory (BAI), and the Symptom Checklist-90-Revised (SCL-90-R). Results revealed moderate to strong correlation across all measures, alpha coefficients that exceeded published alphas for the general population, and overall indicated their validity and reliability of these measures, and a 2-factor solution for the BDI-II. While there were limitations to the study, analysis of the results supports the use of each measure with the Northern Plains Indians (NPI) subpopulation, that the NPI subpopulation scored similar to the general population. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Acute pulmonary embolism in the era of multi-detector CT: a reality in sub-Saharan Africa.
The advantages of multi-detector computed tomography (MDCT) have made it the imaging modality of choice for some patients with suspected cardiothoracic disease, of which pulmonary embolism (PE) is an exponent. The aim of this study was to assess the incidence of PE in patients with clinical suspicion of acute PE using MDCT in a sub-Saharan setting, and to describe the demographic characteristics of these patients. Consecutive records of patients who underwent MDCT pulmonary angiography for suspected acute PE over a two-year period at the Radiology Department of a university-affiliated hospital were systematically reviewed. All MDCT pulmonary angiograms were performed with a 16-detector computed tomography (CT) scanner using real-time bolus tracking technique. Authorization for the study was obtained from the institutional authorities. Forty-one MDCT pulmonary angiograms were reviewed of which 37 were retained. Of the 4 excluded studies, 3 were repeat angiograms and 1 study was not technically adequate. Twelve of 37 patients (32.4%) had CT angiograms that were positive for PE, of which 7 were males. The mean age of these patients was 47.6±10.5 years (age range from 33 to 65 years). Twenty five patients out of 37 (67.6%) had CT angiograms that were negative for PE. Eleven PE-positive patients (91.7%) had at least 1 identifiable thromboembolic risk factor whilst 5 PE-negative patients (20%) also had at least a thromboembolic risk factor. The relative risk of the occurrence of PE in patients with at least a thromboembolic risk factor was estimated at 14.4. Acute PE is a reality in sub-Saharan Africa, with an increased likelihood of MDCT evidence in patients with clinical suspicion of PE who have at least a thromboembolic risk factor. The increasing availability of MDCT will help provide more information on the occurrence of PE in these settings.


Childhood Experiences and Intimate Partner Violence Among Kenyan Males: Mediation by Self-Esteem and Impulsivity.
This study evaluates associations between childhood social environments and current intimate partner conflict tactics in early adulthood. The subsample for this study (n = 251 men) were participants in a larger community-based study of men's mental and behavioral health in semirural Kenya. A survey questionnaire was administered by trained interviewers, including validated recall measures from childhood, collective self-esteem and impulsivity, and the conflict tactics scale short form. Analyses utilized regression and mediation methods. The recall measures evaluated the degree of relational warmth and safety recalled from early childhood and forms of abuse, neglect and dysfunction present in the childhood home. Collective self-esteem assessed the perceived value of one's social groups and one's value as a member of these groups. Impulsivity measured the propensity to act without thinking. The conflict tactics scale evaluates the presence and frequency of specific behaviors following intimate partner conflict, which lead to two factors-negotiation-based tactics and violence tactics. More early memories of relational warmth, responsiveness, and safety during childhood predict fewer violent intimate conflict tactics. More adverse childhood experiences predict more violent conflict tactics and fewer negotiation-based conflict tactics. Self-esteem and impulsivity mediated associations between recalled childhood experiences and conflict tactics. Further research is required to explore other predisposing factors, psychological processes, and cultural and social norms surrounding the use of violent and nonviolent intimate partner conflict resolution by young men in Sub-Saharan Africa. Violence prevention strategies and policies should explicitly link intimate partner violence prevention with prevention of violence against boys. Interventions should recognize men who perpetrate intimate partner violence are more likely victims of violent childhoods than men who do not perpetrate intimate partner violence. Promoting collective self-esteem and reducing impulsivity among young men may reduce violence against women.


Direct Determination of Grain Boundary Atomic Structure in SrTiO3.
An atomic structure model for a 25 degrees [001] symmetric tilt grain boundary in SrTiO(3) has been determined directly from experimental data with the use of high-resolution Z-contrast imaging coupled with electron energy loss spectroscopy. The derived model of the grain boundary was refined by bond-valence sum calculations and reveals candidate sites for dopant atoms in the boundary plane. These results show how the combined techniques can be used to deduce the atomic structure of defects and interfaces without recourse to preconceived structural models or image simulations.


