Driving after Concussion: Is It Safe To Drive after Symptoms Resolve?
Post-concussion impairments may result in unsafe driving performance, but little research is available to guide consensus on when concussed individuals should return to driving. The purpose of this study was to compare driving performance between individuals with and without a concussion and to explore relationships between neuropsychological and driving performance. Fourteen participants with concussion (age 20.2 ± 0.9 years old) and 14 non-concussed age- and driving experience-matched controls (age 20.4 ± 1.1 years old) completed a graded symptom checklist, a brief neuropsychological exam, and a 20.5 km driving simulation task. Participants with a concussion completed driving simulation within 48 h of becoming asymptomatic (15.9 ± 9.0 days post-concussion). One-way analyses of variance were used to compare total number of crashes, tickets, and lane excursions, as well as standard deviation of lateral position (SDLP) and standard deviation of speed. Pearson's correlations were conducted to explore the relationship between the neuropsychological and driving performance separately by group (α = 0.05). Participants with a concussion committed more frequent lane excursions (concussed 10.9 ± 4.5; controls 7.4 ± 2.4; p = 0.017) and exhibited greater SDLP, compared with controls, during the first curve (concussed 45.7 ± 21.3 cm, controls 27.4 ± 6.1 cm; p = 0.030) and final curve (concussed 39.6 ± 24.4 cm; controls 33.5 ± 21.3 cm; p = 0.036). Poorer performance on symbol digit modalities (r = -0.54), Rey Osterrieth Complex Figure (r = -0.53), verbal memory (r = -0.77), and motor speed (r = -0.54) were correlated with more frequent lane excursions in the concussed group, but not in the control group. Despite being asymptomatic, concussed participants exhibited poorer vehicle control, especially when navigating curves. Driving impairments may persist beyond when individuals with a concussion have returned to driving. Our study provides preliminary guidance regarding which neuropsychological functions may best indicate driving impairment following concussion.


The Influence of Food Intake Specificity in Children with Autism on Gut Microbiota.
Autism spectrum disorder (ASD) is a complex of neurodevelopmental conditions with increasing incidence. The microbiota of children with ASD is distinct from neurotypical children, their food habits are also different, and it is known that nutrient intake influences microbiota in a specific way. Thus, this study investigates the food habits of children with ASD and their association with the gut microbiota. Children with ASD had their dietary energy intakes similar to controls, but they more often demonstrated food selectivity, which seemed to result in deficiency of micronutrients such as vitamins K, B6, C, iron, cooper, docosahexaenoic and docosapentanoic acid. Using high-throughput sequencing, a DNA library of intestinal microbiota was performed. Core microbiota was similar in children with and without ASD, but Dichelobacter, Nitriliruptor and Constrictibacter were found to be putative markers of ASD. The changes in gut microbiota that we observed in connection to food selectivity, intake of fats and omega-3 in particular, fermented milk products and animal/plant protein consumption had similar character, independent of diagnosis. However, high fibre intake was connected with a decreased α-diversity only in children with ASD. High carbohydrate and fibre intake influenced β-diversity, changing the abundance of Bacteroides and other genera, many of them members of the Clostidiaceae. Modulating food habits of ASD children can influence their gut microbiota composition.


A simulated patient study assessing over the counter supply and counseling in Jordan: responding to headache complaints.
Background Community pharmacists are the most accessible health professionals for patients seeking advice on minor ailments and over the counter supply. Objectives To assess the management of patients seeking advice for headache in community pharmacies in Jordan. Method A cross-sectional study was conducted using simulated patient in three cities in Jordan. A trained simulated patient enacted an advice-seeking scenario for the treatment of a headache. The visits were evaluated using pre-defined criteria relating to content and communication skills. Results Of 72 community pharmacies invited, 50 (69.4%) agreed to participate. Of these, 38 (76%) pharmacies were visited. The median duration of the visit was 2 min (20 s-4 min). All visits resulted in selling a drug. Paracetamol combinations often with caffeine were recommended in over 50% of visits. Drug sale recommendations were often made without obtaining essential information about symptoms or patient medical history. Only brand names and doses were often highlighted to the simulated patient. No written information was offered. Conclusion Community pharmacies in Jordan appear not to offer adequate counseling for patients seeking advice for headache. Both counseling and communication skills are suboptimal. Exploration of factors and reasons of suboptimal practice is recommended.


Ancient lowland Maya complexity as revealed by airborne laser scanning of northern Guatemala.
Lowland Maya civilization flourished in the tropical region of the Yucatan peninsula and environs for more than 2500 years (~1000 BCE to 1500 CE). Known for its sophistication in writing, art, architecture, astronomy, and mathematics, Maya civilization still poses questions about the nature of its cities and surrounding populations because of its location in an inaccessible forest. In 2016, an aerial lidar survey across 2144 square kilometers of northern Guatemala mapped natural terrain and archaeological features over several distinct areas. We present results from these data, revealing interconnected urban settlement and landscapes with extensive infrastructural development. Studied through a joint international effort of interdisciplinary teams sharing protocols, this lidar survey compels a reevaluation of Maya demography, agriculture, and political economy and suggests future avenues of field research.


Surface anatomy of major anatomical landmarks of the neck in an adult population: A Ct Evaluation of Vertebral Level.
To compare the projectional surface anatomy of healthy individuals in an adult population with those with a thyroid mass, using computed tomography (CT). Sixteen slice CT images of 101 individuals were analyzed using a 32-bit Radiant DICOM viewer to establish the relationships among major anatomical landmarks in the neck and their vertebral levels. The structures investigated included: hard palate (HP), hyoid bone (HB) including body and lesser horns, soft palate (SP), thyroid gland (TG) (both superior and inferior poles), thyroid gland anteroposterior (APD) and superoinferior (SID) diameters, thyroid isthmus (TI) superoinferior dimension, epiglottis, vertebral arteries (right and left), and both right and left parotid glands (superior and inferior extents). The vertebral levels noted most frequently were: body of hyoid bone (C4, 42.71%); lesser horns of hyoid bone (C3, 36.46%); thyroid gland superior pole (C6, 31.25%); and thyroid gland inferior pole (T2, 30.2%). TG-ID, TG-APD, and TG-SID were not significantly different between males and females in the healthy group; however, there was a significant gender difference in thyroid gland inferior diameter in the pathology group [males 2.16(±1.16) vs. females 3.37(±1.30), P = 0.01, paired sample t-test]. Further studies are needed to determine whether neck pathology in those with a thyroid mass affects the dimensions of the thyroid gland. Moreover, the surface anatomy of the neck should be revisited using modern imaging techniques to address inconsistencies in anatomy and clinical reference texts. Clin. Anat. 30:781-787, 2017. © 2017Wiley Periodicals, Inc.


Utilizing general human movement models to predict the spread of emerging infectious diseases in resource poor settings.
Human mobility is an important driver of geographic spread of infectious pathogens. Detailed information about human movements during outbreaks are, however, difficult to obtain and may not be available during future epidemics. The Ebola virus disease (EVD) outbreak in West Africa between 2014-16 demonstrated how quickly pathogens can spread to large urban centers following one cross-species transmission event. Here we describe a flexible transmission model to test the utility of generalised human movement models in estimating EVD cases and spatial spread over the course of the outbreak. A transmission model that includes a general model of human mobility significantly improves prediction of EVD's incidence compared to models without this component. Human movement plays an important role not only to ignite the epidemic in locations previously disease free, but over the course of the entire epidemic. We also demonstrate important differences between countries in population mixing and the improved prediction attributable to movement metrics. Given their relative rareness, locally derived mobility data are unlikely to exist in advance of future epidemics or pandemics. Our findings show that transmission patterns derived from general human movement models can improve forecasts of spatio-temporal transmission patterns in places where local mobility data is unavailable.


Use of trastuzumab for breast cancer: the role of age.
Indication for the use of trastuzumab was given in Italy in 2000 for the treatment of HER-2 metastatic breast cancer and in 2006 for early stage breast cancer. Information on trastuzumab use and on its possible variation with age in Italy is however limited. Using health care administrative databases, we evaluated the prevalence of the use of trastuzumab, and the probability for administration since the first hospitalization for breast cancer in various age groups, in two series of Italian women diagnosed with breast cancer in the Lombardy region (2004-2009) and in the Palermo district. The ratio between trastuzumab users and patients with a hospitalization for breast cancer increased from 2.9% in 2004 up to 17.2% in 2009 in Lombardy. Patients aged <65 years were more frequent users (9.6%) compared to those aged ≥ 75 years (1.3%). Similarly, in the Palermo district the ratio increased from 10.6% in 2006 to 28.5% in 2008, with subjects aged <65 years more frequently using trastuzumab (19.1%), than subjects aged ≥ 75 years (6.2%). The age ratio between younger and older patients decreased over time in both settings (from 15 in 2004 to 10.2 in 2006, and 5.2 in 2009 in Lombardy, and from 4.0 in 2006 to 2.3 in 2009 in the Palermo district). The proportion of breast cancer patients using trastuzumab increased over time both in Lombardy and in Palermo district, though geographical differences persisted. Younger breast cancers patients were more likely to receive a trastuzumab treatment than elderly ones, but the difference declined over calendar period.


