Moderators of treatment response in adults with ADHD treated with a vitamin-mineral supplement.
To date there has been no research investigating moderators of response to micronutrient treatment of mental illness, specifically baseline nutrient levels. We conducted analyses of data from a randomized placebo-controlled trial (RCT) of 80 adults (≥16years) with Attention-Deficit/Hyperactivity Disorder (ADHD), whereby participants were treated acutely (8weeks) with micronutrients or placebo followed by an open-label (OL) phase of 8weeks whereby all participants received micronutrients. To ensure that all participants had been exposed to the micronutrients for 8weeks, only those 64 who had adhered to the treatment protocol and completed 8weeks on nutrients were included in the data analysis: 34 from the group that had been randomized to the micronutrient arm, and 30 from the group that had been randomized to the placebo group and hence had only received nutrients in the OL phase. Six outcomes were examined: change in ADHD symptoms (self/clinician), ADHD responder, Clinical Global Impression-Improvement (CGI-I), change in mood, and change in Global Assessment of Functioning (GAF). Demographic, developmental and psychiatric history, current clinical characteristics, and baseline nutrient levels were all considered as putative predictors. There were significant changes in all outcome variables after 8weeks exposure to the micronutrients. Among the nutrients recorded at baseline, substantial deficiencies (27%) were only observed for vitamin D. However, other than an association showing that higher iron at baseline was correlated with higher baseline depression scores, baseline nutrient levels were not correlated with baseline psychiatric variables/current clinical characteristics. Regression analyses revealed that higher baseline ferritin and lower baseline copper and vitamin D levels were associated with a better response to treatment for some but not all outcomes. None of the other nutrient levels was found to be associated with outcome, including zinc, vitamin B12, iron, and folate. There were no childhood risk factors, demographic variables or clinical correlates that contraindicated micronutrient treatment; more severe symptoms at baseline and greater number of developmental risk factors predicted greater treatment response. Further research looking at nutrients more broadly is required to confirm these initial observations about ferritin, vitamin D and copper; however, the results suggest that serum nutrient levels have limited value for identifying who will respond to treatment.


[Evaluation of breastfeeding support: meanings from mothers receiving care at primary health care units in the State of Rio de Janeiro].
This article aims at understanding the meanings expressed by women concerning the breastfeeding support received at primary health care (PHC) units. A study was conducted in 24 PHC units in the State of Rio de Janeiro for the purpose of investigating why pregnant women and mothers felt supported (or not) by these units regarding breastfeeding. Heidegger's phenomenological approach was used to develop five structures of meaning, evincing the breastfeeding support provided as "none", "dubious", "incentive", "guidance", and "partnership". When the mothers were asked for suggestions about how the unit could help them breastfeed, their answers generated a new structure of meaning: "continuous support". Some women gave no suggestions, stating that they had none or were satisfied with the support provided. The women indicated possibilities for care based on the singularity of the clientele and on the authenticity of the health-care staff/user relationship. In that process, solicitude needs to be incorporated into the practice of PHC units, so that they can be an effective space for breastfeeding promotion, protection, and support.


A multicentre study of patients with Timothy syndrome.
Timothy syndrome (TS) is an extremely rare multisystem disorder characterized by marked QT prolongation, syndactyly, seizures, behavioural abnormalities, immunodeficiency, and hypoglycaemia. The aim of this study was to categorize the phenotypes and examine the outcomes of patients with TS. All patients diagnosed with TS in the United Kingdom over a 24-year period were reviewed. Fifteen centres in the British Congenital Arrhythmia Group network were contacted to partake in the study. Six patients with TS were identified over a 24-year period (4 boys and 2 girls). Five out of the six patients were confirmed to have a CACNA1C mutation (p.Gly406Arg) and the other patient was diagnosed clinically. Early presentation with heart block, due to QT prolongation was frequently seen. Four are still alive, two of these have a pacemaker and two have undergone defibrillator implantation. Five out of six patients have had a documented cardiac arrest with three occurring under general anaesthesia. Two patients suffered a cardiac arrest while in hospital and resuscitation was unsuccessful, despite immediate access to a defibrillator. Surviving patients seem to have mild developmental delay and learning difficulties. Timothy syndrome is a rare disorder with a high attrition rate if undiagnosed. Perioperative cardiac arrests are common and not always amenable to resuscitation. Longer-term survival is possible, however, patients invariably require pacemaker or defibrillator implantation.


Analysis of the cerebellar proteome in a transgenic mouse model of inherited prion disease reveals preclinical alteration of calcineurin activity.
Inherited prion diseases are linked to insertional and point mutations in the prion protein (PrP) gene, which favor conversion of PrP into a conformationally altered, pathogenic isoform. The cellular mechanism by which this process causes neurological dysfunction is unknown. Transgenic (Tg) (PG14) mice express a mouse PrP homolog of a nine-octapeptide insertion associated with an inherited prion disorder. These mice develop a progressive neurological syndrome characterized by ataxia and cerebellar atrophy due to synaptic degeneration in the molecular layer and massive apoptosis of granule neurons. To investigate the molecular events that may contribute to neurological dysfunction, we carried out a differential proteomic analysis of cerebella from Tg(PG14) mice at the preclinical, onset, and symptomatic phases of their neurological illness. 2-D maps of cerebellar proteins from Tg(PG14) mice were compared to those obtained from age-matched Tg(WT) mice that express wild-type PrP and remain healthy. Proteins whose levels were significantly modified in at least one stage of the Tg(PG14) disease were identified by PMF. Analysis detected a preclinical decrease of the calcium/calmodulin-dependent phosphatase calcineurin (CaN) in granule neurons, suggesting that dysregulation of CaN activity induced by mutant PrP may be responsible for the cerebellar dysfunction in Tg(PG14) mice.


Alterations of the outer membrane composition in Escherichia coli lacking the histone-like protein HU.
Escherichia coli cells lacking the histone-like protein HU form filaments and have an abnormal number of anucleate cells. Furthermore, their phenotype resembles that of rfa mutants, the well-characterized deep-rough phenotype, as they show an enhanced permeability that renders them hypersensitive to chloramphenicol, novobiocin, and detergents. We show that, unlike rfa mutants, hupAB mutants do not have a truncated lipopolysaccharide but do have an abnormal abundance of OmpF porin in their outer membrane. While the complete absence of HU does not abolish the osmoregulation of OmpF protein synthesis, the steady-state level of micF RNA, the negative regulator of OmpF, decreases in bacteria lacking HU, increasing the basal level of this membrane protein. These findings demonstrate a novel link between a bacterial chromosomal protein and the outer membrane composition.


SDS-induced hexameric oligomerization of myotoxin-II from Bothrops asper assessed by sedimentation velocity and nuclear magnetic resonance.
We report the solution behavior, oligomerization state, and structural details of myotoxin-II purified from the venom of Bothrops asper in the presence and absence of sodium dodecyl sulfate (SDS) and multiple lipids, as examined by analytical ultracentrifugation and nuclear magnetic resonance. Molecular functional and structural details of the myotoxic mechanism of group II Lys-49 phospholipase A2 homologues have been only partially elucidated so far, and conflicting observations have been reported in the literature regarding the monomeric vs. oligomeric state of these toxins in solution. We observed the formation of a stable and discrete, hexameric form of myotoxin-II, but only in the presence of small amounts of SDS. In SDS-free medium, myotoxin-II was insensitive to mass action and remained monomeric at all concentrations examined (up to 3 mg/ml, 218.2 μM). At SDS concentrations above the critical micelle concentration, only dimers and trimers were observed, and at intermediate SDS concentrations, aggregates larger than hexamers were observed. We found that the amount of SDS required to form a stable hexamer varies with protein concentration, suggesting the need for a precise stoichiometry of free SDS molecules. The discovery of a stable hexameric species in the presence of a phospholipid mimetic suggests a possible physiological role for this oligomeric form, and may shed light on the poorly understood membrane-disrupting mechanism of this myotoxic protein class.


Utilization and impact of a postmastectomy radiation boost for invasive breast cancer.
Additional radiation following postmastectomy radiation (PMRT) has an undefined benefit. We investigate those likely to be selected for a chest wall boost (CWB) and its effect on breast cancer survival (BCS) and overall survival (OS). A total of 4747 women diagnosed from 2005 to 2009 were treated with PMRT identified from the California Cancer Registry (CCR); 2686 (57%) received a CWB. Univariate and multivariate analyses compared those receiving and not receiving a CWB for BCS and OS. With a median follow-up of 43.6 months, patients likely to receive a CWB were stage III (P ≤ .001), grade 3/4 (P = .03), positive nodes (P = .04), HER 2+ (P =.02). CWB was not related to BCS in the univariate (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.82-1.21), multivariate (HR, 1.04; 95% CI, 0.86 -1.26) analyses, and was not related OS for the univariate (HR, 0.92; 95% CI, 0.78-1.10), multivariate (HR, 0.95; 95% CI, 0.80-1.13) analyses. However, in multivariate analysis, patients not receiving chemotherapy who had a CWB had better BCS (HR, 1.77; 95% CI, 1.11-2.83). The majority of patients were treated with a CWB. We found no difference in BCS or OS with the addition of a CWB.