The effectiveness of a 15 minute weekly massage in reducing physical and psychological stress in nurses.
To investigate the effectiveness of massage therapy in reducing physiological and psychological indicators of stress in nurses employed in an acute care hospital. Randomised controlled trial. Acute care hospital in Queensland. Sixty nurses were recruited to the five week study and randomly assigned to two groups. A 15 minute back massage once a week. The control group did not receive any therapy. Demographic information, a life events questionnaire and a brief medical history of all participants was completed at enrolment. Physiological stress was measured at weeks one, three and five by urinary cortisol and blood pressure readings. Psychological stress levels were measured at weeks one and five with the State-Trait Anxiety Inventory (STAI). Differences in the change in urinary cortisol and blood pressure between the two groups did not reach statistical significance. However, STAI scores decreased over the five weeks for those participants who received a weekly massage. The STAI scores of the control group increased over the five week period. These differences between the groups were statistically significant. The results of this study suggest that massage therapy is a beneficial tool for the health of nurses as it may reduce psychological stress levels. It is recommended that further large studies be conducted to measure the symptoms of stress rather than the physiological signs of stress in nurses.


Tumor vasculature: the Achilles' heel of cancer?
Tumor-associated angiogenesis is one of the essential hallmarks underlying cancer development and metastasis. Anti-angiogenic agents accordingly aim to restrain cancer progression by blocking the formation of new vessels, improving the delivery of chemotherapeutic agents to the tumor site and reducing the shedding of metastatic cells into the circulation. This review article addresses some key issues in the use of angiogenesis inhibitors in cancer. The authors review the complex interactions between cell signaling pathways involved in tumor angiogenesis, and focus in particular on the molecular mechanisms that may induce resistance to angiogenesis inhibitors. They will also discuss some novel therapeutic strategies evolving within anti-angiogenic therapy such as the targeting of VEGFR-3, endothelial integrins and hepatocyte growth factor-MET signaling. Although anti-angiogenic therapy is targeted at the non-malignant part of the tumor, the intricate network of growth promoting signaling pathways and in particular the redundancy when single pathways are targeted in endothelial cells represents a major therapeutic obstacle. A key challenge will be to develop more efficient inhibitors, combined with an individualized approach based on each tumor's own endothelial signaling profile. Furthermore, reliable biomarkers which pinpoint those patients that will benefit from anti-angiogenic therapy need to be identified.


Low Molecular Weight Sulfated Chitosan: Neuroprotective Effect on Rotenone-Induced In Vitro Parkinson's Disease.
The present investigation was an attempt to study the effect of low molecular weight sulfated chitosan (LMWSC) on in vitro rotenone model of Parkinson's disease (PD) by evaluating cell viability, oxidative stress, mitochondrial membrane potential, DNA fragmentation, and apoptosis. Incubation of SH-SY5Y cells with 100 nm rotenone resulted in neuronal cell death, redox imbalanced mitochondrial dysfunction, DNA fragmentation, condensation, and apoptotic cellular morphology. Rotenone exposure enhanced the expression of preapoptotic (cytochrome C (cyto c), caspase-3, -8, -9, and Bax) and down-regulated the expression of anti-apoptotic (Bcl-2) markers. Reduction of the intracellular reactive oxygen species (ROS) levels ensued due to pretreatment of LMWSC along with consequent normalization of antioxidant enzymes, mitigation of rotenone induced mitochondrial dysfunction and apoptosis. Our current findings suggested that LMWSC exhibit the pronounced neuroprotective effects, which could be due to its antioxidant, mitochondrial protection, and anti-apoptotic properties. We thus conclude that LMWSC could be developed as a novel therapeutic molecule for the benefit of reducing the consequences of PD. However, further extensive preclinical and clinical studies are warranted.


Psychoeducation to facilitate return to work in individuals on sick leave and at risk of having a mental disorder: protocol of a randomised controlled trial.
Sickness absence due to poor mental health is a common problem in many Western countries. To facilitate return to work, it may be important to identify individuals on sick leave and at risk of having a mental disorder and subsequently to offer appropriate treatment. Psychoeducation alone has not previously been used as a return to work intervention, but may be a promising tool to facilitate return to work. Therefore, the aim of the study is to evaluate the effectiveness of psychoeducation designed specifically to facilitate return to work for individuals on sick leave and at risk of having a mental disorder. The psychoeducation was a supplement to the various standard offers provided by the job centres. The study is a randomised controlled trial, in which individuals on sick leave either receive psychoeducation and standard case management or standard case management alone. Participants were individuals with mental health symptoms, who had been on sick leave from part-time or full-time work or unemployment for about 4-8 weeks. The psychoeducational intervention was group-based and the course consisted of 2 hour sessions once a week for 6 weeks. The course was given by psychiatric nurses, a psychologist, a social worker, a physiotherapist and a person who had previously been on sick leave due to mental health problems. The sessions focused on stress and work life, and the purpose was to provide individuals on sick leave the skills to understand and improve their mental functioning.The primary outcome is the duration of sickness absence measured by register data. Secondary outcomes include psychological symptoms, mental health-related quality of life, and locus of control. These outcomes are measured by questionnaires at the start of the intervention and at 3 and 6 months follow-up. On the basis of this trial, the effect of psychoeducation for individuals on sick leave and at risk of having a mental disorder will be studied. The results will contribute to the continuing research on sickness absence and mental health. It will primarily show whether psychoeducation can lead to faster and sustainable return to work. Clinical Trial.gov NCT01637363. Registered 6 July 2012.