Proposed Clinical Decision Rules to Diagnose Acute Rhinosinusitis Among Adults in Primary Care.
To reduce inappropriate antibiotic prescribing, we sought to develop a clinical decision rule for the diagnosis of acute rhinosinusitis and acute bacterial rhinosinusitis. Multivariate analysis and classification and regression tree (CART) analysis were used to develop clinical decision rules for the diagnosis of acute rhinosinusitis, defined using 3 different reference standards (purulent antral puncture fluid or abnormal finding on a computed tomographic (CT) scan; for acute bacterial rhinosinusitis, we used a positive bacterial culture of antral fluid). Signs, symptoms, C-reactive protein (CRP), and reference standard tests were prospectively recorded in 175 Danish patients aged 18 to 65 years seeking care for suspected acute rhinosinusitis. For each reference standard, we developed 2 clinical decision rules: a point score based on a logistic regression model and an algorithm based on a CART model. We identified low-, moderate-, and high-risk groups for acute rhinosinusitis or acute bacterial rhinosinusitis for each clinical decision rule. The point scores each had between 5 and 6 predictors, and an area under the receiver operating characteristic curve (AUROCC) between 0.721 and 0.767. For positive bacterial culture as the reference standard, low-, moderate-, and high-risk groups had a 16%, 49%, and 73% likelihood of acute bacterial rhinosinusitis, respectively. CART models had an AUROCC ranging from 0.783 to 0.827. For positive bacterial culture as the reference standard, low-, moderate-, and high-risk groups had a likelihood of acute bacterial rhinosinusitis of 6%, 31%, and 59% respectively. We have developed a series of clinical decision rules integrating signs, symptoms, and CRP to diagnose acute rhinosinusitis and acute bacterial rhinosinusitis with good accuracy. They now require prospective validation and an assessment of their effect on clinical and process outcomes.


Repurposing the Cord Blood Bank for Haplobanking of HLA-Homozygous iPSCs and Their Usefulness to Multiple Populations.
Although autologous induced pluripotent stem cells (iPSCs) can potentially be useful for treating patients without immune rejection, in reality it will be extremely expensive and labor-intensive to make iPSCs to realize personalized medicine. An alternative approach is to make use of human leukocyte antigen (HLA) haplotype homozygous donors to provide HLA matched iPSC products to significant numbers of patients. To establish a haplobank of iPSCs, we repurposed the cord blood bank by screening ∼4,200 high resolution HLA typed cord blood samples, and selected those homozygous for the 10 most frequent HLA-A,-B,-DRB1 haplotypes in the Korean population. Following the generation of 10 iPSC lines, we conducted a comprehensive characterization, including morphology, expression of pluripotent markers and cell surface antigens, three-germ layer formation, vector clearance, mycoplasma/microbiological/viral contamination, endotoxin, and short tandem repeat (STR) assays. Various genomic analyses using microarray and comparative genomic hybridization (aCGH)-based single nucleotide polymorphism (SNP) and copy number variation (CNV) were also conducted. These 10 HLA-homozygous iPSC lines match 41.07% of the Korean population. Comparative analysis of HLA population data shows that they are also of use in other Asian populations, such as Japan, with some limited utility in ethnically diverse populations, such as the UK. Taken together, the generation of the 10 most frequent Korean HLA-homozygous iPSC lines serves as a useful pointer for the development of optimal methods for iPSC generation and quality control and indicates the benefits and limitations of collaborative HLA driven selection of donors for future stocking of worldwide iPSC haplobanks. Stem Cells 2018;36:1552-1566.


1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure fails to produce delayed degeneration of substantia nigra neurons in monkeys.
We assessed the presence of degenerating neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) of parkinsonian monkeys. For this purpose, we used two histological markers of cellular death, Fluoro Jade B (FJB) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL). Eight monkeys were subacutelly treated with four to six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections (1-1.5 mg/kg, cumulative dose) and sacrificed 1 week and 11 months after last MPTP injection. Eight additional monkeys were chronically exposed to MPTP (4.5-15.3 mg/kg, cumulative dose) and sacrificed 6-35 months after last MPTP dose. Three intact monkeys served as controls. The number of tyrosine hydroxylase (TH)- and TUNEL-positive cells was quantified in SNpc and VTA and colocalization of FJB-positive and TUNEL-positive cells with neuronal (TH, NeuN, MAP2) and glial markers (human ferritin, GFAP) assessed on doubly labelled tissue sections. Only MPTP monkeys with 1-week survival displayed few doubly FJB-TH-labelled cells. Both groups of subacute MPTP monkeys, but not chronic MPTP monkeys, showed a significant increased number of TUNEL-positive cells in SNpc. TUNEL-positive cells exhibited morphological features and histological markers indicative of glial cells, whereas TUNEL/NeuN or TUNEL/MAP-2 colocalization was not observed. Our results indicate that MPTP treatment produced a nonapoptotic cell death of dopaminergic cells and the activation of the apoptotic cascade in glial cells. More importantly, we failed to demonstrate the existence of a delayed neurodegenerative process in the dopaminergic neurons after concluding MPTP injection thus, casting doubt on the validity of the "progressive model" created by repeated MPTP administration to monkeys.


Presynaptic external calcium signaling involves the calcium-sensing receptor in neocortical nerve terminals.
Nerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. Consequently characterization of the functional properties of ion channels at nerve terminals is crucial to understand the regulation of transmitter release. Direct recordings from small neocortical nerve terminals have revealed that external [Ca(2+)] ([Ca(2+)](o)) indirectly regulates a non-selective cation channel (NSCC) in neocortical nerve terminals via an unknown [Ca(2+)](o) sensor. Here, we identify the first component in a presynaptic calcium signaling pathway. By combining genetic and pharmacological approaches with direct patch-clamp recordings from small acutely isolated neocortical nerve terminals we identify the extracellular calcium sensor. Our results show that the calcium-sensing receptor (CaSR), a previously identified G-protein coupled receptor that is the mainstay in serum calcium homeostasis, is the extracellular calcium sensor in these acutely dissociated nerve terminals. The NSCC currents from reduced function mutant CaSR mice were less sensitive to changes in [Ca(2+)](o) than wild-type. Calindol, an allosteric CaSR agonist, reduced NSCC currents in direct terminal recordings in a dose-dependent and reversible manner. In contrast, glutamate and GABA did not affect the NSCC currents. Our experiments identify CaSR as the first component in the [Ca(2+)](o) sensor-NSCC signaling pathway in neocortical terminals. Decreases in [Ca(2+)](o) will depress synaptic transmission because of the exquisite sensitivity of transmitter release to [Ca(2+)](o) following its entry via voltage-activated Ca(2+) channels. CaSR may detects such falls in [Ca(2+)](o) and increase action potential duration by increasing NSCC activity, thereby attenuating the impact of decreases in [Ca(2+)](o) on release probability. CaSR is positioned to detect the dynamic changes of [Ca(2+)](o) and provide presynaptic feedback that will alter brain excitability.


BMI not WHR modulates BOLD fMRI responses in a sub-cortical reward network when participants judge the attractiveness of human female bodies.
In perceptual terms, the human body is a complex 3d shape which has to be interpreted by the observer to judge its attractiveness. Both body mass and shape have been suggested as strong predictors of female attractiveness. Normally body mass and shape co-vary, and it is difficult to differentiate their separate effects. A recent study suggested that altering body mass does not modulate activity in the reward mechanisms of the brain, but shape does. However, using computer generated female body-shaped greyscale images, based on a Principal Component Analysis of female bodies, we were able to construct images which covary with real female body mass (indexed with BMI) and not with body shape (indexed with WHR), and vice versa. Twelve observers (6 male and 6 female) rated these images for attractiveness during an fMRI study. The attractiveness ratings were correlated with changes in BMI and not WHR. Our primary fMRI results demonstrated that in addition to activation in higher visual areas (such as the extrastriate body area), changing BMI also modulated activity in the caudate nucleus, and other parts of the brain reward system. This shows that BMI, not WHR, modulates reward mechanisms in the brain and we infer that this may have important implications for judgements of ideal body size in eating disordered individuals.


Use of genotype × environment interaction model to accommodate genetic heterogeneity for residual feed intake, dry matter intake, net energy in milk, and metabolic body weight in dairy cattle.
Feed efficiency in dairy cattle has gained much attention recently. Due to the cost-prohibitive measurement of individual feed intakes, combining data from multiple countries is often necessary to ensure an adequate reference population. It may then be essential to model genetic heterogeneity when making inferences about feed efficiency or selecting efficient cattle using genomic information. In this study, we constructed a marker × environment interaction model that decomposed marker effects into main effects and interaction components that were specific to each environment. We compared environment-specific variance component estimates and prediction accuracies from the interaction model analyses, an across-environment analyses ignoring population stratification, and a within-environment analyses using an international feed efficiency data set. Phenotypes included residual feed intake, dry matter intake, net energy in milk, and metabolic body weight from 3,656 cows measured in 3 broadly defined environments: North America (NAM), the Netherlands (NLD), and Scotland (SAC). Genotypic data included 57,574 single nucleotide polymorphisms per animal. The interaction model gave the highest prediction accuracy for metabolic body weight, which had the largest estimated heritabilities ranging from 0.37 to 0.55. The within-environment model performed the best when predicting residual feed intake, which had the lowest estimated heritabilities ranging from 0.13 to 0.41. For traits (dry matter intake and net energy in milk) with intermediate estimated heritabilities (0.21 to 0.50 and 0.17 to 0.53, respectively), performance of the 3 models was comparable. Genomic correlations between environments also were computed using variance component estimates from the interaction model. Averaged across all traits, genomic correlations were highest between NAM and NLD, and lowest between NAM and SAC. In conclusion, the interaction model provided a novel way to evaluate traits measured in multiple environments in which genetic heterogeneity may exist. This model allowed estimation of environment-specific parameters and provided genomic predictions that approached or exceeded the accuracy of competing within- or across-environment models.


Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres.
Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female-focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2 years and older receiving care at selected HTCs were eligible for enrollment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand's disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1-8 deamino-D-arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical-gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population.


Graphic designed bedroom doors to support dementia wandering in residential care homes: Innovative practice.
Dementia-friendly designs are important in residential care homes but an aspect that remains neglected is the potential role of door designs in promoting wayfinding. A pilot project in NSW, Australia, tested the effects of unique room door designs for a small group of individuals living with dementia in a residential care home. Internal doors were transformed using a giant adhesive poster created by a commercial graphic designer. The poster replicated the look of traditional front doors, including a range of bright bold colours and architectural features, such as brass doorknockers, letterboxes and door guards. The Revised Algase Wandering Scale (RAWS) was used to identify the effects of introducing the doors on persistent walking, eloping behaviours and spatial disorientation. A total of nine individuals living with dementia participated in the project. The post-intervention data demonstrated that there was a reduction in persistent walking, eloping behaviours and spatial disorientation. In addition, ongoing anecdotal evidence found that individuals continued to seek out others to showcase their unique door.