HIV serostatus disclosure and lived experiences of adolescents at the Transition Clinic of the Infectious Diseases Clinic in Kampala, Uganda: a qualitative study.
Most studies on HIV serostatus disclosure and adolescents focus on whether, how and when to disclose to adolescents their HIV diagnosis. Fewer studies have examined HIV serostatus disclosure by adolescents who know they are infected with HIV. This study presents qualitative data examining HIV serostatus and treatment disclosure practices and concerns of young people living with HIV in Uganda and the extent to which they are satisfied with current norms around HIV serostatus and treatment disclosure. We conducted two focus groups and interviewed 20 HIV-infected young people aged 15-23 receiving HIV care and treatment at the Transition Clinic in Kampala. Respondents perceived disclosure as a relationship encompassing both communication and self-conduct. Adolescents employed unique strategies to disclose their HIV status, notably joking to "test the waters" and emotionally prepare the other person before later disclosing in a more serious manner. Findings reinforce the idea that HIV disclosure is a process, not a one-time event. Interviewees anticipated both positive and negative outcomes of disclosure, including financial and emotional support, stigma, discrimination and rejection. They described a sense of violation of their autonomy when confidentiality was breached by third party disclosure, and also expressed fear of emotional distress for their loved ones. Although adolescents yearned to be in control of information about their HIV status and treatment, they have little space to call their own, and privacy is often compromised, especially because in traditional African settings, young people are considered to be dependents under the full responsibility of caregivers. Further exploration of disclosure outcomes and strategies specific to adolescents can help better tailor interventions towards youth. Antiretroviral therapy programmes should consider counselling for caretakers to appreciate and respect the privacy and disclosure concerns of their HIV-infected children.


Visceral leishmaniasis in an infant following a holiday trip to Spain.
Imported leishmaniasis is rare in non-endemic countries such as the UK. Visceral leishmaniasis (VL) can be life-threatening and its recognition is imperative for successful clinical management. We present a case of VL in an 11-month-old infant several months after returning from a 1-week holiday trip to the South of Spain. The infant suffered from intermittent fever for 5 weeks, and hepatosplenomegaly and pancytopenia, and was successfully treated with a short course of liposomal amphotericin B. This case of VL is to highlight the possibility of transmission of unusual pathogens when travelling to the Mediterranean and therefore the importance of taking a detailed travel history. VL should be considered in the differential diagnosis in returning travellers presenting with prolonged fever, hepatosplenomegaly and/or pancytopenia.


Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients.
The effect of metformin treatment on various aspects of carbohydrate and lipoprotein metabolism has been defined in 12 patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients were studied before and after approximately 4 mo of metformin therapy. Treatment was initiated with a single dose of 500 mg/day, increased at weekly intervals, and maintained at a final dose of 2.5 g/day (given at divided intervals) for the last 3 mo of the treatment program. Results demonstrated that both fasting and postprandial glucose concentrations were significantly lower after metformin administration, with the greatest change seen after meals. As a result, the total incremental plasma glucose response above basal measured from 0800 to 1600 after metformin was less than 25% of that seen initially. The improvement in ambient plasma glucose concentration in association with metformin occurred despite a modest but statistically significant decrease in circulating plasma insulin concentration. In addition, insulin-stimulated glucose uptake measured during hyperinsulinemic clamp studies was similar before and after metformin treatment. Furthermore, changes in insulin binding and insulin internalization by isolated monocytes did not correlate with the improvement in glycemic control. Thus, the ability of metformin to lower plasma glucose concentration in NIDDM does not appear to be secondary to an improvement in insulin action. Finally, metformin treatment was associated with a significant (P less than 0.01) decrease in plasma triglyceride concentration and an increase in plasma high-density lipoprotein cholesterol concentration. These results indicate that metformin treatment of patients with NIDDM led to an improvement in both glycemic control and lipoprotein metabolism.


Folic acid delays age-related cognitive decline in senescence-accelerated mouse prone 8: alleviating telomere attrition as a potential mechanism.
The occurrence of telomere attrition in brain may cause senescence and death of neurons, leading to cognitive decline. Folic acid (FA) has been reported to improve cognitive performance in mild cognitive impairment; however, its association with telomere remains unclear. The study aimed to investigate if alleviation of telomere attrition by FA supplementation could act as a potential mechanism to delay age-related cognitive decline in senescence-accelerated mouse prone 8 (SAMP8). Aged SAMP8 mice were assigned to four treatment groups: FAdeficient diet (FA-D) group, FA-normal diet (FA-N) group, low FA-supplemented diet (FA-L) group and high FAsupplemented diet (FA-H) group. There was also an age-matched senescence-accelerated mouse resistant 1 (SAMR1) control group (Con-R), and a young SAMP8 control group (Con-Y). The results demonstrated that FA supplementation delayed age-related cognitive decline and neurodegeneration in SAMP8 mice. Importantly, this effect could be attributed to the alleviated telomere attrition, which might be interpreted by the decreased levels of reactive oxygen species. Additionally, improved telomere integrity stimulated mitochondrial function via telomere-p53-mithondria pathway, consequently delayed neuronal degeneration. In conclusion, we demonstrate that FA supplementation delays age-related neurodegeneration and cognitive decline in SAMP8 mice, in which alleviated telomere attrition could serve as one influential factor in the process.


Assessment of endocrine disruption potential of essential oils of culinary herbs and spices involving glucocorticoid, androgen and vitamin D receptors.
Essential oils (EOs) of culinary herbs and spices are consumed on a daily basis. They are multicomponent mixtures of compounds with already demonstrated biological activities. Taking into account regular dietary intake and the chemical composition of EOs, they may be considered as candidates for endocrine-disrupting entities. Therefore, we examined the effects of 31 EOs of culinary herbs and spices on transcriptional activities of glucocorticoid receptor (GR), androgen receptor (AR) and vitamin D receptor (VDR). Using reporter gene assays in stably transfected cell lines, weak anti-androgen and anti-glucocorticoid activity was observed for EO of vanilla and nutmeg, respectively. Moderate augmentation of calcitriol-dependent VDR activity was caused by EOs of ginger, thyme, coriander and lemongrass. Mixed anti-glucocorticoid and VDR-stimulatory activities were displayed by EOs of turmeric, oregano, dill, caraway, verveine and spearmint. The remaining 19 EOs were inactive against all receptors under investigation. Analyses of GR, AR and VDR target genes by means of RT-PCR confirmed the VDR-stimulatory effects, but could not confirm the anti-glucocorticoid and anti-androgen effects of EOs. In conclusion, although we observed minor effects of several EOs on transcriptional activities of GR, AR and VDR, the toxicological significance of these effects is very low. Hence, 31 EOs of culinary herbs and spices may be considered safe, in terms of endocrine disruption involving receptors GR, AR and VDR.


Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice.
p21ras has been implicated in the hypertrophic response of cultured cardiac myocytes to defined growth stimuli. To determine if activation of ras-dependent intracellular signaling pathways is sufficient to induce in vivo hypertrophy, transgenic mice were created that express oncogenic ras in the cardiac ventricular chamber. Mice homozygous for the transgene displayed morphological, physiological, and genetic markers of marked cardiac muscle hypertrophy. Miniaturized catheterization technology documented a selective prolongation of cardiac relaxation, similar to that seen in early human hypertrophic heart disease. An increase in left atrial mass, in the absence of transgene expression in that chamber, further supported physiologically abnormal left ventricular diastolic function. Histological analysis revealed myofibrillar disarray, indistinguishable from that in hypertrophic cardiomyopathy in man. These studies establish a ras-dependent pathway for hypertrophic heart disease and document the feasibility of mapping in vivo signaling pathways for cardiac hypertrophy and dysfunction by applying in vivo microphysiological assays to genetically manipulated mice. ras-dependent pathways may also be a rational target for developing new approaches to inhibit the genesis of hypertrophy in certain pathological settings.


Reactivation of p53 by inhibiting Mdm2 E3 ligase: a novel antitumor approach.
The p53 tumor suppressor has been pursued as a cancer therapeutic target based on its ability to induce cell cycle arrest and apoptosis. Reactivation of p53 in the approximately 50% of tumors that retain a functional p53 has served as potential approach in the development of cancer drug therapy. Mdm2 is a major negative regulator of p53 and has long been thought to inhibit p53 in two ways: through ubiquitination of p53, signaling for its degradation by the proteasome, and through directly binding to p53, masking its transactivation domain. Research on Mdm2 E3 function and regulation has important implications for the feasibility of targeting Mdm2 in cancer treatment. By targeting Mdm2 in cancers, especially those harboring wild-type p53, it may be possible to restore p53 function to control tumor growth. Several inhibitors for Mdm2 have been developed and have shown promise in restoring p53 function. This review will summarize the current progress of targeting Mdm2 in cancer treatment with a focus on regulating Mdm2 E3 ubiquitin ligase activity via a number of small Mdm2 binding proteins and the post-translational modification of Mdm2 itself. The potential of inhibitors of Mdm2 E3 ligase as a new novel class of anticancer drugs will also be discussed.


Legume-nodulating betaproteobacteria: diversity, host range, and future prospects.
Rhizobia form specialized nodules on the roots of legumes (family Fabaceae) and fix nitrogen in exchange for carbon from the host plant. Although the majority of legumes form symbioses with members of genus Rhizobium and its relatives in class Alphaproteobacteria, some legumes, such as those in the large genus Mimosa, are nodulated predominantly by betaproteobacteria in the genera Burkholderia and Cupriavidus. The principal centers of diversity of these bacteria are in central Brazil and South Africa. Molecular phylogenetic studies have shown that betaproteobacteria have existed as legume symbionts for approximately 50 million years, and that, although they have a common origin, the symbiosis genes in both subclasses have evolved separately since then. Additionally, some species of genus Burkholderia, such as B. phymatum, are highly promiscuous, effectively nodulating several important legumes, including common bean (Phaseolus vulgaris). In contrast to genus Burkholderia, only one species of genus Cupriavidus (C. taiwanensis) has so far been shown to nodulate legumes. The recent availability of the genome sequences of C. taiwanensis, B. phymatum, and B. tuberum has paved the way for a more detailed analysis of the evolutionary and mechanistic differences between nodulating strains of alpha- and betaproteobacteria. Initial analyses of genome sequences have suggested that plant-associated Burkholderia spp. have lower G+C contents than Burkholderia spp. that are opportunistic human pathogens, thus supporting previous suggestions that the plant- and human-associated groups of Burkholderia actually belong in separate genera.