Gastrointestinal diseases during pregnancy: what does the gastroenterologist need to know?
Pregnancy is characterized by numerous physiological changes that may lead to a diversity of symptoms and frequently to gastrointestinal complaints, such as heartburn, nausea and vomiting, or constipation. Chronic gastrointestinal diseases require treatment maintenance during this period, raising the challenging question whether outcomes beneficial to the mother may be harmful for the fetus. In addition, certain diseases, such as acute fatty liver of pregnancy, only develop during pregnancy and may require urgent procedures, such as fetus delivery. Even though they are not present in our day-to-day practice, knowledge of pregnancy-related diseases is fundamental and collaboration between gastroenterologists and obstetricians is often necessary. Herein, we review pregnancy-related diseases and systematize the most appropriate treatment choices according to the recent literature and guidelines, so that the article can serve as a guide to the gastroenterologist regarding the medical approach to pregnancy-related gastrointestinal and liver diseases and their therapeutic management.


Lyase activities intrinsic to Escherichia coli polymerases IV and V.
Escherichia coli DNA polymerase IV and V (pol IV and pol V) are error-prone DNA polymerases that are induced as part of the SOS regulon in response to DNA damage. Both are members of the Y-family of DNA polymerases. Their principal biological roles appear to involve translesion synthesis (TLS) and the generation of mutational diversity to cope with stress. Although neither enzyme is known to be involved in base excision repair (BER), we have nevertheless observed apurinic/apyrimidinic 5'-deoxyribose phosphate (AP/5'-dRP) lyase activities intrinsic to each polymerase. Pols IV and V catalyze cleavage of the phosphodiester backbone at the 3'-side of an apurinic/apyrimidinic (AP) site as well as the removal of a 5'-deoxyribose phosphate (dRP) at a preincised AP site. The specific activities of the two error-prone polymerase-associated lyases are approximately 80-fold less than the associated lyase activity of human DNA polymerase beta, which is a key enzyme used in short patch BER. Pol IV forms a covalent Schiff's base intermediate with substrate DNA that is trapped by sodium borohydride, as proscribed by a beta-elimination mechanism. In contrast, a NaBH(4) trapped intermediate is not observed for pol V, even though the lyase specific activity of pol V is slightly higher than that of pol IV. Incubation of pol V (UmuD'(2)C) with a molar excess of UmuD drives an exchange of subunits to form UmuD'D+insoluble UmuC causing inactivation of polymerase and lyase activities. The concomitant loss of both activities is strong evidence that pol V contains a bona fide lyase activity.


Mechanisms involved in the contraceptive effects of ulipristal acetate.
The use of emergency contraception (EC) methods is increasing worldwide as it constitutes an effective way to prevent unplanned pregnancy after unprotected sexual intercourse. During the last decade, ulipristal acetate (UPA), a selective progesterone receptor modulator, has emerged as the most effective EC pill, and it is now recommended as first-line hormonal treatment for EC in several countries. Its principal mechanism of action involves inhibition or delay of follicular rupture, but only when administered during the follicular phase before the luteinizing hormone (LH) peak. However, considering the high efficacy of UPA, it is possible that it also exerts contraceptive effects besides ovulation. In the present review, we summarize and discuss the existing evidence obtained on the effect of UPA on sperm function and post-ovulatory events as potential additional mechanisms to prevent pregnancy. The bulk of evidence collected so far indicates that UPA would not affect gamete function; however, it could impair embryo-uterine interaction. Thus, besides the described effects on ovarian function, UPA contraceptive effectiveness might also be attributed to post-ovulatory effects, depending on the moment of the female cycle in which the drug is administered.