The biology of incipient, pre-invasive or intraepithelial neoplasia.
Invasive tumors (cancers or malignant lesions) typically develop in the setting in which there is the presence of putative non-invasive lesions and the development of these non-invasive lesions frequently precedes the development of cancers. For some organs, such as the oral cavity, cervix and skin, the respective putative pre-invasive lesions can be observed over time and documented to progress to invasive lesions. However, for less readily observable lesions, such as those of the prostate, the progression of the pre-invasive lesions, e.g., prostatic intraepithelial neoplasia (PIN) and prostatic proliferative inflammatory atrophy (PIA) to prostatic cancer are more difficult to document. Thus, for most organ systems, specific pre-invasive neoplastic lesions have been proposed based upon the apparent observations of one or more of the following: 1) microinvasive disease developing from a pre-invasive neoplastic lesion, 2) the general association of the pre-invasive lesion with invasive lesions, 3) the subsequent development of invasive lesions following diagnosis of the pre-invasive lesion, 4) correlations of the molecular features of the putative pre-invasive lesion with the matching invasive lesions, and 5) reductions in the rate of cancer following removal of the pre-invasive lesion. When there are mixtures of pre-invasive lesions with actual cancers in the same case, some of the above specific associations are more difficult to make. Several terms have been used to describe pre-invasive lesions, many of which are now less useful as our knowledge of these lesions increases. It is now commonly accepted that these lesions are a features of the spectrum of neoplastic development and most are accepted as ``neoplastic lesions'' with associated molecular features, even though they may be reversible even if they have mutations in suppressor genes (e.g., p53) or are associated with viral etiologies (e.g., cervical intraepithelial neoplasia). The overall term, "pre-invasive neoplasia", seems to best describe these putative pre-invasive lesions. Thus, terms such as incipient neoplasia should be abandoned. The term "intra-epithelial neoplasia" with an associated grade, which has been developed for pre-invasive neoplastic lesions of the cervix, i.e. cervical intraepithelial neoplasia (CIN), seems to be a terminology that adds consistency across epithelial organs. Thus, adoption of these terms for the additional organ sites of pancreas (PanIN) and prostate (PIN) seems accepted. Less descriptive terms such as the degrees of dysplasia of the oral cavity and bronchopulmonary system and actinic keratosis and Bowen's disease of the skin might be better designated as oral intraepithelial neoplasia (OIN), pulmonary intraepithelial neoplasia (PulIN) and dermal intraepithelial neoplasia (DIN). The etiology of pre-invasive neoplasia is the etiology of the matching cancers. Some obvious initiating factors include exposure to the whole range of ionizing and non-ionizing radiation, tobacco abuse and a broad range of other carcinogens (e.g., benzene). A frequent initiation factor is the setting of long standing continuing damage, inflammation and repair (LOCDIR) which leads to early molecular features associated with neoplasia after about one year. An excellent example of this is ulcerative colitis (UC) in which dysregulation of microsatellite repair enzymes have been documented one year following diagnosis of UC. While the nomenclature, description, diagnosis and etiology of pre-invasive neoplasia has advanced, approaches to therapy of such lesions have not progressed adequately even though it has been identified that, for example, removal of polyps periodically from the colorectum, DCIS from the breast, and high grade CIN from the cervix, results in a reduction in the development of cancers of the colorectum, breast, and cervix, respectively. With the development of more molecularly targeted therapy with fewer side effects, preventive therapies may be more successfully targeted to pre-invasive neoplastic lesions.


Four Weeks of Time-Restricted Feeding Combined with Resistance Training Does Not Differentially Influence Measures of Body Composition, Muscle Performance, Resting Energy Expenditure, and Blood Biomarkers.
Recently, interest in time-restricted feeding (TRF) has increased from reports highlighting improvements in body composition and muscular performance measures. Twenty-six recreationally active males were randomly assigned to either TRF (n = 13; ~22.9 years; 82.0 kg; 178.1 cm; 8 h eating window, 25% caloric deficit, 1.8 g/kg/day protein) or normal diet (ND; n = 13; ~22.5 years; 83.3 kg; 177.5 cm; normal meal pattern; 25% caloric deficit, 1.8 g/kg/day protein) groups. Participants underwent 4-weeks of supervised full body resistance training. Changes in body composition (fat mass (FM), fat free mass (FFM), and body fat percentage (BF%)), skeletal muscle cross sectional area (CSA) and muscle thickness (MT) of the vastus lateralis (VL), rectus femoris, (RF), and biceps brachii (BB) muscles, resting energy expenditure (REE), muscular performance, blood biomarkers, and psychometric parameters were assessed. Significant (p < 0.05) decreases were noted in BM, FM, BF%, testosterone, adiponectin, and REE, along with significant increases in BP1RM, LP1RM, VJHT, VJPP, VLCSA, BBCSA, and BBMT in both groups. Plasma cortisol levels were significantly elevated at post (p = 0.018) only in ND. Additionally, FFM was maintained equally between groups. Thus, a TRF style of eating does not enhance reductions in FM over caloric restriction alone during a 4-week hypocaloric diet.


Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of eating disorders.
This clinical practice guideline for treatment of DSM-5 feeding and eating disorders was conducted as part of the Royal Australian and New Zealand College of Psychiatrists (RANZCP) Clinical Practice Guidelines (CPG) Project 2013-2014. The CPG was developed in accordance with best practice according to the National Health and Medical Research Council of Australia. Literature of evidence for treatments of anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), other specified and unspecified eating disorders and avoidant restrictive food intake disorder (ARFID) was sourced from the previous RANZCP CPG reviews (dated to 2009) and updated with a systematic review (dated 2008-2013). A multidisciplinary working group wrote the draft CPG, which then underwent expert, community and stakeholder consultation, during which process additional evidence was identified. In AN the CPG recommends treatment as an outpatient or day patient in most instances (i.e. in the least restrictive environment), with hospital admission for those at risk of medical and/or psychological compromise. A multi-axial and collaborative approach is recommended, including consideration of nutritional, medical and psychological aspects, the use of family based therapies in younger people and specialist therapist-led manualised based psychological therapies in all age groups and that include longer-term follow-up. A harm minimisation approach is recommended in chronic AN. In BN and BED the CPG recommends an individual psychological therapy for which the best evidence is for therapist-led cognitive behavioural therapy (CBT). There is also a role for CBT adapted for internet delivery, or CBT in a non-specialist guided self-help form. Medications that may be helpful either as an adjunctive or alternative treatment option include an antidepressant, topiramate, or orlistat (the last for people with comorbid obesity). No specific treatment is recommended for ARFID as there are no trials to guide practice. Specific evidence based psychological and pharmacological treatments are recommended for most eating disorders but more trials are needed for specific therapies in AN, and research is urgently needed for all aspects of ARFID assessment and management. Associate Professor Susan Byrne, Dr Angelica Claudino, Dr Anthea Fursland, Associate Professor Jennifer Gaudiani, Dr Susan Hart, Ms Gabriella Heruc, Associate Professor Michael Kohn, Dr Rick Kausman, Dr Sarah Maguire, Ms Peta Marks, Professor Janet Treasure and Mr Andrew Wallis.


ATP-binding cassette transporter A1: A promising therapy target for prostate cancer.
ATP-binding cassette transporter A1 (ABCA1) has been found to mediate the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I (apoA-I), and is essential for the synthesis of high-density lipoprotein. Mutations of the ABCA1 gene may induce Tangier disease and familial hypoalphalipoproteinemia; they may also lead to loss of cellular cholesterol homeostasis in prostate cancer, and increased intracellular cholesterol levels are frequently found in prostate cancer cells. Recent studies have demonstrated that ABCA1 may exert anticancer effects through cellular cholesterol efflux, which has been attracting increasing attention in association with prostate cancer. The aim of the present review was to focus on the current views on prostate cancer progression and the various functions of ABCA1, in order to provide new therapeutic targets for prostate cancer.


Outcome of 121 patients with renal amyloid a amyloidosis.
Amyloid A (AA) amyloidosis is a multisystem, progressive and fatal disease. Renal involvement occurs early in the course of AA. We aimed to investigate the etiology, clinical and laboratory features, and outcome of patients with biopsy-proven renal AA amyloidosis. A total of 121 patients (male/female: 84/37, mean age 42.6 ± 14.4 years) were analyzed retrospectively between January of 2001 and May of 2013. Demographic, clinical and laboratory features and outcomes data were obtained from follow-up charts. Familial Mediterranean fever (37.2%) and tuberculosis (24.8%) were the most frequent causes of amyloidosis. Mean serum creatinine and proteinuria at diagnosis were 2.3 ± 2.1 mg/dL and 6.7 ± 5.3 g/day, respectively. Sixty-eight (56.2%) patients were started dialysis treatment during the follow-up period. Mean duration of renal survival was 64.7 ± 6.3 months. Age, serum creatinine and albumin levels were found as predictors of end-stage renal disease. Fifty patients (%41.3) died during the follow-up period. The mean survival of patients was 88.7 ± 7.8 months (median: 63 ± 13.9). 1, 2 and 5 years survival rates of patients were 80.7%, 68.2% and 51.3%, respectively. Older age, male gender, lower levels of body mass index, estimated glomerular filtration rate, serum albumin, calcium, and higher levels of phosphor, intact parathyroid hormone and proteinuria were associated with a higher mortality. Higher serum creatinine, lower albumin, dialysis requirement and short time to dialysis were predictors of mortality. The outcome of patients with AA amyloidosis and renal involvement is poor, particularly in those who had massive proteinuria, severe hypoalbuminemia and dialysis requirement at the outset.


Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment.
Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.


Endurance Training Improves GLP-1 Sensitivity and Glucose Tolerance in Overweight Women.
Obesity and inactivity are risk factors for developing impaired glucose tolerance characterized by insulin resistance and reduced beta-cell function. The stimulatory effect of glucagon-like peptide 1 (GLP-1) on insulin secretion is also impaired in obese, inactive individuals. The aim of this study was to investigate whether endurance training influences beta-cell sensitivity to GLP-1. Twenty-four female participants, age 46 ± 2 years, body mass index 32.4 ± 0.9 kg/m2, and maximal oxygen consumption 24.7 ± 0.8 mL/kg/min participated in a 10-week exercise training study. Beta-cell sensitivity to GLP-1 was assessed in a subset of participants (n = 6) during a 120-minute hyperglycemic glucose clamp (8.5 mM) including a 1-hour GLP-1 (7-36 amide) infusion (0.4 pmol/kg/min). Changes in glucose tolerance, body composition, and cardiorespiratory fitness were assessed by oral glucose tolerance tests (OGTTs), dual-energy X-ray absorptiometry scans, magnetic resonance scans, and maximal oxygen consumption (VO2max) tests, respectively. The c-peptide response to infusion of GLP-1 increased 28 ± 3% (P < 0.05) toward the end of the hyperglycemic clamp. The insulin response remained unchanged. Training improved glucose tolerance and reduced GLP-1, insulin, and glucagon levels during the OGTTs. Training increased VO2max (from 24.7 ± 0.8 to 27.0 ± 0.7 mL/kg/min; P < 0.05) and reduced visceral fat volume (from 4176 ± 265 to 3888 ± 266 cm3; P < 0.01). Along with improved glycemic control, endurance training improved beta-cell sensitivity to GLP-1 in overweight women. The study was deemed not to constitute a clinical trial and was not registered as such.


Melatonin: an antioxidant in edible plants.
Melatonin, a molecule with antioxidant properties that is widely distributed in the animal kingdom, has now been shown to exist in the plant kingdom, including edible plants. Our findings show that melatonin is not only an endogenously produced antioxidant, but that it is also consumed in the diet. Since melatonin concentrations in the blood correlate with the total antioxidant status of this fluid, it is likely that dietary melatonin could be important in protecting against oxidative damage.


'Why not you?' Discourses of widening access on UK medical school websites.
In the UK, applications to medicine from those in lower socio-economic groups remain low despite significant investments of time, interest and resources in widening access (WA) to medicine. This suggests that medical schools' core messages about WA may be working to embed or further reinforce marginalisation, rather than to combat this. Our objective was to investigate how the value of WA is communicated by UK medical schools through their websites, and how this may create expectations regarding who is 'suitable' for medicine. We conducted a critical discourse analysis of the webpages of UK medical schools in relation to WA. Our conceptual framework was underpinned by a Foucauldian understanding of discourse. Analysis followed an adapted version of Hyatt's analytical framework. This involved contextualising the data by identifying drivers, levers and warrants for WA, before undertaking a systematic investigation of linguistic features to reveal the discourses in use, and their assumptions. Discourses of 'social mobility for the individual' justified WA as an initiative to support individuals with academic ability and commitment to medicine, but who were disadvantaged by their background in the application process. This meritocratic discourse communicated the benefits of WA as flowing one way, with medical schools providing opportunities to applicants. Conversely, discourses justifying WA as an initiative to benefit patient care were marginalised and largely excluded. Alternative strengths typically attributed to students from lower socio-economic groups were not mentioned, which implies that these were not valued. Current discourses of WA on UK medical school websites do not present non-traditional applicants as bringing gains to medicine through their diversity. This may work as a barrier to attracting larger numbers of diverse applicants. Medical schools should reflect upon their website discourses, critically evaluate current approaches to encouraging applications from those in lower socio-economic groups, and consider avenues for positive change.


The activity of circulating dipeptidyl peptidase-4 is associated with subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus.
Patients with type 2 diabetes mellitus (T2DM) present subclinical left ventricular systolic and/or diastolic dysfunction (LVD). Dipeptidyl peptidase-4 (DPP4) inactivates peptides that possess cardioprotective actions. Our aim was to analyze whether the activity of circulating DPP4 is associated with echocardiographically defined LVD in asymptomatic patients with T2DM. In this cross-sectional study, we examined 83 T2DM patients with no coronary or valve heart disease and 59 age and gender-matched non-diabetic subjects. Plasma DPP4 activity (DPP4a) was measured by enzymatic assay and serum amino-terminal pro-brain natriuretic peptide (NT-proBNP) was measured by enzyme-linked immunosorbent assay. LV function was assessed by two-dimensional echocardiographic imaging, targeted M-mode recordings and Doppler ultrasound measurements. Differences in means were assessed by t-tests and one-way ANOVA. Associations were assessed by adjusted multiple linear regression and logistic regression analyses. DPP4a was increased in T2DM patients as compared with non-diabetic subjects (5855 ± 1632 vs 5208 ± 957 pmol/min/mL, p < 0.05). Clinical characteristics and echocardiographic parameters assessing LV morphology were similar across DPP4a tertiles in T2DM patients. However, prevalence of LVD progressively increased across incremental DPP4a tertiles (13%, 39% and 71%, all p < 0.001). Multivariate regression analysis confirmed the independent associations of DPP4a with LVD in T2DM patients (p < 0.05). Similarly, multiple logistic regression analysis showed that an increase of 100 pmol/min/min plasma DPP4a was independently associated with an increased frequency of LVD with an adjusted odds ratio of 1.10 (95% CI, 1.04 to 1.15, p = 0.001). An excessive activity of circulating DPP4 is independently associated with subclinical LVD in T2DM patients. Albeit descriptive, these findings suggest that DPP4 may be involved in the mechanisms of LVD in T2DM.


Mid-level providers in emergency obstetric and newborn health care: factors affecting their performance and retention within the Malawian health system.
Malawi has a chronic shortage of human resources for health. This has a significant impact on maternal health, with mortality rates amongst the highest in the world. Mid-level cadres of health workers provide the bulk of emergency obstetric and neonatal care. In this context these cadres are defined as those who undertake roles and tasks that are more usually the province of internationally recognised cadres, such as doctors and nurses. While there have been several studies addressing retention factors for doctors and registered nurses, data and studies addressing the perceptions of these mid-level cadres on the factors that influence their performance and retention within health care systems are scarce. This exploratory qualitative study took place in four rural mission hospitals in Malawi. The study population was mid-level providers of emergency obstetric and neonatal care. Focus group discussions took place with nursing and medical cadres. Semi-structured interviews with key human resources, training and administrative personnel were used to provide context and background. Data were analysed using a framework analysis. Participants confirmed the difficulties of their working conditions and the clear commitment they have to serving the rural Malawian population. Although insufficient financial remuneration had a negative impact on retention and performance, the main factors identified were limited opportunities for career development and further education (particularly for clinical officers) and inadequate or non-existent human resources management systems. The lack of performance-related rewards and recognition were perceived to be particularly demotivating. Mid-level cadres are being used to stem Africa's brain drain. It is in the interests of both the government and mission organizations to protect their investment in these workers. For optimal performance and quality of care they need to be supported and properly motivated. A structured system of continuing professional development and functioning human resources management would show commitment to these cadres and support them as professionals. Action needs to be taken to prevent staff members from leaving the health sector for less stressful, more financially rewarding alternatives.


High prevalence of hpv multiple genotypes in women with persistent chlamydia trachomatis infection.
Chlamydia trachomatis interaction with HR-HPV types has highlighted a central role in cervical cancer development. The aim of this study was to investigate HPV prevalence and genotypes distribution in women at risk for C. trachomatis infection and negative for intraepithelial lesion or malignancy. 1071 cervical swabs were tested for C. trachomatis by Real Time PCR and genotyping by ompA gene sequencing. Additionally, a quantitative Real time-PCR was performed to assess the expression of the C. trachomatis Hsp60-encoding gene (Ct604 portion), linked to a persistent status of infection. HPV infection and genotypes was investigated in C. trachomatis positive women using Luminex technology. C. trachomatis infection was detected in 53 out of 1071 (4.5%) samples, of which the 53% resulted positive for Hsp60 gene expression. The overall prevalence of HPV infection in C. trachomatis positive samples was of 60.4% (32/53): in 37.5% of samples was present a single genotype, while multiple genotypes infections were found in the 62.5% of them. Among women with a C. trachomatis chronic infection, 68% were HPV co-infected and the 79% showed multiple genotypes. Should be noted that levels of C. trachomatis Hsp60 expression in HPV co-infected women were significantly lower compared to women infected only with C. trachomatis. The C. trachomatis serotype F was found in the majority of samples, independently of HPV infection. A high prevalence of HPV multiple infections have been found in young women affected with a C. trachomatis chronic infection. These observations suggested that the expression of CHSP60-1, interfering with both apoptotic and cellular senescence pathways, may promote a favourable local microenvironment for HPV infection.