A novel role for endothelial tetrahydrobiopterin in mitochondrial redox balance.
The redox co-factor tetrahydrobiopterin (BH4) regulates nitric oxide (NO) and reactive oxygen species (ROS) production by endothelial NOS (eNOS) and is an important redox-dependent signalling molecule in the endothelium. Loss of endothelial BH4 is observed in cardiovascular disease (CVD) states and results in decreased NO and increased superoxide (O2-) generation via eNOS uncoupling. Genetic mouse models of augmented endothelial BH4 synthesis have shown proof of concept that endothelial BH4 can alter CVD pathogenesis. However, clinical trials of BH4 therapy in vascular disease have been limited by systemic oxidation, highlighting the need to explore the wider roles of BH4 to find novel therapeutic targets. In this study, we aimed to elucidate the effects of BH4 deficiency on mitochondrial function and bioenergetics using targeted knockdown of the BH4 synthetic enzyme, GTP Cyclohydrolase I (GTPCH). Knockdown of GTPCH by >90% led to marked loss of cellular BH4 and a striking induction of O2- generation in the mitochondria of murine endothelial cells. This effect was likewise observed in BH4-depleted fibroblasts devoid of NOS, indicating a novel NOS-independent role for BH4 in mitochondrial redox signalling. Moreover, this BH4-dependent, mitochondria-derived ROS further oxidised mitochondrial BH4, concomitant with changes in the thioredoxin and glutathione antioxidant pathways. These changes were accompanied by a modest increase in mitochondrial size, mildly attenuated basal respiratory function, and marked changes in the mitochondrial proteome and cellular metabolome, including the accumulation of the TCA intermediate succinate. Taken together, these data reveal a novel NOS-independent role for BH4 in the regulation of mitochondrial redox signalling and bioenergetic metabolism.


Paralympic Sprint Performance Between 1992 and 2012.
The Paralympic Games have undergone many changes since their inception in 1960, one being the advances made in running-specific prostheses (RSPs) for track athletes with lower-limb amputations. To investigate the sprinting-performance changes in athletes with lower-limb amputations since 1992 to assess whether the influence of developments in RSP technology is evident. The results of the Olympic and Paralympic Games ranging between 1992 and 2012 for the 100-m and 200-m were collected, and performance trends, percentage change in performance, and competition density (CD) were calculated. The results indicate that the greatest performance increases were seen in athletes with lower-limb amputations (T42 = 26%, T44 = 14%). These performance improvements were greater than for Olympic athletes (<3%), as well as Paralympic athletes from other selected classes (<10%). The T42 and T44 classes also showed the lowest CD values. These results suggest that although there is an overall trend for improved Paralympic sprint performances, RSP technology has played a noteworthy role in the progression of performances of athletes with amputations. It is also hypothesized that the difference in the performance improvements between the T42 and T44 classes is due to the level of disability and therefore the extent to which technology is required to enable locomotion. It is evident that RSP technology has played a significant role in the progression of performances in athletes with lower-limb amputations.


The effect of congenital diaphragmatic hernia on the development of left-sided heart structures.
Patients with congenital diaphragmatic hernias often have concomitant congenital heart disease (CHD), with small left-sided cardiac structures as a frequent finding. The goal of this study is to evaluate which left-sided heart structures are affected in neonates with congenital diaphragmatic hernias. Retrospective review of neonates between May 2007 and April 2015 with a diagnosis of a congenital diaphragmatic hernia was performed. Clinical and echocardiographic data were extracted from the electronic medical record and indexed to body surface area and compared to normative values. Univariable regression models assessed for associations between different variables and length of stay. Data of 52 patients showed decreased mean z scores for the LVIDd (-3.16), LVIDs (-3.05), aortic annulus (-1.68), aortic sinuses (-2.11), transverse arch (-3.11), and sinotubular junction (-1.47) with preservation of the aorta at the diaphragm compared to age-matched normative data with similar body surface areas. Regression analysis showed a percent reduction in length of stay per 1 mm size increase for LVIDd (8%), aortic annulus (27%), aortic sinuses (18%), sinotubular junctions (20%), and transverse arches (25%). Patients with congenital diaphragmatic hernias have significantly smaller left-sided heart structures compared to age-matched normative data. Aortic preservation at the diaphragm provides evidence for a mass effect aetiology with increased right-to-left shunting at the fetal ductus resulting in decreased size. Additionally, length of stay appears to be prolonged with decreasing size of several of these structures. These data provide quantitative evidence of smaller left-sided heart structures in patients with congenital diaphragmatic hernias.


Experimental techniques for the characterization of carbon nanoparticles - a brief overview.
X-ray diffraction, Raman spectroscopy, electron paramagnetic resonance and four-point electrical conductivity measurements is presented to characterize carbon nanoparticles. Two types of carbon nanoparticle systems are discussed: one comprising the powder of individual carbon nanoparticles and the second as a structurally interconnected nanoparticle matrix in the form of a fiber. X-ray diffraction and Raman spectroscopy reveal the atomic structure of the carbon nanoparticles and allow for observation of the changes in the quasi-graphitic ordering induced by ultrasonic irradiation and with the so-called quasi-high pressure effect under adsorption conditions. Structural changes have strong influence on the electronic properties, especially the localization of charge carriers within the nanoparticles, which can be observed with the EPR technique. This in turn can be well-correlated with the four-point electrical conductivity measurements which directly show the character of the charge carrier transport within the examined structures.


Presenting signs and symptoms of artificial urinary sphincter cuff erosion.
To characterize the most common presentation and clinical risk factors for artificial urinary sphincter (AUS) cuff erosion to distinguish the relative frequency of symptoms that should trigger further evaluation in these patients. We retrospectively reviewed our tertiary center database to identify men who presented with AUS cuff erosion between 2007 - 2020. A similar cohort of men who underwent AUS placement without erosion were randomly selected from the same database for symptom comparison. Risk factors for cuff erosion - pelvic radiation, androgen deprivation therapy (ADT), high-grade prostate cancer (Gleason score ≥ 8) - were recorded for each patient. Presenting signs and symptoms of cuff erosion were grouped into three categories: obstructive symptoms, worsening incontinence, and localized scrotal inflammation (SI). Of 893 men who underwent AUS placement during the study interval, 61 (6.8%) sustained cuff erosion. Most erosion patients (40/61, 66%) presented with scrotal inflammatory changes including tenderness, erythema, and swelling. Fewer men reported obstructive symptoms (26/61, 43%) and worsening incontinence (21/61, 34%). Men with SI or obstructive symptoms presented significantly earlier than those with worsening incontinence (SI 14 ± 18 vs. obstructive symptoms 15 ± 16 vs. incontinence 37 ± 48 months after AUS insertion, p<0.01). Relative to the non-erosion control group (n=61), men who suffered erosion had a higher prevalence of pelvic radiation (71 vs. 49%, p=0.02). AUS cuff erosion most commonly presents as SI symptoms. Obstructive voiding symptoms and worsening incontinence are also common. Any of these symptoms should prompt further investigation of cuff erosion.


Traumatic subdural hygromas: proposed pathogenesis based classification.
Traumatic subdural hygroma (TSHy) is an accumulation of cerebrospinal fluid (CSF) in the subdural space after head injury. It appears to be relatively common, but its onset time and natural history are not well defined. Considered a benign epiphenomenon of trauma, the pathogenesis of TSHy is still unclear and many questions remain unanswered. This study adds to the information on TSHy, and proposes a classification based on pathogenesis. Thirty-four consecutive adult patients with TSHy were analyzed for clinical evolution and serial CT scan, during a period of several months. TSHy diagnosis was based on published CT scan criteria of hypodense subdural collection after trauma, without enhancement and neomembrane, with a minimum distance of 3 mm between the skull and brain. Ventricle size was analyzed by calculating the bicaudate index (BCI). For comparison, the BCI was measured from CT scan at three moments: admission, at time of TSHy diagnosis, and from last CT scan. There were 34 patients, aged between 16 and 85 years (mean 40), half of them were below 40 years. Road traffic crashes were the main cause of head injury. The mean time for hygroma diagnosis was 9 days. Twenty-one patients (61.8%) underwent conservative treatment for TSHy and 13 (38.2%), surgical treatment. TSHy are early lesions and can be detected in the first 24 hours after trauma, usually as small subdural effusion (SSEff). Based on clinical and CT scan findings, we divided the 34 patients into 3 groups, (Ia and Ib) without evident mass effect and (II) with evident mass effect. Group Ia includes patients without ventricle dilation; Ib, patients with associated ventricle dilations. SSEff detected in the first 24 hours posttrauma in our series evolved into TSHy suggesting that this is an early lesion; all THSy were divided in three groups according to the pathophysiologic mechanism. These three groups probably represent a continuum of CSF absorption impairment. Group Ia represents what most authors consider a simple hygroma, with no impairment on CSF absorption. Group Ib represent the external hydrocephalus form with various degrees of CSF imbalance, and group II were the cases presenting marked mass effect.


Applying machine learning techniques to predict the properties of energetic materials.
We present a proof of concept that machine learning techniques can be used to predict the properties of CNOHF energetic molecules from their molecular structures. We focus on a small but diverse dataset consisting of 109 molecular structures spread across ten compound classes. Up until now, candidate molecules for energetic materials have been screened using predictions from expensive quantum simulations and thermochemical codes. We present a comprehensive comparison of machine learning models and several molecular featurization methods - sum over bonds, custom descriptors, Coulomb matrices, Bag of Bonds, and fingerprints. The best featurization was sum over bonds (bond counting), and the best model was kernel ridge regression. Despite having a small data set, we obtain acceptable errors and Pearson correlations for the prediction of detonation pressure, detonation velocity, explosive energy, heat of formation, density, and other properties out of sample. By including another dataset with ≈300 additional molecules in our training we show how the error can be pushed lower, although the convergence with number of molecules is slow. Our work paves the way for future applications of machine learning in this domain, including automated lead generation and interpreting machine learning models to obtain novel chemical insights.