Importance of charge independent effects in readout of the trimethyllysine mark by HP1 chromodomain.
Histone modifications are implicated in epigenetic inheritance and are of central importance in regulating chromatin structure and gene expression. A prototype example is the trimethylation (Me3) of lysine 9 on histone 3 (H3), which is a readout by an aromatic cage of the chromodomain of heterochromatin-associated protein 1 (HP1) thereby leading to transcriptional repression and heterochromatin formation. Considering that the lysine methylation does not change the charge state of the histone tail and such aromatic-cage mediated recognition of the quaternary ammonium moiety is emerging as the most striking mechanistic commonality for the state-specific recognition of histone lysine methylation, it is of particular interest and importance to understand the physical origin regarding how the aromatic cage distinguishes between the H3K9Me3 mark and its unmethylated counterpart. Here we have simulated relative binding free energies among HP1 chromodomain-H3 tail complexes differing at position 9 of the H3 tail. Our simulated results further confirm the essential role of cation-pi interactions for the binding of a methylated H3 tail by an HP1 chromodomain but indicate that the effect from an electrostatic origin is not dominant in distinguishing between the H3K9Me3 mark and its unmethylated counterpart. Meanwhile, our calculated free energy difference between H3-tert-butyl norleucine 9 and H3-methylnorleucine 9 in their binding to the HP1 clearly reveals the importance of the charge independent interactions for the state-specific readout of histone lysine trimethylation marks.


Models for the field-based toxicity of copper and zinc salts to wheat in 11 Australian soils and comparison to laboratory-based models.
Laboratory-based relationships that model the phytotoxicity of metals using soil properties have been developed. This paper presents the first field-based phytotoxicity relationships. Wheat (Triticum aestivum L.) was grown at 11 Australian field sites at which soil was spiked with copper (Cu) and zinc (Zn) salts. Toxicity was measured as inhibition of plant growth at 8 weeks and grain yield at harvest. The added Cu and Zn EC10 values for both endpoints ranged from approximately 3 to 4760 mg/kg. There were no relationships between field-based 8-week biomass and grain yield toxicity values for either metal. Cu toxicity was best modelled using pH and organic carbon content while Zn toxicity was best modelled using pH and the cation exchange capacity. The best relationships estimated toxicity within a factor of two of measured values. Laboratory-based phytotoxicity relationships could not accurately predict field-based phytotoxicity responses.


Effects of hormones on the expression of matrix metalloproteinases and their inhibitors in bovine spermatozoa.
Proteases and protease inhibitors play key roles in most physiological processes, including cell migration, cell signaling, and cell surface and tissue remodeling. Among these, the matrix metalloproteinase (MMPs) pathway is one of the most efficient biosynthetic pathways for controlling the activation of enzymes responsible for protein degradation. This also indicates the association of MMPs with the maturation of spermatozoa. In an attempt to investigate the effect of MMP activation and inhibitors in cultures with various hormones during sperm capacitation, we examined and monitored the localization and expression of MMPs (MMP-2 and MMP-9), tissue inhibitors of metalloproteinases (TIMP-2 and TIMP-3), as well as their expression profiles. Matured spermatozoa were collected from cultures with follicle-stimulating hormone (FSH), luteinizing hormone (LH), and Lutalyse at 1 h, 6 h, 18 h, and 24 h. ELISA detected the expression of MMP-2, MMP-9, TIMP-2, and TIMP-3 in all culture media, regardless of medium type (FSH-supplemented fertilization Brackett-Oliphant medium (FFBO), LH-supplemented FBO (LFBO), or Lutalyse-supplemented FBO (LuFBO)). TIMP-2 and TIMP-3 expression patterns decreased in LFBO and LuFBO. MMP-2 and MMP-9 activity in FBO and FFBO progressively increased from 1 h to 24 h but was not detected in LFBO and LuFBO. The localization and expression of TIMP-2 and TIMP-3 in sperm heads was also measured by immunofluorescence analysis. However, MMPs were not detected in the sperm heads. MMP and TIMP expression patterns differed according to the effect of various hormones. These findings suggest that MMPs have a role in sperm viability during capacitation. In conjunction with hormones, MMPs play a role in maintaining capacitation and fertilization by controlling extracellular matrix inhibitors of sperm.


A quantum chemistry study of natural gas hydrates.
The structure and properties of natural gas hydrates containing hydrocarbons, CO₂, and N₂ molecules were studied by using computational quantum chemistry methods via the density functional theory approach. All host cages involved in I, II, and H types structures where filled with hydrocarbons up to pentanes, CO₂ and N₂ molecules, depending on their size, and the structures of these host-guest systems optimized. Structural properties, vibrational spectra, and density of states were analyzed together with results from atoms-in-a-molecule and natural bond orbitals methods. The inclusion of dispersion terms in the used functional plays a vital role for obtaining reliable information, and thus, B97D functional was shown to be useful for these systems. Results showed remarkable interaction energies, not strongly affected by the type of host cage, with molecules tending to be placed at the center of the cavities when host cages and guest molecules cavities are of similar size, but with molecules approaching hexagonal faces for larger cages. Vibrational properties show remarkable features in certain regions, with shiftings rising from host-guest interactions, and useful patterns in the terahertz region rising from water surface vibrations strongly coupled with guest molecules. Likewise, calculations on crystal systems for the I and H types were carried out using a pseudopotential approach combined with Grimme's method to take account of dispersion.