Interaction of ouabain with the Na+ pump in intact epithelial cells.
To determine the specificity and efficacy of [(3)H]ouabain binding as a quantitative measure of the Na(+) pump (Na(+), K(+)-ATPase) and as a marker for the localization of pumps involved in transepithelial Na(+)-transport, we analyzed the interaction of [(3)H]ouabain with its receptor in pig kidney epithelial (LLC-PK(1)) cells. When these epithelial cells are depleted of Na(+) and exposed to 2 muM [(3)H]ouabain in a Na(+)-free medium, binding is reduced by 90 percent. When depleted of K(+) and incubated in a K(+)- free medium, the ouabain binding rate is increase compared with that measured at 5 mM. This increase is only demonstable when Na(+) is present. The increased rate could be attributed to the predominance of the Na(+)-stimulated phosphorylated form of the pump, as K(+) is not readily available to stimulate dephosphorylation. However, some binding in the K(+)-free medium is attributable to pump turnover (and therefore, recycling of K(+)), because analysis of K(+)-washout kinetics demonstrated that addition of 2 muM ouabain to K(+)-depleted cells increased the rate of K(+) loss. These results indicate that in intact epithelial cells, unlike isolated membrane preparations, the most favorable condition for supporting ouabain binding occurs when the Na(+), K(+)-ATPase is operating in the Na(+)-pump mode or is phosphorylated in the presence of Na(+). When LLC-PK(1) cells were exposed to ouabain at 4 degrees C, binding was reduced by 97 percent. Upon rewarming, the rate of binding was greater than that obtained on cells kept at a constant 37 degrees C. However, even at this accelerated rate, the time to reach equilibrium was beyond what is required for cells, swollen by exposure to cold, to recover normal volume. Thus, results from studies that have attempted to use ouabain to eliminate the contribution of the conventional Na(+) pump to volume recovery must be reevaluated if the exposure to ouabain was done in the cold or under conditions in which the Na(+) pump is not operating.


What killed Frame Lake? A precautionary tale for urban planners.
Frame Lake, located within the city of Yellowknife, Northwest Territories, Canada, has been identified as requiring significant remediation due to its steadily declining water quality and inability to support fish by the 1970s. Former gold mining operations and urbanization around the lake have been suspected as probable causes for the decline in water quality. While these land-use activities are well documented, little information is available regarding their impact on the lake itself. For this reason, Arcellinida, a group of shelled protozoans known to be reliable bioindicators of land-use change, were used to develop a hydroecological history of the lake. The purpose of this study was to use Arcellinida to: (1) document the contamination history of the lake, particularly related to arsenic (As) associated with aerial deposition from mine roaster stacks; (2) track the progress of water quality deterioration in Frame Lake related to mining, urbanization and other activities; and (3) identify any evidence of natural remediation within the lake. Arcellinida assemblages were assessed at 1-cm intervals through the upper 30 cm of a freeze core obtained from Frame Lake. The assemblages were statistically compared to geochemical and loss-on-ignition results from the core to document the contamination and degradation of conditions in the lake. The chronology of limnological changes recorded in the lake sediments were derived from 210Pb, 14C dating and known stratigraphic events. The progress of urbanization near the lake was tracked using aerial photography. Using Spearman correlations, the five most significant environmental variables impacting Arcellinida distribution were identified as minerogenics, organics, As, iron and mercury (p < 0.05; n = 30). Based on CONISS and ANOSIM analysis, three Arcellinida assemblages are identified. These include the Baseline Limnological Conditions Assemblage (BLCA), ranging from 17-30 cm and deposited in the early Holocene >7,000 years before present; the As Contamination Assemblage (ACA), ranging from 7-16 cm, deposited after ∼1962 when sedimentation began in the lake again following a long hiatus that spanned to the early Holocene; and the Eutrophication Assemblage (EA), ranging from 1-6 cm, comprised of sediments deposited after 1990 following the cessation of As and other metal contaminations. The EA developed in response to nutrient-rich waters entering the lake derived from the urbanization of the lake catchment and a reduction in lake circulation associated with the development at the lake outlet of a major road, later replaced by a causeway with rarely open sluiceways. The eutrophic condition currently charactering the lake-as evidenced by a population explosion of eutrophication indicator taxa Cucurbitella tricuspis-likely led to a massive increase in macrophyte growth and winter fish-kills. This ecological shift ultimately led to a system dominated by Hirudinea (leeches) and cessation of the lake as a recreational area.


Telomeric ORFs (TLOs) in Candida spp. Encode mediator subunits that regulate distinct virulence traits.
The TLO genes are a family of telomere-associated ORFs in the fungal pathogens Candida albicans and C. dubliniensis that encode a subunit of the Mediator complex with homology to Med2. The more virulent pathogen C. albicans has 15 copies of the gene whereas the less pathogenic species C. dubliniensis has only two (CdTLO1 and CdTLO2). In this study we used C. dubliniensis as a model to investigate the role of TLO genes in regulating virulence and also to determine whether TLO paralogs have evolved to regulate distinct functions. A C. dubliniensis tlo1Δ/tlo2Δ mutant is unable to form true hyphae, has longer doubling times in galactose broth, is more susceptible to oxidative stress and forms increased levels of biofilm. Transcript profiling of the tlo1Δ/tlo2Δ mutant revealed increased expression of starvation responses in rich medium and retarded expression of hypha-induced transcripts in serum. ChIP studies indicated that Tlo1 binds to many ORFs including genes that exhibit high and low expression levels under the conditions analyzed. The altered expression of these genes in the tlo1Δ/tlo2Δ null mutant indicates roles for Tlo proteins in transcriptional activation and repression. Complementation of the tlo1Δ/tlo2Δ mutant with TLO1, but not TLO2, restored wild-type filamentous growth, whereas only TLO2 fully suppressed biofilm growth. Complementation with TLO1 also had a greater effect on doubling times in galactose broth. The different abilities of TLO1 and TLO2 to restore wild-type functions was supported by transcript profiling studies that showed that only TLO1 restored expression of hypha-specific genes (UME6, SOD5) and galactose utilisation genes (GAL1 and GAL10), whereas TLO2 restored repression of starvation-induced gene transcription. Thus, Tlo/Med2 paralogs encoding Mediator subunits regulate different virulence properties in Candida spp. and their expansion may account for the increased adaptability of C. albicans relative to other Candida species.


Cloning and expression analysis of four heat shock protein genes in Ericerus pela (Homoptera: Coccidae).
To explore the function of small heat shock protein genes (shsps) and hsp70 in Ericerus pela, we cloned the full-length cDNA sequences of hsp21.5, hsp21.7, hsp70, and hsc70 and the genomic sequence of hsc70. Open reading frames of the four hsps were 570, 564, 1,908, and 1,962 base pairs (bp), respectively, which encode proteins with calculated molecular mass of 21.5, 21.7, 69.8, and 71.6 kDa. Amino acid sequence analysis revealed the presence of the conserved Hsp motifs in all four proteins. The genomic DNA of hsc70 had four introns. ep-hsp21.5 was orthologous and ep-hsp21.7 was species specific. Expression of all four transcripts during heat or cold stress and development was examined by quantitative real-time polymerase chain reaction. All four hsps were upregulated during heat or cold stress in female adults, indicating a correlation between the four hsps and heat or cold-stress tolerance in female adults. ep-hsp21.7 and ep-hsp70 were upregulated during heat stress in male larvae, implying a correlation between the two hsps and heat-stress tolerance in male larvae. The four ep-hsps were also upregulated during the developmental process in males, and ep-hsp21.5, ep-hsp70, and ep-hsc70 were upregulated in females, which indicates their possible role in the developmental regulation of E. pela.


Central slip extensor tendon injuries: a systematic review of treatments.
This systematic review describes and compares outcomes of operative and non-operative management of central slip extensor tendon injuries. A PRISMA-compliant methodology identified 3785 studies. Of these, 29 underwent full text review. No randomized controlled trials were identified. Nine studies evaluated treatment modalities specific to cohorts with acute central slip injuries in adults. A range of operative and non-operative elements of management was identified although no studies directly compared the two. Where aspects of rehabilitation were studied, this was always after surgery. The evidence base regarding treatment of central slip injury is limited and the roles of different treatment strategies for open as well as closed injuries are not well-supported by evidence.


Preconcentration of Cu (II) from seawater using a novel and stable phenol-formaldehyde resin.
Preconcentration of Cu (II) from seawater using a novel phenol-formaldehyde (P-F) resin was investigated. 1,2-dihydroxybenzene-4-azo-3-hydroxybenzene-formaldehyde resin (DAHBF) was prepared by condensing 1,2-dihydroxybenzene-4-azo-3-hydroxybenzene with formaldehyde (1:2 mole ratio) in the presence of oxalic acid as catalyst. Polychelates were obtained when the DAHBF was treated with the aqueous solution of Cu (II) ions. The polymeric resin and polymer-metal complexes were characterized with thermal analysis and spectral studies. The IR spectra of polychelates suggest that the metal was coordinated through the oxygen atoms of the dihydroxybenzene moiety. The TGA data revealed the thermal stability of the resin and the polychelates. X-ray diffraction study revealed the incorporation of the metal ion significantly enhanced the degree of crystallinity. The sorption properties of the chelate forming resin towards divalent metal ion [Cu(II)] was studied as a function of pH, preconcentration time, metal concentration, amount of resin, aqueous phase volume and presence of electrolyte. This procedure was validated for recovery of copper from seawater samples. The method has adequate accuracy and it can be used for determination of copper in sea water samples.


Prolotherapy: a clinical review of its role in treating chronic musculoskeletal pain.
Prolotherapy is a technique that involves the injection of an irritant, usually a hyperosmolar dextrose solution, typically in the treatment of chronic painful musculoskeletal conditions. Despite its long history and widespread use as a form of complementary therapy, there still are disparities over its optimal indications and injection preparations. There are, however, numerous studies available regarding the use and efficacy of prolotherapy for various musculoskeletal conditions. The most frequently published indication is in the treatment of chronic low back pain, but there are recent studies that examined its use in the management of refractory tendinopathies as well as osteoarthritis. There is growing evidence to suggest that prolotherapy may be helpful in treating chronic low back pain when coupled with adjunctive therapies, such as spinal manipulation or corticosteroid injections. There is also evidence to suggest that prolotherapy is effective in treating refractory tendinopathies, particularly for lateral epicondylosis and Achilles tendinopathy. Additional larger, randomized controlled trials are needed to make specific recommendations regarding ideal protocols and indications. There is emerging evidence for the use of prolotherapy as a treatment option for osteoarthritis; however, further studies are needed to conclusively demonstrate its efficacy. Overall, prolotherapy remains a promising option for the treatment of painful musculoskeletal conditions, particularly when other standard treatments have proved ineffective.