[A Case of Locally Advanced Gastric Cancer - R0 Resection Was Performed by Pancreaticoduodenectomy with Portal Vein Resection Following Neoadjuvant Therapy].
A 76-year-old woman, complained of weight loss, was admitted in our hospital. After investigation, she was diagnosed with clinical Stage III B gastric cancer with invasion into the pancreas and transverse colon. After performing the staging laparoscopy and gastrojejunostomy for pyloric stenosis, she was treated with 2 courses of SOX therapy as neoadjuvant therapy, and subsequently underwent pancreaticoduodenectomy and right hemicolectomy combined with portal vein resection due to severe adhesion by the tumor. The pathological diagnosis was pT4b(colon), pN0(0/22), pM0, pStage III B. There were no findings of tumor invasion into the pancreas or the portal vein. She was discharged without any complications. She did not receive the adjuvant chemotherapy, and died of other illness at 10 months after surgery. For the locally advanced gastric cancer such as invasion to the pancreas, the extended resection as an R0 resection could be achieved more safely, by evaluating accurately the incurable factors and planning an effective strategy according to the patient's condition.


Predicting tipranavir and darunavir resistance using genotypic, phenotypic, and virtual phenotypic resistance patterns: an independent cohort analysis of clinical isolates highly resistant to all other protease inhibitors.
Genotypic interpretation systems (GISs) for darunavir and tipranavir susceptibility are rarely tested by the use of independent data sets. The virtual phenotype (the phenotype determined by Virco [the "Vircotype"]) was used to interpret all genotypes in Québec, Canada, and phenotypes were determined for isolates predicted to be resistant to all protease inhibitors other than darunavir and tipranavir. We used multivariate analyses to predict relative phenotypic susceptibility to darunavir and tipranavir. We compared the performance characteristics of the Agence Nationale de Recherche sur le Sida scoring algorithm, the Stanford HIV database scoring algorithm (with separate analyses of the discrete and numerical scores), the Vircotype, and the darunavir and tipranavir manufacturers' scores for prediction of the phenotype. Of the 100 isolates whose phenotypes were determined, 89 and 72 were susceptible to darunavir and tipranavir, respectively. In multivariate analyses, the presence of I84V and V82T and the lack of L10F predicted that the isolates would be more susceptible to darunavir than tipranavir. The presence of I54L, V32I, and I47V predicted that the isolates would be more susceptible to tipranavir. All GISs except the system that provided the Stanford HIV database discrete score performed well in predicting the darunavir resistance phenotype (R(2) = 0.61 to 0.69); the R(2) value for the Stanford HIV database discrete scoring system was 0.38. Other than the system that provided the Vircotype (R(2) = 0.80), all GISs performed poorly in predicting the tipranavir resistance phenotype (R(2) = 0.00 to 0.31). In this independent cohort harboring highly protease inhibitor-resistant HIV isolates, reduced phenotypic susceptibility to darunavir and tipranavir was rare. Generally, GISs predict susceptibility to darunavir substantially better than they predict susceptibility to tipranavir.


Optical coherence tomography to monitor vigabatrin toxicity in children.
The antiepileptic drug vigabatrin is known to cause permanent loss of vision. Both visual field testing and electroretinogram are used to detect retinal damage. Adult data on optical coherence tomography (OCT) shows that retinal nerve fiber layer (RNFL) thinning may be an early indicator of vigabatrin-induced retinal toxicity. The purpose of this study was to investigate whether OCT can detect early vigabatrin-induced retinal toxicity in children. Pediatric patients (≤18 years of age) requiring vigabatrin for seizure control who were followed at our institution were invited to participate. Patients were examined according to manufacturer guidelines, with most examinations taking place under general anesthesia. RNFL thickness was measured by OCT (Stratus Model 3000, Zeiss) and compared to total cumulative dose of vigabatrin. In most cases, indirect ophthalmoscopy, fundus photography, and electroretinography were also performed. OCT and complete dosing data was available for 19 patients. Patients with tuberous sclerosis (TS, n = 12) received higher cumulative doses (mean, 1463 g) than non-TS patients (mean, 351 g, P = 0.044). RNFL thinning was detected in the nasal (P < 0.01), superior (P < 0.01), and inferior (P < 0.05) quadrants in patients with TS, particularly once cumulative dose exceeded 1500 g. In our study population of patients with TS, higher cumulative doses of vigabatrin were associated with RNFL thinning in the nasal, superior, and inferior quadrants. These findings were pronounced once cumulative dose exceeded 1500 g. This pattern of RNFL thinning is similar to what has been shown in adult patients taking vigabatrin.


Evaluation of the polyclonal ELISA HPV serology assay as a biomarker for human papillomavirus exposure.
Seropositivity to human papillomavirus (HPV)16 and 18 antibodies is used as a measure of cumulative HPV exposure and as a stratifier of HPV exposure for vaccine efficacy analyses. Overall performance of these assays, as a measure of HPV exposure, has not been evaluated. Using data from the enrollment phase of the HPV16/18 vaccine trial in Costa Rica, we evaluated the performance of the polyclonal enzyme-linked immunosorbent assay (ELISA) HPV16 and 18 serological assays as a measure of HPV exposure. Biologic (e.g., HPV infection at the cervix) and behavioral characteristics (e.g., lifetime number of sexual partners) with known associations with current and past HPV infection were used to define cases and controls (HPV exposed vs. not exposed). Prevaccination serum was measured for antibodies against HPV16 and 18 by ELISA; cervical samples were tested for HPV DNA using PCR SPF10/LiPA25. ELISA results were analyzed using receiver-operator characteristic curves; performance was evaluated at the manufacturer set cut point (HPV16 = 8, HPV18 = 7) and at cut points chosen to optimize sensitivity and specificity (HPV16 = 34, HPV18 = 60). Defining cases as type-specific HPV DNA positive with high-grade abnormal cytology (i.e., combined molecular and microscopic markers of infection), HPV16-ELISA gave sensitivity that was lower at the optimal cut point than the manufacturer cut point (62.2 compared with 75.7, respectively; P = 0.44). However, specificity was higher (85.3 compared with 70.4, respectively; P < 0.0001). Similarly, HPV18-ELISA gave sensitivity that was lower at the optimal cut point than the manufacturer cut point (34.5 compared with 51.7, respectively; P = 0.40), with higher specificities (94.9 compared with 72.6, respectively; P < 0.0001). Modifying cut points did not improve the low sensitivity. The low sensitivity of this assay does not support its use for risk stratification or clinical settings.


Collegiate ACL Injury Rates Across 15 Sports: National Collegiate Athletic Association Injury Surveillance System Data Update (2004-2005 Through 2012-2013).
To present data on the rate of anterior cruciate ligament (ACL) injury in 15 collegiate sports from 2004 to 2005 through 2012 to 2013 updating the 1988-1989 to 2003-2004 data. Prospectively designed descriptive epidemiology study. National Collegiate Athletic Association Schools. National Collegiate Athletic Association School athletes. Injury rate by year and sport. Most ACL injuries to women occurred by a noncontact mechanism (60%) versus a contact mechanism for men (59%). The highest average annual rate of ACL injury for men was found in football (0.17 per 1000 athlete-exposure [A-E]). The highest average annual rate of ACL injury for women was found in lacrosse (0.23 per 1000 A-E). There were statistically significant increases in average annual injury rate for men's (P = 0.04) and women's soccer (P = 0.01) and a statistically significant decrease in women's gymnastics over the 9 years (=0.009). Controlling for exposures, there were statistically significant increases in the average annual number of injuries for men's and women's basketball, ice hockey, field hockey, football, and volleyball and a decrease in the average annual number of injuries for baseball and women's gymnastics. Women continue to sustain ACL injuries at higher rates than men in the comparable sports of soccer, basketball, and lacrosse. Anterior cruciate ligament injury rates continue to rise in men's and women's soccer. Some sports have shown absolute increases in ACL rates, which persist even after exposure rates are taken into account. Despite extensive research and development of prevention programs before and during the time of this study, very few sports showed a reduction in ACL injury rates in this data set.


A pragmatic approach to sonothrombolysis in acute ischaemic stroke: the Norwegian randomised controlled sonothrombolysis in acute stroke study (NOR-SASS).
Ultrasound accelerates thrombolysis with tPA (sonothrombolysis). Ultrasound in the absence of tPA also accelerates clot break-up (sonolysis). Adding intravenous gaseous microbubbles may potentiate the effect of ultrasound in both sonothrombolysis and sonolysis. The Norwegian Sonothrombolysis in Acute Stroke Study aims in a pragmatic approach to assess the effect and safety of contrast enhanced ultrasound treatment in unselected acute ischaemic stroke patients. Acute ischaemic stroke patients ≥ 18 years, with or without visible arterial occlusion on computed tomography angiography (CTA) and treatable ≤ 4(½) hours after symptom onset, are included in NOR-SASS. NOR-SASS is superimposed on a separate trial randomising patients with acute ischemic stroke to either tenecteplase or alteplase (The Norwegian Tenecteplase Stroke Trial NOR-TEST). The NOR-SASS trial has two arms: 1) the thrombolysis-arms (NOR-SASS A and B) includes patients given intravenous thrombolysis (tenecteplase or alteplase), and 2) the no-thrombolysis-arm (NOR-SASS C) includes patients with contraindications to thrombolysis. First step randomisation of NOR-SASS A is embedded in NOR-TEST as a 1:1 randomisation to either tenecteplase or alteplase. Second step NOR-SASS randomisation is 1:1 to either contrast enhanced sonothrombolysis (CEST) or sham CEST. Randomisation in NOR-SASS B (routine alteplase group) is 1:1 to either CEST or sham CEST. Randomisation of NOR-SASS C is 1:1 to either contrast enhanced sonolysis (CES) or sham CES. Ultrasound is given for one hour using a 2-MHz pulsed-wave diagnostic ultrasound probe. Microbubble contrast (SonoVue®) is given as a continuous infusion for ~30 min. Recanalisation is assessed at 60 min after start of CEST/CES. Magnetic resonance imaging and angiography is performed after 24 h of stroke onset. Primary study endpoints are 1) major neurological improvement measured with NIHSS score at 24 h and 2) favourable functional outcome defined as mRS 0-1 at 90 days. NOR-SASS is the first randomised controlled trial designed to test the superiority of contrast enhanced ultrasound treatment given ≤ 4(½) hours after stroke onset in an unselected acute ischaemic stroke population eligible or not eligible for intravenous thrombolysis, with or without a defined arterial occlusion on CTA. If a positive effect and safety can be proven, contrast enhanced ultrasound treatment will be an option for all acute ischaemic stroke patients. EudraCT No 201200032341; www.clinicaltrials.gov NCT01949961.