Impact of oral simvastatin therapy on acute lung injury in mice during pneumococcal pneumonia.
Recent studies suggest that the reported protective effects of statins (HMG-CoA reductase inhibitors) against community-acquired pneumonia (CAP) and sepsis in humans may be due to confounders and a healthy user-effect. To directly test whether statins are protective against Streptococcus pneumoniae, the leading cause of CAP, we examined the impact of prolonged oral simvastatin therapy at physiologically relevant doses in a mouse model of pneumococcal pneumonia. BALB/c mice were placed on rodent chow containing 0 mg/kg (control), 12 mg/kg (low simvastatin diet [LSD]; corresponds to 1.0 mg/kg/day), or 120 mg/kg (high simvastatin diet [HSD]; corresponds to 10 mg/kg/day) simvastatin for four weeks, infected intratracheally with S. pneumoniae serotype 4 strain TIGR4, and sacrificed at 24, 36, or 42 h post-infection for assessment of lung histology, cytokine production, vascular leakage and edema, bacterial burden and bloodstream dissemination. Some mice received ampicillin at 12-h intervals beginning at 48 h post-infection and were monitored for survival. Immunoblots of homogenized lung samples was used to assess ICAM-1 production. Mice receiving HSD had reduced lung consolidation characterized by less macrophage and neutrophil infiltration and a significant reduction in the chemokines MCP-1 (P = 0.03) and KC (P = 0.02) and ICAM-1 in the lungs compared to control mice. HSD mice also had significantly lower bacterial titers in the blood at 36 (P = 0.007) and 42 (P = 0.03) hours post-infection versus controls. LSD had a more modest effect against S. pneumoniae but also resulted in reduced bacterial titers in the lungs and blood of mice after 42 h and a reduced number of infiltrated neutrophils. Neither LSD nor HSD mice had reduced mortality in a pneumonia model where mice received ampicillin 48 h after challenge. Prolonged oral simvastatin therapy had a strong dose-dependent effect on protection against S. pneumoniae as evidenced by reduced neutrophil infiltration, maintenance of vascular integrity, and lowered chemokine production in the lungs of mice on HSD. Statin therapy also protected through reduced bacterial burden in the lungs. Despite these protective correlates, mortality in the simvastatin-receiving cohorts was equivalent to controls. Thus, oral simvastatin at physiologically relevant doses only modestly protects against pneumococcal pneumonia.


Proteomics analyses of prostate cancer cells reveal cellular pathways associated with androgen resistance.
While significant advances have been made in the diagnosis and treatment of prostate cancer, each year tens of thousands of men still die from prostate cancer in the United States. Thus, greater understanding of cellular pathways and molecular basis of prostate cancer progression in the development of androgen resistance is needed to treat these lethal phenotypes. To dissect the mechanism of androgen resistance, we utilize a proteomics approach to study the development of androgen resistance in LNCaP prostate cancer cells. Our results showed the predominant involvement of metabolic pathways that were elevated in androgen resistance phenotype. We further found the amplification of PI3K/AKT pathway and the overexpression of proteasome proteins while the mitochondrial oxidation phosphorylation was severely hampered in castration-resistant LNCaP-95 cells compared to LNCaP cells. Interestingly, we also found the induction of Dicer, a cytoplasmic endoribonuclease microRNA regulator in the androgen-ablated LNCaP-95 prostate cancer cells. We verified some of these data by orthogonal methods including Western blot analysis and in castrated animal xenograft studies. To our knowledge, this is the first report showing induced expression of proteasome proteins in androgen ablation prostate cancer cells. If validated in clinical studies, the findings will have significant implications in understanding the complexity of biochemical recurrence in prostate cancer.