Prevention measures and exploratory pharmacological treatments of celiac disease.
Increasing prevalence, protean clinical manifestations, and lack of pharmacological therapy make celiac disease (CD) a complex and highly relevant illness in gastroenterology. This chronic inflammatory disorder of the small intestine is caused by the ingestion of gluten containing cereals in genetically susceptible individuals, leading to a variety of gastrointestinal (GI) and non-GI manifestations. Awareness among physicians is growing due to accessible and highly accurate diagnostic and screening methods. Recent evidence suggests a possible rising incidence of CD. Environmental factors such as early life gluten exposure, intestinal infections, short duration of breast-feeding, and changes in intestinal microbiota have been proposed to have a role in CD pathogenesis. Thus, prevention approaches to diminish the rising prevalence of CD are currently being evaluated. Still, the cornerstone treatment of CD remains a strict gluten-free diet. This nutritional regime is demanding, and non-adherence is common because of social isolation, financial issues, or restriction of food diversity. Allowing patients to occasionally consume small amounts of gluten would greatly improve their quality of life. Owing to recent advances in the understanding of the pathogenesis of CD, different targets have been identified and have motivated the development of several experimental therapeutic strategies. The main goal of this review is to discuss the mechanisms that can be exploited therapeutically to prevent or delay CD, disease associations and its complications. Current treatments for complications of CD, including refractory CD and malignancy, are beyond the scope of this review.


Current medical management of hereditary angioedema: results from a large survey of US physicians.
Hereditary angioedema (HAE) is a potentially life-threatening condition that affects approximately 1 in 50,000 persons. There are no known surveys of US physicians' knowledge and experience regarding the epidemiology, diagnosis, and management of HAE. This survey of physicians treating patients with HAE assessed physician characteristics, diagnostic and treatment practices, factors that influence physician and patient treatment choices, and physician awareness of new therapies. From October 2009 to February 2010, physicians (N = 172) voluntarily completed an online survey developed by physician-investigators. Data were analyzed with descriptive statistics. Most physicians (73.8%) managed 5 patients or fewer in diverse practice settings. Laboratory testing was considered most important in establishing a diagnosis. Fresh frozen plasma and C1 esterase inhibitors were the most frequently administered treatments for acute events; nearly 50% of respondents prescribed C1 esterase inhibitor for acute attacks. More than 80% of respondents prescribed androgens for long-term prophylaxis. Approximately half of respondents were aware of, and likely to use, new therapies for HAE. Other than efficacy, adverse effects were the most important factor that influenced physicians' treatment recommendations, whereas physicians perceived that patients were most influenced by adverse effects and cost. Wide variability exists in the treatment of patients with HAE. Many patients experience acute attacks that require emergency care or hospitalization. Androgens and fresh frozen plasma are frequently used despite recent availability of effective condition-specific agents, and many physicians are only somewhat aware of medications newly approved by the US Food and Drug Administration. Because the survey was completed shortly after approval of additional HAE therapies by the US Food and Drug Administration, these data will be useful for tracking changes in HAE treatment over time.


Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease.
Glucocerebrosidase (GBA1) gene mutations increase the risk of Parkinson disease (PD). While the cellular mechanisms associating GBA1 mutations and PD are unknown, loss of the glucocerebrosidase enzyme (GCase) activity, inhibition of autophagy and increased α-synuclein levels have been implicated. Here we show that autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase. ALR is a cellular process controlled by mTOR which regenerates functional lysosomes from autolysosomes formed during macroautophagy. A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of GCase deficiency, including primary mouse neurons and the PD patient derived fibroblasts with GBA1 mutations, suggesting that ALR is compromised. Importantly Rab7, a GTPase crucial for endosome-lysosome trafficking and ALR, accumulated in GCase deficient cells, supporting the notion that lysosomal recycling is impaired. Recombinant GCase treatment reversed ALR inhibition and lysosomal dysfunction. Moreover, ALR dysfunction was accompanied by impairment of macroautophagy and chaperone-mediated autophagy, increased levels of total and phosphorylated (S129) monomeric α-synuclein, evidence of amyloid oligomers and increased α-synuclein release. Concurrently, we found increased cholesterol and altered glucosylceramide homeostasis which could compromise ALR. We propose that GCase deficiency in PD inhibits lysosomal recycling. Consequently neurons are unable to maintain the pool of mature and functional lysosomes required for the autophagic clearance of α-synuclein, leading to the accumulation and spread of pathogenic α-synuclein species in the brain. Since GCase deficiency and lysosomal dysfunction occur with ageing and sporadic PD pathology, the decrease in lysosomal reformation may be a common feature in PD.


En masse retraction versus two-step retraction of anterior teeth in extraction treatment of bimaxillary protrusion.
In the present report, two techniques of space closure; two-step anterior teeth retraction (TSR) and en masse retraction (ER) were used in two adult patients who had bimaxillary protrusion and were treated with four premolar extractions and fixed orthodontic appliance therapy. Both patients had a Class I dental malocclusion and the same chief complaint, which is protrusive lips. Anterior teeth were retracted by two-step retraction; canine sliding followed by retraction of incisors with T-loop archwire in the first patient and by en masse retraction using Beta titanium alloy T-loop archwire in the second case. At the end of treatment, good balance and harmony of lips was achieved with maintenance of Class I relationships. The outcome of treatment was similar in the two patients with similar anchorage control. ER can be an acceptable alternative to the TSR during space closure since it is esthetically more acceptable. However, it requires accurate bending and positioning of the T-loop.


Gender-Specific Associations of Sensory Impairments with Depression and Cognitive Impairment in Later Life.
Sensory impairments, such as vision and hearing impairments, increase with age, and studies have shown that self-reported vision and hearing impairments are associated with adverse mental health outcomes in later life. Although gender differences may exist in the associations between sensory impairments and geriatric mental health outcomes, little research has been done examining gender differences in the above associations. Therefore, the purpose of this study was to investigate the relationship between self-reported sensory impairments and geriatric mental health outcomes with the aim of determining whether any association differs by gender. The study sample was drawn from a nationally representative data set, the 2012 Korean Longitudinal Study of Ageing, and the final sample consisted of 2,167 females and 1,664 males aged 65 and over. Self-reported sensory impairments were categorized into four groups: no sensory impairment (reference), vision impairment only, hearing impairment only, and dual sensory impairment. Depression and cognitive impairment were used as dependent variables in separate analyses. Adjusted for confounding variables, results from a multivariate analysis showed that vision impairment was significantly associated with depression only among women. Moreover, hearing impairment was significantly associated with cognitive impairment for women, but not for men. Having dual sensory impairment was associated with depression only among men, while having dual sensory impairment was associated with cognitive impairment only among women. These findings suggest that the associations between sensory impairments and geriatric mental health outcomes vary according to gender. Therefore, gender-specific strategies in healthcare policies are needed.


[Breastfeeding in premature infants: in-hospital clinical management].
To describe the importance of breastfeeding and its promotion in the in-hospital clinical management of premature newborns. The authors made an extensive literature review on the topic, including technical books, theses, publications of national and international organizations, and search on MEDLINE database (1990 to 2003), using the following key words and boolean operators: "breastfeeding AND low birth weight" and "breastfeeding AND preterm infant". Some significant references cited in the reviewed publications were used as well. After this review we conclude that many aspects make the breast milk particularly suitable to the premature newborn feeding. Despite being highly desirable, little success in breastfeeding preterm infants is generally observed, particularly in special care neonatal units, although there is evidence suggesting that a highly supportive hospital environment can make it possible to breastfeed these infants. Although breastfeeding premature infants represents a challenge, it is feasible if appropriate help and support are provided. Mothers of premature infants need information and support to make informed decisions about their infant's feeding.


Disparities between HIV patient subgroups in Oman: An analysis of the 2019 cascade of care.
The HIV cascade of care is a framework for monitoring HIV care, identifying gaps and informing appropriate interventions. This study aimed to describe the cascade of care in Oman in 2019 and highlight disparities at the sub-population level. We used the UNAIDS Spectrum modelling software to estimate the number of people living with HIV. A national HIV surveillance database was used to identify Omani people (≥13 years old) diagnosed with HIV from 1984 through December 2019. We calculated the cascade indicators as of 31 December 2019 stratified by sex, age, HIV risk factor, residence, and region of HIV care. We also performed multivariate logistic regression to determine the predictors of attrition at linkage, retention, on ART, and viral suppression. As of December 2019, the estimated number of people living with HIV in Oman was 2440. Out of the estimated number of people living with HIV, 69% were diagnosed, 66% were linked to care, 61% were retained in care, 60% were on ART, and 55% were virally suppressed. Of the 1673 diagnosed individuals, 96% were linked to care, 88% were retained in care, 87% were on ART, and 81% were virally suppressed. People who received HIV care outside Muscat had the largest attrition (11% loss) in the transition from linkage (97%) to retention (86%). Similarly, people aged 13-24 years had the largest attrition (13% loss) from "on ART" (88%) to viral suppression (75%). Logistic regression showed that both not reporting a specific HIV risk factor and receipt of HIV care outside Muscat independently predicted attrition at each cascade stage from linkage to care through viral suppression. Our findings identified substantial disparities across various subpopulations along the cascade of care in Oman. This analysis will be invaluable in informing future interventions targeting patient subgroups who are at the highest risk of attrition.


Hydrodynamic and Contact Contributions to Continuous Shear Thickening in Colloidal Suspensions.
Shear thickening is a widespread phenomenon in suspension flow that, despite sustained study, is still the subject of much debate. The longstanding view that shear thickening is due to hydrodynamic clusters has been challenged by recent theory and simulations suggesting that contact forces dominate, not only in discontinuous, but also in continuous shear thickening. Here, we settle this dispute using shear reversal experiments on micron-sized silica and latex particles to measure directly the hydrodynamic and contact force contributions to shear thickening. We find that contact forces dominate even continuous shear thickening. Computer simulations show that these forces most likely arise from frictional interactions.