CDKL5 regulates p62-mediated selective autophagy and confers protection against neurotropic viruses.
Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However, the mechanisms leading to viral antigen recognition and capture by autophagic machinery remain poorly understood. Here, we identified cyclin-dependent kinase-like 5 (CDKL5), known to function in neurodevelopment, as an essential regulator of virophagy. Loss of function mutations in CDKL5 are associated with a severe neurodevelopmental encephalopathy. We found deletion of CDKL5 or expression of a clinically-relevant pathogenic mutant of CDKL5 reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid protein aggregates and cellular cytotoxicity. CDKL5 knockout mice displayed increased viral antigen accumulation and neuronal cell death after SINV infection and enhanced lethality after infection with several neurotropic viruses. Mechanistic studies demonstrated that CDKL5 directly binds the canonical selective autophagy receptor p62 and phosphorylates p62 at T269/S272 to promote its interaction with viral capsid aggregates. We found that CDKL5-mediated phosphorylation of p62 facilitated the formation of large p62 inclusion bodies that captured viral capsids to initiate capsid targeting to autophagic machinery. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear intracellular toxic viral protein aggregates during infection.


Dynamics of viral evolution and CTL responses in HIV-1 infection.
Improved understanding of the dynamics of host immune responses and viral evolution is critical for effective HIV-1 vaccine design. We comprehensively analyzed Cytotoxic T-lymphocyte (CTL)-viral epitope dynamics in an antiretroviral therapy-naïve subject over the first four years of HIV-1 infection. We found that CTL responses developed sequentially and required constant antigenic stimulation for maintenance. CTL responses exerting strong selective pressure emerged early and led to rapid escape, proliferated rapidly and were predominant during acute/early infection. Although CTL responses to a few persistent epitopes developed over the first two months of infection, they proliferated slowly. As CTL epitopes were replaced by mutational variants, the corresponding responses immediately declined, most rapidly in the cases of strongly selected epitopes. CTL recognition of epitope variants, via cross-reactivity and de novo responses, was common throughout the period of study. Our data demonstrate that HIV-specific CTL responses, especially in the critical acute/early stage, were focused on regions that are prone to escape. Failure of CTL responses to strongly target functional or structurally critical regions of the virus, as well as the sequential cascade of CTL responses, followed closely by viral escape and decline of the corresponding responses, likely contribute to a lack of sustainable viral suppression. Focusing early and rapidly proliferating CTL on persistent epitopes may be essential for durable viral control in HIV-1 infection.


Long-term intermittent hypoxia elevates cobalt levels in the brain and injures white matter in adult mice.
Exposure to the variable oxygenation patterns in obstructive sleep apnea (OSA) causes oxidative stress within the brain. We hypothesized that this stress is associated with increased levels of redox-active metals and white matter injury. Participants were randomly allocated to a control or experimental group (single independent variable). University animal house. Adult male C57BL/6J mice. To model OSA, mice were exposed to long-term intermittent hypoxia (LTIH) for 10 hours/day for 8 weeks or sham intermittent hypoxia (SIH). Laser ablation-inductively coupled plasma-mass spectrometry was used to quantitatively map the distribution of the trace elements cobalt, copper, iron, and zinc in forebrain sections. Control mice contained 62 ± 7 ng cobalt/g wet weight, whereas LTIH mice contained 5600 ± 600 ng cobalt/g wet weight (P < 0.0001). Other elements were unchanged between conditions. Cobalt was concentrated within white matter regions of the brain, including the corpus callosum. Compared to that of control mice, the corpus callosum of LTIH mice had significantly more endoplasmic reticulum stress, fewer myelin-associated proteins, disorganized myelin sheaths, and more degenerated axon profiles. Because cobalt is an essential component of vitamin B12, serum methylmalonic acid (MMA) levels were measured. LTIH mice had low MMA levels (P < 0.0001), indicative of increased B12 activity. Long-term intermittent hypoxia increases brain cobalt, predominantly in the white matter. The increased cobalt is associated with endoplasmic reticulum stress, myelin loss, and axonal injury. Low plasma methylmalonic acid levels are associated with white matter injury in long-term intermittent hypoxia and possibly in obstructive sleep apnea.


Impact of a single non-sex-related stroke risk factor on atrial fibrillation and oral anticoagulant outcomes: a systematic review and meta-analysis.
Oral anticoagulants (OACs) are crucial for treating atrial fibrillation (AF) patients at high thromboembolic risk. However, in AF patients at intermediate thromboembolic risk with a single non-sex-related stroke risk factor (CHA2DS2-VASc score 1 in men, 2 in women), guidelines advise to consider starting anticoagulation, which may result in OAC non-initiation due to underestimation of the thromboembolic risk of a single stroke risk factor and overestimation of the OAC-related bleeding risk. A critical appraisal of the role of OACs and the benefit-risk profile of non-vitamin K antagonist oral anticoagulants (NOACs) compared with vitamin K antagonists (VKAs) in this patient subgroup are needed. This systematic review provides an overview of literature on the effectiveness and safety of OACs in AF patients with a single non-sex-related stroke risk factor after searching Medline and Embase. Differences between individual stroke risk factors regarding the ischaemic stroke risk in non-anticoagulated AF patients are identified in a meta-analysis, demonstrating the highest increased risk in patients aged 65-74 years old or with diabetes mellitus, followed by heart failure, hypertension and vascular disease. Furthermore, meta-analysis results favour NOACs over VKAs, given their equal effectiveness and superior safety in AF patients at intermediate thromboembolic risk (HR 0.93, 95% CI 0.65 to 1.34 for stroke or systemic embolism; HR 0.60, 95% CI 0.45 to 0.80 for major bleeding; HR 0.48, 95% CI 0.14 to 1.59 for intracranial bleeding; HR 0.58, 95% CI 0.47 to 0.71 for mortality). Our systematic review with meta-analysis favours the use of anticoagulation in AF patients with a single non-sex-related stroke risk factor, especially when age ≥65 years or diabetes mellitus is present, with a preference for NOACs over VKAs.


Income disparities in smoking cessation and the diffusion of smoke-free homes among U.S. smokers: Results from two longitudinal surveys.
Lower rates of successful quitting among low-income populations in the United States may be from slower dissemination of smoke-free homes, a predictor of cessation. To explore the role of smoke-free homes in cessation behavior across income levels. Current smokers who were ≥18 years and who participated in the longitudinal 2002-2003 (n = 2801) or 2010-2011 (n = 2723) Tobacco Use Supplements to the Current Population Survey. We categorized income as multiples of the federal poverty level (FPL) (<300% FPL versus ≥300% FPL). We examined the association of smoke-free homes with 1+day quit attempts and 30+days abstinence at 1-year follow-up. We then conducted a mediation analysis to examine the extent that smoke-free homes contributed to income disparities in 30+days abstinence. Between the two surveys, heavy smoking (≥ 1 pack/day) declined by 17%, and smoking prevalence declined by 15% among those with higher-incomes (>300%FPL). Although similar in 2002, the prevalence of smoke-free homes was 33% lower among individuals living <300% FPL than those living ≥300% FPL. Although the quit attempt rate was similar, the 30+days abstinence rate was higher in the 2010-11 cohort than in 2002-3 cohort (20.6% versus 15.5%, p<0.008). Whereas smoking ≥ 1 pack/ day was associated with lower odds of 30+days abstinence (Adjusted odds ratio [AOR] 0.7; 95% CI 0.5-0.9), having a higher income (AOR 1.9, 95% CI 1.4-2.6) and a smoke-free home (AOR 1.6, 95% CI 1.2-2.1) were associated with greater odds of 30+day abstinence. Differential changes in smoke-free homes across income groups between the two surveys contributed to 36% (95% CI 35.7-36.3) of the observed income disparity in 30+days abstinence. Increasing the diffusion of smoke-free homes among low-income populations may attenuate at least a third of the income disparities in smoking cessation, highlighting the need for interventions to increase adoption of smoke-free homes among low-income households.