[Molecular mechanism and therapeutic strategy for cerebral small vessel disease].
Hypertension is a well known risk factor for cerebral small vessel disease (SVD) characterized by MRI white matter hyperintensities called "leukoaraiosis". However, the molecular basis of SVD remains to be elucidated. Both twin and family studies have shown that leukoaraiosis is the most heritable cerebrovascular phenotype with a heritability estimated to be between 55% and 71%, suggesting genetic factors for SVD. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is hereditary SVD lacking hypertension. We have recently identified the causative gene, FHtrA1, for CARASIL by genome-wide linkage study and a candidate gene approach. HtrA1 is a serine protease that represses signaling by TGF-β family members. We found that mutated HtrA1 did not repress signaling by the TGF-β family members (BMP2, BMP4, and TGF-β1), resulting in vascular fibrosis with synthesis of extracellular matrix proteins. Our results indicate that disinhibition of TGF-β signaling underlies the molecular basis of CARASIL. Marfan's syndrome is an autosomal dominant connective tissue disorder caused by disinhibition of TGF-β signaling associated with FBN1 mutations. In a small cohort study, angiotensin II-receptor blockers (ARBs) therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilatation. This study provides a potential for developing a therapy targeting TGF-β signaling for SVD.


Modern prescription theory and application: realistic expectations for speech recognition with hearing AIDS.
A major decision at the time of hearing aid fitting and dispensing is the amount of amplification to provide listeners (both adult and pediatric populations) for the appropriate compensation of sensorineural hearing impairment across a range of frequencies (e.g., 160-10000 Hz) and input levels (e.g., 50-75 dB sound pressure level). This article describes modern prescription theory for hearing aids within the context of a risk versus return trade-off and efficient frontier analyses. The expected return of amplification recommendations (i.e., generic prescriptions such as National Acoustic Laboratories-Non-Linear 2, NAL-NL2, and Desired Sensation Level Multiple Input/Output, DSL m[i/o]) for the Speech Intelligibility Index (SII) and high-frequency audibility were traded against a potential risk (i.e., loudness). The modeled performance of each prescription was compared one with another and with the efficient frontier of normal hearing sensitivity (i.e., a reference point for the most return with the least risk). For the pediatric population, NAL-NL2 was more efficient for SII, while DSL m[i/o] was more efficient for high-frequency audibility. For the adult population, NAL-NL2 was more efficient for SII, while the two prescriptions were similar with regard to high-frequency audibility. In terms of absolute return (i.e., not considering the risk of loudness), however, DSL m[i/o] prescribed more outright high-frequency audibility than NAL-NL2 for either aged population, particularly, as hearing loss increased. Given the principles and demonstrated accuracy of desensitization (reduced utility of audibility with increasing hearing loss) observed at the group level, additional high-frequency audibility beyond that of NAL-NL2 is not expected to make further contributions to speech intelligibility (recognition) for the average listener.


Sinonasal melioidosis in a returned traveller presenting with nasal cellulitis and sinusitis.
We illustrate a case involving a 51-year-old man who presented to a tertiary hospital with sepsis secondary to an abscess of the nasal vestibule and pustular eruptions of the nasal mucosa. Associated cellulitis extended across the face to the eye, and mucosal thickening of the sinuses was seen on computed tomography. The patient underwent incision and drainage and endoscopic sinus surgery. Blood cultures and swabs were positive for a gram-negative bacillus, Burkholderia pseudomallei. He had multiple risk factors including travel to an endemic area. The patient received extended antibiotic therapy in keeping with published national guidelines. Melioidosis is caused by Burkholderia pseudomallei, found in the soil in Northern Australia and Asia. It is transmitted via cutaneous or inhaled routes, leading to pneumonia, skin or soft tissue abscesses, and genitourinary infections. Risk factors include diabetes, chronic lung disease, and alcohol abuse. It can exist as a latent, active, or reactivated infection. A high mortality rate has been identified in patients with sepsis. Melioidosis is endemic in tropical Northern Australia and northeastern Thailand where it is the most common cause of severe community-acquired sepsis. There is one other report of melioidosis in the literature involving orbital cellulitis and sinusitis.


Dietary cadmium exposure assessment among the Chinese population.
Cadmium, a toxic heavy metal, is widely present in food. It has been reported that chronic cadmium exposure is associated with kidney disease, osteoporosis, cardiovascular disease and cancer. The aim of this study was to assess the dietary cadmium exposure and potential health risk in different age-sex groups of the Chinese population (children aged 4-11 years, young people aged 12-17 years and adults aged over 18 years), and in the southern and northern population using a semi-probabilistic method. Cadmium was detected in 228,687 food samples from 32 food categrories by graphite furnace atomic absorption spectrometry. The dietary cadmium exposures were estimated by combining the cadmium concentration data with food consumption data derived from the China National Nutrient and Health Survey 2002, and evaluated against the Provisional Tolerable Monthly Intake (PTMI) of 25 μg/kg BW/month established by the Joint FAO/WHO expert committee on food additives (JECFA). The mean dietary cadmium exposure of the general Chinese population (15.3 μg/kg BW/month) was below the PTMI. The high consumer exposures (95th percentile, P95) for the general population and different sub-groups were higher than the PTMI. The dietary cadmium exposure of the southern population was apparently higher than that of the northern population. Rice was the most important contributor to cadmium exposure for Chinese people, especially those living in the southern areas of China. These findings indicated that the health risk from dietary cadmium exposure of the general Chinese people was low, but the health risk of cadmium exposure of certain sub-groups should be of concern.