Nanodispersions of beta-carotene: effects on antioxidant enzymes and cytotoxic properties.
Beta-carotene is a carotenoid precursor of vitamin A, known for its biological activities. Due to its high hydrophobicity, nanonization processes, i.e. the transformation into nanoparticles, can improve its water affinity, and therefore the activity in aqueous systems. The objective of this study was to produce beta-carotene nanoparticles by the solid dispersion method and to evaluate their effects on the activity of glutathione-S-transferase and acetylcholinesterase enzymes using Drosophila melanogaster (DM) homogenate, the superoxide dismutase- and catalase-like activities under in vitro conditions, and their cytotoxic properties against tumor and non-tumor cells. The formed nanometric beta-carotene particles resulted in stable colloids, readily dispersed in water, able to modulate acetylcholinesterase (AChE) activity, and presenting high potential to control the cholinergic system. Beta-carotene nanoparticles, at concentrations much lower than the pure pristine beta-carotene, presented in vitro mimetic activity to superoxide dismutase and altered glutathione-S-transferase activity in DM tissue. The content of hydrogen peroxide was neither affected by the nanoparticles (in aqueous solution) nor by pristine beta-carotene (in DMSO). In the cytotoxic assays, beta-carotene nanoparticles dispersed in water showed activity against four different tumor cell lines. Overall, beta-carotene nanoparticles presented significant bioactivity in aqueous medium surpassing their high hydrophobicity constraint.


Misclassification of incident conditions using claims data: impact of varying the period used to exclude pre-existing disease.
Estimating the incidence of medical conditions using claims data often requires constructing a prevalence period that predates an event of interest, for instance the diagnosis of cancer, to exclude those with pre-existing conditions from the incidence risk set. Those conditions missed during the prevalence period may be misclassified as incident conditions (false positives) after the event of interest.Using Medicare claims, we examined the impact of selecting shorter versus longer prevalence periods on the incidence and misclassification of 12 relatively common conditions in older persons. The source of data for this study was the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registry linked to Medicare claims. Two cohorts of women were included: 33,731 diagnosed with breast cancer between 2000 and 2002, who had ≥ 36 months of Medicare eligibility prior to cancer, the event of interest; and 101,649 without cancer meeting the same Medicare eligibility criterion. Cancer patients were followed from 36 months before cancer diagnosis (prevalence period) up to 3 months after diagnosis (incidence period). Non-cancer patients were followed for up to 39 months after the beginning of Medicare eligibility. A sham date was inserted after 36 months to separate the prevalence and incidence periods. Using 36 months as the gold standard, the prevalence period was then shortened in 6-month increments to examine the impact on the number of conditions first detected during the incidence period. In the breast cancer cohort, shortening the prevalence period from 36 to 6 months increased the incidence rates (per 1,000 patients) of all conditions; for example: hypertension 196 to 243; diabetes 34 to 76; chronic obstructive pulmonary disease 29 to 46; osteoarthritis 27 to 36; congestive heart failure 20 to 36; osteoporosis 22 to 29; and cerebrovascular disease 13 to 21. Shortening the prevalence period has less impact on those without cancer. Selecting a short prevalence period to rule out pre-existing conditions can, through misclassification, substantially inflate estimates of incident conditions. In incidence studies based on Medicare claims, selecting a prevalence period of ≥24 months balances the need to exclude pre-existing conditions with retaining the largest possible cohort.


Biomechanics of a posture-controlling cervical artificial disc: mechanical, in vitro, and finite-element analysis.
Different methods have been described by numerous investigators for experimentally assessing the kinematics of cervical artificial discs. However, in addition to understanding how artificial discs affect range of motion, it is also clinically relevant to understand how artificial discs affect segmental posture. The purpose of this paper is to describe novel considerations and methods for experimentally assessing cervical spine postural control in the laboratory. These methods, which include mechanical testing, cadaveric testing, and computer modeling studies, are applied in comparing postural biomechanics of a novel postural control arthroplasty (PCA) device versus standard ball-and-socket (BS) and ball-in-trough (BT) arthroplasty devices. The overall body of evidence from this group of tests supports the conclusion that the PCA device does control posture to a particular lordotic position, whereas BS and BT devices move freely through their ranges of motion.


The contribution of von Willebrand factor-GPIbα interactions to persistent aggregate formation in apheresis platelet concentrates.
Apheresis platelet concentrates sometimes contain persistent aggregates (PA). Because apheresis involves extracorporeal circulation, we hypothesized that interactions between GPIbα and von Willebrand factor (VWF) underlie their origin. Platelets in donations with PA were compared to aggregate-free (AF) controls. Flow cytometry was used to determine platelet bound VWF. Degranulation was measured using P-selectin expression in flow cytometry and cytokine release using immunosorbent assays. Platelet adhesion to VWF was assessed in hydrodynamic flow and real-time video microscopy. Platelets in PA concentrates had significantly more (P = 0·009, n ≥ 8) bound VWF compared to AF platelets, but differences in VWF concentration, VWF collagen binding, activated VWF or GPIbα expression were not found. Degranulation was higher (P = 0·030, n = 7) in PA than AF concentrates on day 1 of storage, but adhesion to immobilized VWF under hydrodynamic flow conditions was normal at that moment. On day 6, however, significantly less VWF adhesion (P = 0·009, n ≥ 6) was found for PA platelets compared to AF, indicating accelerated storage lesion in PA products. In a model that mimicks PA formation by chemically induced binding of VWF to platelets, we found that degranulation, phosphatidylserine expression and metabolism did not differ with paired controls at any time during subsequent storage. Accelerated storage lesion is found in concentrates with PA, but this cannot be explained solely by increased platelet bound VWF following apheresis. Therefore, additional stressors are probably responsible for the increases observed in platelet degranulation and storage lesion in products with PA.


[Multidisciplinary management of malignant hepatic tumors in children: a recent national experience].
Malignant hepatic tumors (Mht) are rare in children. Among them hepatoblastoma (HB) is the most common. To report the results of the multidisciplinary management in 6 consecutive children: five HB and one metastatic Wilms tumor (MWT). The mean age of patients was 42 months. All HB patients had elevated serum alfafetoprotein (median 150,000 ng/ml). All patients received preoperative chemotherapy: HB patients received carboplatin/doxorubicin alternating with cisplatin, and the MWT patient, vincristine alone. Surgery included two formal right and two formal left hepatectomies, one extensive central resection with partial left segmentectomy, and one lateral segmentectomy. Extracorporeal circulation was used in the child with atrial involvement. All patients received postoperative chemotherapy. All tumors had variable regresion on preoperative chemotherapy. Complete resection with negative margins was achieved in all patients. The degree of tumor necrosis on histology ranged from 60% to 90%. Alfafetoprotein levels fell to under 10 ng/ml in all HB cases, one to three months after surgery. All patients survive free of disease at a median follow up of 19 months. A multidisciplinary approach including the well timed used of chemotherapy and surgery is highly effective in the management of pediatric malignant tumors.


Prayer at midlife is associated with reduced risk of cognitive decline in Arabic women.
Midlife habits may be important for the later development of Alzheimer's disease (AD). We estimated the contribution of midlife prayer to the development of cognitive decline. In a door-to-door survey, residents aged ≥65 years were systematically evaluated in Arabic including medical history, neurological, cognitive examination, and a midlife leisure-activities questionnaire. Praying was assessed by the number of monthly praying hours at midlife. Stepwise logistic regression models were used to evaluate the effect of prayer on the odds of mild cognitive impairment (MCI) and AD versus cognitively normal individuals. Of 935 individuals that were approached, 778 [normal controls (n=448), AD (n=92) and MCI (n=238)] were evaluated. A higher proportion of cognitively normal individuals engaged in prayer at midlife [(87%) versus MCI (71%) or AD (69%) (p<0.0001)]. Since 94% of males engaged in prayer, the effect on cognitive decline could not be assessed in men. Among women, stepwise logistic regression adjusted for age and education, showed that prayer was significantly associated with reduced risk of MCI (p=0.027, OR=0.55, 95% CI 0.33-0.94), but not AD. Among individuals endorsing prayer activity, the amount of prayer was not associated with MCI or AD in either gender. Praying at midlife is associated with lower risk of mild cognitive impairment in women.


Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation.
Activation of the cellular DNA damage response is detrimental to adenovirus (Ad) infection. Ad has therefore evolved a number of strategies to inhibit ATM- and ATR-dependent signaling pathways during infection. Recent work suggests that the Ad5 E4orf3 protein prevents ATR activation through its ability to mislocalize the MRN complex. Here we provide evidence to indicate that Ad12 has evolved a different strategy from Ad5 to inhibit ATR. We show that Ad12 utilizes a CUL2/RBX1/elongin C-containing ubiquitin ligase to promote the proteasomal degradation of the ATR activator protein topoisomerase-IIbeta-binding protein 1 (TOPBP1). Ad12 also uses this complex to degrade p53 during infection, in contrast to Ad5, which requires a CUL5-based ubiquitin ligase. Although Ad12-mediated degradation of p53 is dependent upon both E1B-55K and E4orf6, Ad12-mediated degradation of TOPBP1 is solely dependent on E4orf6. We propose that Ad12 E4orf6 has two principal activities: to recruit the CUL2-based ubiquitin ligase and to act as substrate receptor for TOPBP1. In support of the idea that Ad12 E4orf6 specifically prevents ATR activation during infection by targeting TOPBP1 for degradation, we demonstrate that Ad12 E4orf6 can inhibit the ATR-dependent phosphorylation of CHK1 in response to replication stress. Taken together, these data provide insights into how Ad modulates ATR signaling pathways during infection.