A new family of phosphoinositide phosphatases in microorganisms: identification and biochemical analysis.
Phosphoinositide metabolism is essential to membrane dynamics and impinges on many cellular processes, including phagocytosis. Modulation of phosphoinositide metabolism is important for pathogenicity and virulence of many human pathogens, allowing them to survive and replicate in the host cells. Phosphoinositide phosphatases from bacterial pathogens are therefore key players in this modulation and constitute attractive targets for chemotherapy. MptpB, a virulence factor from Mycobacterium tuberculosis, has phosphoinositide phosphatase activity and a distinct active site P-loop signature HCXXGKDR that shares characteristics with eukaryotic lipid phosphatases and protein tyrosine phosphatases. We used this P-loop signature as a "diagnostic motif" to identify related putative phosphatases with phosphoinositide activity in other organisms. We found more than 200 uncharacterised putative phosphatase sequences with the conserved signature in bacteria, with some related examples in fungi and protozoa. Many of the sequences identified belong to recognised human pathogens. Interestingly, no homologues were found in any other organisms including Archaea, plants, or animals. Phylogenetic analysis revealed that these proteins are unrelated to classic eukaryotic lipid phosphatases. However, biochemical characterisation of those from Listeria monocytogenes and Leishmania major, demonstrated that, like MptpB, they have phosphatase activity towards phosphoinositides. Mutagenesis studies established that the conserved Asp and Lys in the P-loop signature (HCXXGKDR) are important in catalysis and substrate binding respectively. Furthermore, we provide experimental evidence that the number of basic residues in the P-loop is critical in determining activity towards poly-phosphoinositides. This new family of enzymes in microorganisms shows distinct sequence and biochemical characteristics to classic eukaryotic lipid phosphatases and they have no homologues in humans. This study provides a foundation for examining the biological role of this new family of phosphatases and their potential as pharmaceutical targets against infectious diseases.


Home Coming? A Story of Reassurance, Opportunity and Hope for Universally Designed Housing in Australia.
This paper shows the complexity of housing and how it is the linch-pin for achieving economic, social and human rights imperatives. In Australia there are no minimum housing standards; the effect is now critical. In October 2017, a regulatory impact assessment was instructed, to consider Livable Housing Australia's Silver and Gold standards, for inclusion in the National Construction Code. A substantial research project provided a knowledge and evidence base of the policy perspective; an expanded statistical context; and detailed analyses of Silver, Gold and Platinum design levels. The policy perspective included greater economic focus. The effect on productivity, directly attributable to housing, is significant. 34 specific policy 'problems' were identified that could be solved or mitigated if acceptable standards of housing were introduced. It is reassuring that universal design has permeated all levels of government policy. The statistical context explored demographics, households, dwelling types; tenure; occupants; disability and carers. Detailed analyses challenged many common assumptions and re-framed accessible housing into a mainstream problem. 73% of all dwellings are separate houses and the average home has 3.1 bedrooms. There are tremendous opportunities for universally design-led mainstream solutions. The compliance gap analyses show which design features might cost more; have potential to be designed out; or be cost neutral. Many design features are cost neutral and arguably should be included within mandated standards. As there is a minimal gap between universal design standards and current housing, there is hope that all Australians will, one day, live in a universally designed home.


Differential expression of miR-17~92 identifies BCL2 as a therapeutic target in BCR-ABL-positive B-lineage acute lymphoblastic leukemia.
Despite advances in allogeneic stem cell transplantation, BCR-ABL-positive acute lymphoblastic leukaemia (ALL) remains a high-risk disease, necessitating the development of novel treatment strategies. As the known oncomir, miR-17~92, is regulated by BCR-ABL fusion in chronic myeloid leukaemia, we investigated its role in BCR-ABL translocated ALL. miR-17~92-encoded miRNAs were significantly less abundant in BCR-ABL-positive as compared to -negative ALL-cells and overexpression of miR-17~19b triggered apoptosis in a BCR-ABL-dependent manner. Stable isotope labelling of amino acids in culture (SILAC) followed by liquid chromatography and mass spectroscopy (LC-MS) identified several apoptosis-related proteins including Bcl2 as potential targets of miR-17~19b. We validated Bcl2 as a direct target of this miRNA cluster in mice and humans, and, similar to miR-17~19b overexpression, Bcl2-specific RNAi strongly induced apoptosis in BCR-ABL-positive cells. Furthermore, BCR-ABL-positive human ALL cell lines were more sensitive to pharmacological BCL2 inhibition than negative ones. Finally, in a xenograft model using patient-derived leukaemic blasts, real-time, in vivo imaging confirmed pharmacological inhibition of BCL2 as a new therapeutic strategy in BCR-ABL-positive ALL. These data demonstrate the role of miR-17~92 in regulation of apoptosis, and identify BCL2 as a therapeutic target of particular relevance in BCR-ABL-positive ALL.


Transfusion complications in thalassemia patients: a report from the Centers for Disease Control and Prevention (CME).
Transfusions are the primary therapy for thalassemia but have significant cumulative risks. In 2004, the Centers for Disease Control and Prevention (CDC) established a national blood safety monitoring program for thalassemia. This report summarizes the population and their previous nonimmune and immune transfusion complications. The CDC Thalassemia Blood Safety Network is a consortium of centers longitudinally following patients. Enrollment occurred from 2004 through 2012. Demographics, transfusion history, infectious exposures, and transfusion and nontransfusion complications were summarized. Logistic regression analyses of factors associated with allo- and autoimmunization were employed. The race/ethnicity of these 407 thalassemia patients was predominantly Asian or Caucasian. The mean ± SD age was 22.3 ± 13.2 years and patients had received a mean ± SD total number of 149 ± 103.4 units of red blood cells (RBCs). Multiorgan dysfunction was common despite chelation. Twenty-four percent of transfused patients had previous exposure to possible transfusion-associated pathogens including one case of babesia. As 27% were immigrants, the infection source cannot be unequivocally linked to transfusion. Transfusion reactions occurred in 48%, including allergic, febrile, and hemolytic; 19% were alloimmunized. Common antigens were E, Kell, and C. Years of transfusion was the strongest predictor of alloimmunization. Autoantibodies occurred in 6.5% and were associated with alloimmunization (p < 0.0001). Local institutional policies, not patient characteristics, were major determinants of blood preparation and transfusion practices. Hemosiderosis, transfusion reactions, and infections continue to be major problems in thalassemia. New pathogens were noted. National guidelines for RBC phenotyping and preparation are needed to decrease transfusion-related morbidity.


Loss of microbial diversity in soils is coincident with reductions in some specialized functions.
Loss of microbial diversity is considered a major threat because of its importance for ecosystem functions, but there is a lack of conclusive evidence that diversity itself is reduced under anthropogenic stress, and about the consequences of diversity loss. Heavy metals are one of the largest, widespread pollutant types globally, and these represent a significant environmental stressor for terrestrial microbial communities. Using combined metagenomics and functional assays, we show that the compositional and functional response of microbial communities to long-term heavy metal stress results in a significant loss of diversity. Our results indicate that even at a moderate loss of diversity, some key specialized functions (carried out by specific groups) may be compromised. Together with previous work, our data suggest disproportionate impact of contamination on microbes that carry out specialized, but essential, ecosystem functions. Based on these findings, we propose a conceptual framework to explicitly consider diversity of functions and microbial functional groups to test the relationship between biodiversity and soil functions.


Characterization of the hemopoietic defect in early stages of the myelodysplastic syndromes.
Myelodysplasia (MDS) is a heterogeneous disorder characterised by bone marrow failure and progression to acute myeloid leukaemia where the molecular and cellular haematopoietic defects are poorly understood. To gain insight into this the pathogenesis of this condition, we analyzed gene expression profiles of bone marrow CD34+ stem/progenitor cells from patients with MDS at a early stage in the disease and compared them with profiles from CD34+ cells from age-matched controls and patients with non-MDS anaemia. Given the heterogeneity of early MDS, a surprisingly consistent finding was decreased expression of B-cell lineage affiliated genes in MDS patients compared to normal controls and samples with non-MDS anaemia. These findings were then confirmed in the original samples and further samples from a new MDS patient group by Taqman Real Time PCR. Flow cytometry on unfractionated marrow from independent samples also demonstrated reduced B-cell progenitors in MDS patients compared to normal controls. These novel findings suggest a common perturbation in early MDS haematopoiesis. They also provide the rationale for a larger study to evaluate the diagnostic utility of reduced B-cell progenitor number as a diagnostic biomarker of early low risk MDS which can pose a diagnostic challenge.


African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat.
The African trypanosome Trypanosoma brucei spp. is a paradigm for antigenic variation, the orchestrated alteration of cell surface molecules to evade host immunity. The parasite elicits robust antibody-mediated immune responses to its variant surface glycoprotein (VSG) coat, but evades immune clearance by repeatedly accessing a large genetic VSG repertoire and 'switching' to antigenically distinct VSGs. This persistent immune evasion has been ascribed exclusively to amino-acid variance on the VSG surface presented by a conserved underlying protein architecture. We establish here that this model does not account for the scope of VSG structural and biochemical diversity. The 1.4-Å-resolution crystal structure of the variant VSG3 manifests divergence in the tertiary fold and oligomeric state. The structure also reveals an O-linked carbohydrate on the top surface of VSG3. Mass spectrometric analysis indicates that this O-glycosylation site is heterogeneously occupied in VSG3 by zero to three hexose residues and is also present in other VSGs. We demonstrate that this O-glycosylation increases parasite virulence by impairing the generation of protective immunity. These data alter the paradigm of antigenic variation by the African trypanosome, expanding VSG variability beyond amino-acid sequence to include surface post-translational modifications with immunomodulatory impact.


Chronic strongyloidiasis in World War II Far East ex-prisoners of war.
Fifty-two of 142 (37%) American ex-prisoners of war that worked on the Burma-Thailand Railroad during World War II were found to have previously unrecognized symptomatic Strongyloides stercoralis infections. A characteristic urticarial creeping skin eruption on the abdomen, buttocks and thighs occurred in 92%. Infection was also associated with pruritus ani, abdominal pain, indigestion, heartburn, and diarrhea. Demonstration of larvae in ether-formalin stool concentrates in these chronic low density infections required 5 hours of microscopy per case to detect 90% of positive cases. Therapy with thiabendazole resulted in a clinical cure in 93% and a microscopic cure in 100%; but was associated with frequent side effects. Chronic strongyloidiasis should be considered in veterans of Far East conflicts and in others with intimate soil contact in rural Strongyloides stercoralis-endemic areas who present with recurrent creeping skin eruption, abdominal pain, and eosinophilia.