Cardiovascular risk reduction in diabetes: underemphasised and overdue. Messages from major trials.
Diabetes markedly increases the risk of coronary artery disease and death, but is underrecognised as a cardiovascular risk factor, despite the existence of effective treatments. Because patients with diabetes are at high risk for coronary disease, they have more to gain from prevention. There is evidence from clinical trials that select cardiovascular therapies may work better in diabetes, beyond their expected benefit, and may prevent diabetes itself.


Chronic Porphyromonas gingivalis infection accelerates the occurrence of age-related granules in ApoE-/- mice brains.
This study explored the origin of age-related granules in the apolipoprotein E gene knockout (ApoE-/-) B6 background mice brains following chronic gingival infection with Porphyromonas gingivalis for 24 weeks. Intracerebral localization of P. gingivalis was detected by fluorescence in situ hybridization (FISH) and its protease by immunohistochemistry. The age-related granules were observed by periodic acid-Schiff (PAS), silver impregnation, and immunostaining. FISH showed intracerebral dissemination of P. gingivalis cells (p = 0.001). PAS and silver impregnation demonstrated the presence of larger inclusions restricted to the CA1, CA2, and dentate gyrus sectors of the hippocampus. A specific monoclonal antibody to bacterial peptidoglycan detected clusters of granules with variable sizes in mice brains infected with P. gingivalis (p = 0.004), and also highlighted areas of diffuse punctate staining equating to physical tissue damage. Mouse immunoglobulin G was observed in the capillaries of the cerebral parenchyma of all P. gingivalis-infected brains (p = 0.001), and on pyramidal neurons in some severely affected mice, compared with the sham-infected mice. Gingipains was also observed in microvessels of the hippocampus in the infected mice. This study supports the possibility of early appearance of age-related granules in ApoE-/- mice following inflammation-mediated tissue injury, accompanied by loss of cerebral blood-brain barrier integrity.


Awareness, Prevalence, Treatment, and Control of Hypertension in Western Nepal.
Hypertension is a significant contributor to cardiovascular and renal diseases. In low-income settings like Nepal, there are few epidemiological studies assessing hypertension burden. Thus, the purpose was to determine prevalence, awareness, treatment, and control of hypertension in Nepal. A cross-sectional survey was conducted in semi-urban area of western Nepal among randomly selected participants, aged between 25 and 65 years. Systolic blood pressure (BP) ≥140 mm Hg and/or diastolic BP of ≥90 mm Hg and/or taking current antihypertensive medicine defined as hypertension. Study included 2,815 participants, 1,844 were women. The age- and sex-adjusted prevalence of hypertension was 28%. Of the study participants, 17% were daily smokers, 12% harmful alcohol drinkers, 90% consuming low levels of fruit and/or vegetable, and 7% reported low physical activity. Among hypertensive participants, 46% were aware of their preexisting hypertension, 31% were on hypertensive medication, and 15% met BP control targets. Increasing age (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.06; 1.08), higher body mass index (OR: 1.09, 95% CI: 1.06; 1.12), men (OR: 1.63, 95% CI: 1.25; 2.14), harmful alcohol intake (Or: 2.46; 95% CI: 1.73; 3.51), family history of hypertension (OR: 1.42; 95% CI: 1.14; 1.76), and diabetes (OR: 2.08, 95% CI: 1.30; 3.33) were independently associated with hypertension. The prevalence of hypertension was found high in western Nepal. A number of risk factors were identified as possible drivers of this burden. Thus, there is an urgent need to address modifiable risk factors in semi-urban settings of western Nepal.


Unraveling adaptive evolution: how a single point mutation affects the protein coregulation network.
Understanding the mechanisms of evolution requires identification of the molecular basis of the multiple (pleiotropic) effects of specific adaptive mutations. We have characterized the pleiotropic effects on protein levels of an adaptive single-base pair substitution in the coding sequence of a signaling pathway gene in the bacterium Pseudomonas fluorescens SBW25. We find 52 proteomic changes, corresponding to 46 identified proteins. None of these proteins is required for the adaptive phenotype. Instead, many are found within specific metabolic pathways associated with fitness-reducing (that is, antagonistic) effects of the mutation. The affected proteins fall within a single coregulatory network. The mutation 'rewires' this network by drawing particular proteins into tighter coregulating relationships. Although these changes are specific to the mutation studied, the quantitatively altered proteins are also affected in a coordinated way in other examples of evolution to the same niche.