Systematic Review: The Impact of Cancer Treatment on the Gut and Vaginal Microbiome in Women With a Gynecological Malignancy.
Worldwide, 1,470,900 women are diagnosed yearly with a gynecological malignancy (21,000 in the UK). Some patients treated with pelvic radiotherapy develop chronic changes in their bowel function. This systematic review summarizes current research on the impact of cancer treatment on the gut and vaginal microbiome in women with a gynecological malignancy. The Preferred reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews were used to ensure transparent and complete reporting. Quantitative studies exploring the gut or vaginal microbiome in this patient cohort were included. Animal studies were excluded. There were no language restrictions. No studies examined the possible effects of surgery or chemotherapy for gynecological cancers on the gut or vaginal microbiome.Three prospective cohort studies were identified using sequencing of changes in the gut microbiome reporting on a total of 23 women treated for gynecological cancer. All studies included patients treated with radiotherapy with a dosage ranging from 43.0 to 54.0 Gy. Two studies assessed gastrointestinal toxicity formally; 8 women (57%) developed grade 2 or 3 diarrhea during radiotherapy. The outcomes suggest a correlation between changes in the intestinal microbiome and receiving radiotherapy and showed a decrease in abundance and diversity of the intestinal bacterial species. Before radiotherapy, those who developed diarrhea had an increased abundance of Bacteroides, Dialister, and Veillonella (P < 0.01), and a decreased abundance of Clostridium XI and XVIII, Faecalibacterium, Oscillibacter, Parabacteroides, Prevotella, and unclassified bacteria (P < 0.05). The limited evidence to date implies that larger studies including both the vaginal and gut microbiome in women treated for a gynecological malignancy are warranted to explore the impact of cancer treatments on the microbiome and its relation to developing long-term gastrointestinal toxicity. This may lead to new avenues to stratify those at risk and explore personalized treatment options and prevention of gastrointestinal consequences of cancer treatments.


The accumulation of influenza A virus segment 7 spliced mRNAs is regulated by the NS1 protein.
The influenza A virus M1 mRNA is alternatively spliced to produce M2 mRNA, mRNA(3), and in some cases, M4 mRNA. Splicing of influenza mRNAs is carried out by the cellular splicing machinery and is thought to be regulated, as both spliced and unspliced mRNAs encode proteins. In this study, we used radioactively labelled primers to investigate the accumulation of spliced and unspliced M segment mRNAs in viral infection and ribonucleoprotein (RNP) reconstitution assays in which only the minimal components required for transcription and replication to occur were expressed. We found that co-expression of the viral NS1 protein in an RNP reconstitution assay altered the accumulation of spliced mRNAs compared with when it was absent, and that this activity was dependent on the RNA-binding ability of NS1. These findings suggest that the NS1 protein plays a role in the regulation of splicing of influenza virus M1 mRNA.


Effects of oral iron chelator deferasirox on human malignant lymphoma cells.
Iron is essential for cell proliferation and viability. It has been reported that iron depletion by a chelator inhibits proliferation of some cancer cells. Deferasirox is a new oral iron chelator, and a few reports have described its effects on lymphoma cells. The goal of this study was to determine the anticancer effects of deferasirox in malignant lymphoma cell lines. Three human malignant lymphoma cell lines (NCI H28:N78, Ramos, and Jiyoye) were treated with deferasirox at final concentrations of 20, 50, or 100 µM. Cell proliferation was evaluated by an MTT assay, and cell cycle and apoptosis were analyzed by flow cytometry. Western blot analysis was performed to determine the relative activity of various apoptotic pathways. The role of caspase in deferasirox-induced apoptosis was investigated using a luminescent assay. The MTT assay showed that deferasirox had dose-dependent cytotoxic effects on all 3 cell lines. Cell cycle analysis showed that the sub-G1 portion increased in all 3 cell lines as the concentration of deferasirox increased. Early apoptosis was also confirmed in the treated cells by Annexin V and PI staining. Western blotting showed an increase in the cleavage of PARP, caspase 3/7, and caspase 9 in deferasirox-treated groups. We demonstrated that deferasirox, a new oral iron-chelating agent, induced early apoptosis in human malignant lymphoma cells, and this apoptotic effect is dependent on the caspase-3/caspase-9 pathway.


Development of the Global Network for Women's and Children's Health Research's socioeconomic status index for use in the network's sites in low and lower middle-income countries.
Socioeconomic status (SES) is an important determinant of health globally and an important explanatory variable to assess causality in epidemiological research. The 10th Sustainable Development Goal is to reduce disparities in SES that impact health outcomes globally. It is easier to study SES in high-income countries because household income is representative of the SES. However, it is well recognized that income is poorly reported in low- and middle- income countries (LMIC) and is an unreliable indicator of SES. Therefore, there is a need for a robust index that will help to discriminate the SES of rural households in a pooled dataset from LMIC. The study was nested in the population-based Maternal and Neonatal Health Registry of the Global Network for Women's and Children's Health Research which has 7 rural sites in 6 Asian, sub-Saharan African and Central American countries. Pregnant women enrolling in the Registry were asked questions about items such as housing conditions and household assets. The characteristics of the candidate items were evaluated using confirmatory factor analyses and item response theory analyses. Based on the results of these analyses, a final set of items were selected for the SES index. Using data from 49,536 households of pregnant women, we reduced the data collected to a 10-item index. The 10 items were feasible to administer, covered the SES continuum and had good internal reliability and validity. We developed a sum score-based Item Response Theory scoring algorithm which is easy to compute and is highly correlated with scores based on response patterns (r = 0.97), suggesting minimal loss of information with the simplified approach. Scores varied significantly by site (p < 0.001). African sites had lower mean SES scores than the Asian and Central American sites. The SES index demonstrated good internal consistency reliability (Cronbach's alpha = 0.81). Higher SES scores were significantly associated with formal education, more education, having received antenatal care, and facility delivery (p < 0.001). While measuring SES in LMIC is challenging, we have developed a Global Network Socioeconomic Status Index which may be useful for comparisons of SES within and between locations. Next steps include understanding how the index is associated with maternal, perinatal and neonatal mortality. Trial Registration NCT01073475 Socioeconomic status (SES) is an important determinant of health globally, and improving SES is important to reduce disparities in health outcomes. It is easier to study SES in high-income countries because it can be measured by income and what income is spent on, but this concept does not translate easily to low and middle income countries. We developed a questionnaire that includes 10 items to determine SES in low-resource settings that was added to an ongoing Maternal and Neonatal Health Registry that is funded by the National Institutes of Child Health and Human Development's Global Network. The Registry includes sites that collect outcomes of pregnancies in women and their babies in rural areas in 6 countries in South Asia, sub-Saharan Africa and Central America. The Registry is population based and tracks women from early in pregnancy to day 42 post-partum. The questionnaire is easy to administer and has good reliability and validity. Next steps include understanding how the index is associated with maternal, fetal and neonatal mortality.


Associations of Child Maltreatment and Intimate Partner Violence With Elder Abuse in a US Chinese Population.
People who have experienced abuse as a child or violence with an intimate partner might have higher odds of being abused again, but this has been insufficiently investigated regarding elder abuse. More conclusive evidence might be critical to assessment and prevention strategies. To examine the associations of child maltreatment and intimate partner violence with elder abuse. Cross-sectional data of 3157 community-dwelling US Chinese older adults (60 years or older) in Chicago, Illinois, were collected during 2011 through 2013. Cases of child maltreatment and intimate partner violence. Cases of elder abuse. Of the 3157 US Chinese older adults included in the study, 1328 (42.1%) were men, and the mean (SD) age was 72.8 (8.3) years. The prevalence of elder abuse, child maltreatment, and intimate partner violence in the cohort was 15.2%, 11.4%, and 6.5%, respectively. After adjusting for sociodemographic variables, health status, quality of life, and health change, individuals reporting child maltreatment had increased odds of intimate partner violence (13.4% vs 5.6%; adjusted odds ratio [aOR], 2.57; 95% CI, 1.78-3.71) and elder abuse (25.2% vs 13.8%; aOR, 2.08; 95% CI, 1.57-2.75) than those not reporting child maltreatment. Individuals reporting intimate partner violence had increased odds of elder abuse than those not reporting intimate partner violence (48.8% vs 12.9%; aOR, 5.53; 95% CI, 4.01-7.64). Prior abuse across major lifespan stages is associated with higher odds of elder abuse. Health care professionals should be more aware of the possibility of abuse when there is a known history of violence in a patient and consider the cumulative effect of violence among those exposed to elder abuse.


Ozone-Induced Rice Grain Yield Loss Is Triggered via a Change in Panicle Morphology That Is Controlled by ABERRANT PANICLE ORGANIZATION 1 Gene.
Rice grain yield is predicted to decrease in the future because of an increase in tropospheric ozone concentration. However, the underlying mechanisms are unclear. Here, we investigated the responses to ozone of two rice (Oryza Sativa L.) cultivars, Sasanishiki and Habataki. Sasanishiki showed ozone-induced leaf injury, but no grain yield loss. By contrast, Habataki showed grain yield loss with minimal leaf injury. A QTL associated with grain yield loss caused by ozone was identified in Sasanishiki/Habataki chromosome segment substitution lines and included the ABERRANT PANICLE ORGANIZATION 1 (APO1) gene. The Habataki allele of the APO1 locus in a near-isogenic line also resulted in grain yield loss upon ozone exposure, suggesting APO1 involvement in ozone-induced yield loss. Only a few differences in the APO1 amino acid sequences were detected between the cultivars, but the APO1 transcript level was oppositely regulated by ozone exposure: i.e., it increased in Sasanishiki and decreased in Habataki. Interestingly, the levels of some phytohormones (jasmonic acid, jasmonoyl-L-isoleucine, and abscisic acid) known to be involved in attenuation of ozone-induced leaf injury tended to decrease in Sasanishiki but to increase in Habataki upon ozone exposure. These data indicate that ozone-induced grain yield loss in Habataki is caused by a reduction in the APO1 transcript level through an increase in the levels of phytohormones that reduce leaf damage.