Prevalence, distribution, and diversity of Salmonella enterica in a major produce region of California.
A survey was initiated to determine the prevalence of Salmonella enterica in the environment in and around Monterey County, CA, a major agriculture region of the United States. Trypticase soy broth enrichment cultures of samples of soil/sediment (n = 617), water (n = 252), wildlife (n = 476), cattle feces (n = 795), and preharvest lettuce and spinach (n = 261) tested originally for the presence of pathogenic Escherichia coli were kept in frozen storage and later used to test for the presence of S. enterica. A multipathogen oligonucleotide microarray was employed to identify a subset of samples that might contain Salmonella in order to test various culture methods to survey a larger number of samples. Fifty-five of 2,401 (2.3%) samples yielded Salmonella, representing samples obtained from 20 different locations in Monterey and San Benito Counties. Water had the highest percentage of positives (7.1%) among sample types. Wildlife yielded 20 positive samples, the highest number among sample types, with positive samples from birds (n = 105), coyotes (n = 40), deer (n = 104), elk (n = 39), wild pig (n = 41), and skunk (n = 13). Only 16 (2.6%) of the soil/sediment samples tested positive, and none of the produce samples had detectable Salmonella. Sixteen different serotypes were identified among the isolates, including S. enterica serotypes Give, Typhimurium, Montevideo, and Infantis. Fifty-four strains were sensitive to 12 tested antibiotics; one S. Montevideo strain was resistant to streptomycin and gentamicin. Pulsed-field gel electrophoresis (PFGE) analysis of the isolates revealed over 40 different pulsotypes. Several strains were isolated from water, wildlife, or soil over a period of several months, suggesting that they were persistent in this environment.


BCL-2: the pendulum of the cell fate.
The homeostasis of normal tissues is a balance between cell proliferation and cell death. Alterations of both pathways contribute to a clonal expansion of cancer cells. Bcl-2 and its family play an important role in the regulation of the apoptotic pathway. Apoptosis or programmed cell death is an active form of cell suicide that is characterized by specific morphological and biochemical events. These include cleavege of genomic DNA into oligonucleosome-length DNA fragments by endonucleases, chromatin condensation and marginalization, nuclear fragmentation, plasma membrane blebbing, and cell shrinkage. Though the role of apoptosis is clearly defined in the maintaining of physiological tissue homeostasis, several pathological conditions and external factors cause apoptosis. Anticancer drugs and radiation, two of the most important tools in the cancer treatment, cause apoptotic cell death. The understanding of the mechanisms underlying the regulation of the apoptosis in response to different types of DNA damage might provide relevant information to improve cancer treatment. In this review we mainly discuss bcl-2 and its partners in human cancers and how their disregulation might contribute to the development and the difficult treatment of cancer.


A genetic study of a melanization response to Sephadex beads in Plasmodium-refractory and -susceptible strains of Anopheles gambiae.
A previously selected Plasmodium-refractory strain of Anopheles gambiae melanotically encapsulates many species of Plasmodium. Genetic studies of this strain have shown that this refractory phenotype is controlled by a limited number of genes, and the existence of two such genes, Pif-B and Pif-C, has been demonstrated. Further work to determine the molecular basis for this mode of refractoriness led to the discovery that the host-parasite interaction is mimicked by the mosquito's response to carboxymethyl (CM)-Sephadex beads injected into the thorax. These small beads are melanized within 24 hr in refractory mosquitoes but are rarely melanized in susceptible ones. Because of the considerable potential in using bead melanization as a model for Plasmodium refractoriness, we performed a genetic analysis of the differential response to beads. Reciprocal crosses of susceptible (4arr) and refractory (L35) mosquitoes and an analysis of F1 phenotypes were done. The F1 progeny had a phenotype similar to that of the parental refractory mosquitoes; therefore, dominant refractory allele(s) must be present in the refractory strain. Males from the reciprocal crosses had identical phenotypes, indicating that X-linked loci did not have a visible effect on the melanizing phenotype. To further study the mode of inheritance of the melanizing trait, a backcross of F1 females to 4arr males was done. The phenotypic distribution of the backcross progeny was bimodal, and the melanization phenotypes were similar to those of the susceptible and refractory parents. These data suggest that a small number of loci are responsible for the differential response to CM-Sephadex beads, and that one chromosomal region contributes strongly to the melanizing trait. Because the 4arr strain carries mutations in the pink eye (X) and red eye (III) genes, possible linkage of the melanizing phenotype to these two genes was tested. No linkage with either marker was detected. The pattern of inheritance of the melanizing phenotype is similar to that of the refractory phenotype of Pif-B; therefore, the genetic basis of the two responses may be the same.


Military return to duty and civilian return to work factors following burns with focus on the hand and literature review.
Functional recovery and outcome from severe burns is oftentimes judged by the time required for a person to return to work (RTW) in civilian life. The equivalent in military terms is return to active duty. Many factors have been described in the literature as associated with this outcome. Hand function, in particular, is thought to have a great influence on the resumption of preburn activities. The purpose of this investigation was to compare factors associated with civilian RTW with combat injured military personnel. A review of the literature was performed to assimilate the many factors reported as involved with RTW or duty. Additionally, a focus on the influence of hand burns is included. Thirty-four different parameters influencing RTW have been reported inconsistently in the literature. In a military population of combat burns, TBSA burn, length of hospitalization and intensive care and inhalation injury were found as the most significant factors in determining return to duty status. In previous RTW investigations of civilian populations, there exists a scatter of factors reported to influence patient disposition with a mixture of conflicting results. In neither military nor civilian populations was the presence of a hand burn found as a dominant factor. Variety in patient information collected and statistical approaches used to analyze this information were found to influence the results and deter comparisons between patient populations. There is a need for a consensus data set and corresponding statistical approach used to evaluate RTW and duty outcomes after burn injury.


Impact of personalised feedback about physical activity on change in objectively measured physical activity (the FAB study): a randomised controlled trial.
Low levels of physical activity are a major public health concern, and interventions to promote physical activity have had limited success. Whether or not personalised feedback about physical activity following objective measurement motivates behaviour change has yet to be rigorously examined. And Findings: In a parallel group, open randomised controlled trial, 466 healthy adults aged 32 to 54 years were recruited from the ongoing population-based Fenland Study (Cambridgeshire, UK). Participants were randomised to receive either no feedback until the end of the trial (control group, n=120) or one of three different types of feedback: simple, visual, or contextualised (intervention groups, n=346). The primary outcome was physical activity (physical activity energy expenditure (PAEE) in kJ/kg/day and average body acceleration (ACC) in m/s(2)) measured objectively using a combined heart rate monitor and accelerometer (Actiheart(®)). The main secondary outcomes included self-reported physical activity, intention to increase physical activity, and awareness of physical activity (the agreement between self-rated and objectively measured physical activity). At 8 weeks, 391 (83.9%) participants had complete physical activity data. The intervention had no effect on objectively measured physical activity (PAEE: β=-0.92, 95% CI=-3.50 to 1.66, p=0.48 and ACC: β=0.01, 95% CI=-0.00 to 0.02, p=0.21), self-reported physical activity (β=-0.39, 95% CI=-1.59 to 0.81), or intention to increase physical activity (β=-0.05, 95% CI=-0.22 to 0.11). However, it was associated with an increase in awareness of physical activity (OR=1.74, 95% CI=1.05 to 2.89). Results did not differ according to the type of feedback. Personalised feedback about physical activity following objective measurement increased awareness but did not result in changes in physical activity in the short term. Measurement and feedback may have a role in promoting behaviour change but are ineffective on their own. Current Controlled Trials ISRCTN92551397 http://www.controlled-trials.com/ISRCTN92551397.


Microglial activation and tyrosine hydroxylase immunoreactivity in the substantia nigral region following transient focal ischemia in rats.
The temporal profiles of the changes of dopaminergic cells and microglial activation induced by transient cerebral ischemia were investigated in the substantia nigra pars compacta (SNc) located outside ischemic areas of rat brain. Transient cerebral ischemia was induced by intraluminal occlusion of the right middle cerebral artery for 2 h and reperfusion was continued for 1, 2, 3, 4, 7, 10, 14, 28, 60, and 120 days. Dopaminergic cells immunostained with tyrosine hydroxylase (TH)-antibody in the ipsilateral SNc were significantly decreased at 7 days post-ischemia compared with those in the contralateral side (P<0.05). However, at 60 and 120 days, there were no significant differences between ipsilateral and contralateral side of the SNc. Unlike the TH immunoreactivity, activated microglial cells immunostained with OX-42 antibody were significantly increased at 2 and 3 days and then decreased gradually until 10 days post-ischemia. Activated microglial cells were increased at 2 weeks post-ischemia, and this pattern remained until 60 days. These results suggest that the transient changes of TH-immunoreactive cells in the SNc caused by transient focal ischemia are correlated with a biphasic microglial cell activation response.


New microbiological aspects of fosfomycin.
The discovery of fosfomycin more than 40 years ago was an important milestone in antibiotic therapy. The antibiotic's usefulness, alone or in combination, for treating infections caused by multidrug-resistant microorganisms is clearer than ever. Both the European Medicines Agency and the US Food and Drug Administration have open processes for reviewing the accumulated information on the use of fosfomycin and the information from new clinical trials on this compound. The agencies' objectives are to establish common usage criteria for Europe and authorize the sale of fosfomycin in the US, respectively. Fosfomycin's single mechanism of action results in no cross-resistance with other antibiotics. However, various fosfomycin-resistance mechanisms have been described, the most important of which, from the epidemiological standpoint, is enzymatic inactivation, which is essentially associated with a gene carrying a fosA3-harboring plasmid. Fosfomycin has been found more frequently in Asia in extended-spectrum beta-lactamase-producing and carbapenemase-producing Enterobacterales. Although fosfomycin presents lower intrinsic activity against Pseudomonas aeruginosa compared with that presented against Escherichia coli, fosfomycin's activity has been demonstrated in biofilms, especially in combination with aminoglycosides. The current positioning of fosfomycin in the therapeutic arsenal for the treatment of infections caused by multidrug-resistant microorganisms requires new efforts to deepen our understanding of this compound, including those related to the laboratory methods employed in the antimicrobial susceptibility testing study.


Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR).
With infertility populations in the developed world rapidly aging, treatment of diminished ovarian reserve (DOR) assumes increasing clinical importance. Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances with DOR, and is now utilized by approximately one third of all IVF centers world-wide. Increasing DHEA utilization and publication of a first prospectively randomized trial now warrants a systematic review. PubMed, Cochrane and Ovid Medline were searched between 1995 and 2010 under the following strategy: [<dehydroepiandrosterone or DHEA or androgens or testosterone > and <ovarian reserve or diminished ovarian reserve or ovarian function >]. Bibliographies of relevant publications were further explored for additional relevant citations. Since only one randomized study has been published, publications, independent of evidence levels and quality assessment, were reviewed. Current best available evidence suggests that DHEA improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates. DHEA over time also appears to objectively improve ovarian reserve. Recent animal data support androgens in promoting preantral follicle growth and reduction in follicle atresia. Improvement of oocyte/embryo quality with DHEA supplementation potentially suggests a new concept of ovarian aging, where ovarian environments, but not oocytes themselves, age. DHEA may, thus, represent a first agent beneficially affecting aging ovarian environments. Others can be expected to follow.


A new look towards BAC-based array CGH through a comprehensive comparison with oligo-based array CGH.
Currently, two main technologies are used for screening of DNA copy number; the BAC (Bacterial Artificial Chromosome) and the recently developed oligonucleotide-based CGH (Chromosomal Comparative Genomic Hybridization) arrays which are capable of detecting small genomic regions with amplification or deletion. The correlation as well as the discriminative power of these platforms has never been compared statistically on a significant set of human patient samples. In this paper, we present an exhaustive comparison between the two CGH platforms, undertaken at two independent sites using the same batch of DNA from 19 advanced prostate cancers. The comparison was performed directly on the raw data and a significant correlation was found between the two platforms. The correlation was greatly improved when the data were averaged over large chromosomic regions using a segmentation algorithm. In addition, this analysis has enabled the development of a statistical model to discriminate BAC outliers that might indicate microevents. These microevents were validated by the oligo platform results. This article presents a genome-wide statistical validation of the oligo array platform on a large set of patient samples and demonstrates statistically its superiority over the BAC platform for the Identification of chromosomic events. Taking advantage of a large set of human samples treated by the two technologies, a statistical model has been developed to show that the BAC platform could also detect microevents.


CLoNe is a new method to target single progenitors and study their progeny in mouse and chick.
Cell lineage analysis enables us to address pivotal questions relating to: the embryonic origin of cells and sibling cell relationships in the adult body; the contribution of progenitors activated after trauma or disease; and the comparison across species in evolutionary biology. To address such fundamental questions, several techniques for clonal labelling have been developed, each with its shortcomings. Here, we report a novel method, CLoNe that is designed to work in all vertebrate species and tissues. CLoNe uses a cocktail of labelling, targeting and transposition vectors that enables targeting of specific subpopulations of progenitor types with a combination of fluorophores resulting in multifluorescence that describes multiple clones per specimen. Furthermore, transposition into the genome ensures the longevity of cell labelling. We demonstrate the robustness of this technique in mouse and chick forebrain development, and show evidence that CLoNe will be broadly applicable to study clonal relationships in different tissues and species.


Genetic and environmental determinants of violence risk in psychotic disorders: a multivariate quantitative genetic study of 1.8 million Swedish twins and siblings.
Patients diagnosed with psychotic disorders (for example, schizophrenia and bipolar disorder) have elevated risks of committing violent acts, particularly if they are comorbid with substance misuse. Despite recent insights from quantitative and molecular genetic studies demonstrating considerable pleiotropy in the genetic architecture of these phenotypes, there is currently a lack of large-scale studies that have specifically examined the aetiological links between psychotic disorders and violence. Using a sample of all Swedish individuals born between 1958 and 1989 (n=3 332 101), we identified a total of 923 259 twin-sibling pairs. Patients were identified using the National Patient Register using validated algorithms based on International Classification of Diseases (ICD) 8-10. Univariate quantitative genetic models revealed that all phenotypes (schizophrenia, bipolar disorder, substance misuse, and violent crime) were highly heritable (h(2)=53-71%). Multivariate models further revealed that schizophrenia was a stronger predictor of violence (r=0.32; 95% confidence interval: 0.30-0.33) than bipolar disorder (r=0.23; 0.21-0.25), and large proportions (51-67%) of these phenotypic correlations were explained by genetic factors shared between each disorder, substance misuse, and violence. Importantly, we found that genetic influences that were unrelated to substance misuse explained approximately a fifth (21%; 20-22%) of the correlation with violent criminality in bipolar disorder but none of the same correlation in schizophrenia (Pbipolar disorder<0.001; Pschizophrenia=0.55). These findings highlight the problems of not disentangling common and unique sources of covariance across genetically similar phenotypes as the latter sources may include aetiologically important clues. Clinically, these findings underline the importance of assessing risk of different phenotypes together and integrating interventions for psychiatric disorders, substance misuse, and violence.


Engrailed-1 expression marks a primitive class of inhibitory spinal interneuron.
Studies in chicks and mice have suggested that transcription factors mark functional subtypes of interneurons in the developing spinal cord. We used genetic, morphological, and physiological studies to test this proposed association in zebrafish. We found that Engrailed-1 expression uniquely marks a class of ascending interneurons, called circumferential ascending (CiA) interneurons, with ipsilateral axonal projections in both motor and sensory regions of spinal cord. These cells express the glycine transporter 2 gene and are the only known ipsilateral interneurons positive for this marker of inhibitory transmission. Patch recordings show that the CiA neurons are rhythmically active during swimming. Pairwise recordings from the CiA interneurons and postsynaptic cells reveal that the Engrailed-1 neurons produce monosynaptic, strychnine-sensitive inhibition of dorsal sensory interneurons and also inhibit more ventral neurons, including motoneurons and descending interneurons. We conclude that Engrailed-1 expression marks a class of inhibitory interneuron that seems to provide all of the ipsilateral glycinergic inhibition in the spinal cord of embryonic and larval fish. Individual Engrailed-1-positive cells are multifunctional, playing roles in both sensory gating and motor pattern generation. This primitive cell type may have given rise to several, more specialized glycinergic inhibitory interneurons in birds and mammals. Our data support the view that the subdivision of spinal cord into different regions by transcription factors defines a primitive functional organization of spinal interneurons that formed a developmental and evolutionary foundation on which more complex systems were built.


Neighborhood Design, Physical Activity, and Wellbeing: Applying the Walkability Model.
Neighborhood design affects lifestyle physical activity, and ultimately human wellbeing. There are, however, a limited number of studies that examine neighborhood design types. In this research, we examine four types of neighborhood designs: traditional development, suburban development, enclosed community, and cluster housing development, and assess their level of walkability and their effects on physical activity and wellbeing. We examine significant associations through a questionnaire (n = 486) distributed in Tucson, Arizona using the Walkability Model. Among the tested neighborhood design types, traditional development showed significant associations and the highest value for walkability, as well as for each of the two types of walking (recreation and transportation) representing physical activity. Suburban development showed significant associations and the highest mean values for mental health and wellbeing. Cluster housing showed significant associations and the highest mean value for social interactions with neighbors and for perceived safety from crime. Enclosed community did not obtain the highest means for any wellbeing benefit. The Walkability Model proved useful in identifying the walkability categories associated with physical activity and perceived crime. For example, the experience category was strongly and inversely associated with perceived crime. This study provides empirical evidence of the importance of including vegetation, particularly trees, throughout neighborhoods in order to increase physical activity and wellbeing. Likewise, the results suggest that regular maintenance is an important strategy to improve mental health and overall wellbeing in cities.


Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.
We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.


Presence of Irritable Bowel Syndrome Symptoms in Quiescent Inflammatory Bowel Disease Is Associated with High Rate of Anxiety and Depression.
Inflammatory bowel disease (IBD; Crohn's disease, CD and Ulcerative colitis, UC) and irritable bowel syndrome (IBS) have overlapping symptoms. Few prevalence studies of IBS in quiescent IBD have used colonoscopy with histology to confirm inactive disease. The aims were (1) to determine the percentage of IBD patients in deep remission whose persistent IBS-like symptoms (IBD/IBS+) would cause them to be classified as having active disease, based on the calculation of Harvey Bradshaw Index (HBI) or UC disease activity index (UCDAI); (2) to identify demographic and disease characteristics that are associated with IBD/IBS+. This was a prospective study at a single tertiary care IBD center. 96/112 patients with colonoscopy and histology confirmed quiescent disease consented and completed Rome III criteria for IBS Survey, and the hospital anxiety and depression scale (HADS). Other demographic and disease specific data were collected. 36% (28/77) and 37% (7/19) of CD and UC patients, respectively, met diagnostic criteria for IBS. Significantly higher HBI/UCDAI scores (p = 0.005) and low short inflammatory bowel disease questionnaire (SIBDQ) scores (p ≤ 0.0001) were seen in IBD/IBS+ patients. 29% of patients in deep remission were mis-categorized by HBI/UCDAI as having active disease when they fulfilled Rome III criteria for IBS. Psychiatric diagnosis (OR 3.53 95% CI 1.2-10.2) and earlier onset of IBD (OR 1.056 95% CI 1.015-1.096) were associated with IBD/IBS+. Patients fulfilling IBS criteria had higher hospital anxiety and depression scale (HADS). IBD/IBS+ affect scoring of IBD disease activity scales and become less useful in guiding treatment plans.