Information bounds for Gaussian copulas.
Often of primary interest in the analysis of multivariate data are the copula parameters describing the dependence among the variables, rather than the univariate marginal distributions. Since the ranks of a multivariate dataset are invariant to changes in the univariate marginal distributions, rank-based estimators are natural candidates for semiparametric copula estimation. Asymptotic information bounds for such estimators can be obtained from an asymptotic analysis of the rank likelihood, i.e. the probability of the multivariate ranks. In this article, we obtain limiting normal distributions of the rank likelihood for Gaussian copula models. Our results cover models with structured correlation matrices, such as exchangeable or circular correlation models, as well as unstructured correlation matrices. For all Gaussian copula models, the limiting distribution of the rank likelihood ratio is shown to be equal to that of a parametric likelihood ratio for an appropriately chosen multivariate normal model. This implies that the semiparametric information bounds for rank-based estimators are the same as the information bounds for estimators based on the full data, and that the multivariate normal distributions are least favorable.


What's on YouTube? A Case Study on Food and Beverage Advertising in Videos Targeted at Children on Social Media.
Unhealthy food marketing to children is a key risk factor for childhood obesity. Online video platforms have surpassed television as the primary choice for screen viewing among children but the extent of food marketing through such media is relatively unknown. We aimed to examine food and beverage advertisements (ads) encountered in YouTube videos targeting children in Malaysia. The social media analytics site SocialBlade.com was used to identify the most popular YouTube videos (n = 250) targeting children. Ads encountered while viewing these videos were recorded and analyzed for type of product promoted and ad format (video vs. overlay). Food and beverage ads were further coded based on food category and persuasive marketing techniques used. In total 187 ads were encountered in sampled videos. Food and beverage ads were the most common at 38% (n=71), among which 56.3% (n = 40) promoted noncore foods. Ads for noncore foods were more commonly delivered as video rather than overlay ads. Among ads promoting noncore foods, the most commonly employed persuasive marketing techniques found were taste appeal (42.3%), uniqueness/novelty (32.4%), the use of animation (22.5%), fun appeal (22.5%), use of promotional characters (15.5%), price (12.7%), and health and nutrition benefits (8.5%). Similar to television, unhealthy food ads predominate in content aimed toward children on YouTube. Policies regulating food marketing to children need to be extended to cover online content in line with a rapidly-evolving digital media environment. Service providers of social media can play a part in limiting unhealthy food advertising to children.


Antimitochondrial antibodies of primary biliary cirrhosis recognize dihydrolipoamide acyltransferase and inhibit enzyme function of the branched chain alpha-ketoacid dehydrogenase complex.
Antimitochondrial antibodies (AMA) recognizing the acetyltransferase (E2) of the pyruvate dehydrogenase (PDH) complex have been previously well-documented and the immunodominant epitope mapped. In this study, we demonstrate that sera from patients with primary biliary cirrhosis (PBC) react with another lipoic acid containing acyltransferase enzyme, namely the E2 of the branched chain alpha-ketoacid dehydrogenase (BCKD) complex. Indeed, 85/120 (71%) sera from patients with PBC reacted with BCKD-E2 by immunoblotting against purified BCKD complex. In contrast, sera from patients with chronic active hepatitis or progressive sclerosing cholangitis as well as sera from healthy volunteers did not react with any component enzymes of the BCKD complex. More importantly, BCKD enzyme activity was inhibited after incubation of the BCKD complex with either PBC sera against BCKD-E2 or with affinity purified antisera to BCKD-E2. Enzyme activity was unaltered by control sera or with PBC sera that reacted with PDH-E2 but not BCKD-E2. Furthermore, immunoblots of purified mitochondria probed with PBC sera absorbed with BCKD-E2 demonstrated that BCKD-E2 and PDH-E2 are each recognized by distinct AMA populations which do not cross-react. In addition, affinity purified PBC sera against BCKD-E2 did not react with PDH-E2 nor inhibit PDH enzyme activity, thus providing further evidence that BCKD-E2 and PDH-E2 are recognized by separate AMA. These data further suggest that the BCKD-E2 epitope recognized by AMA contains, or is close to, a functional domain of this enzyme. The availability of cDNA clones encoding BCKD-E2 and PDH-E2 will allow the study of how key metabolic enzymes may be involved in the immunology and pathology of PBC.