Socioeconomic status and psychological function in children with chromosome 22q11.2 deletion syndrome: implications for genetic counseling.
The purpose of this study is to examine the association between parental socio-economic status (SES) and childhood neurocognition and behavior in children with chromosome 22q11.2 deletion syndrome (22q11DS). Although undoubtedly, the deletion of genes in the 22q11.2 interval is primarily responsible for the psychological manifestations, little is known about the role of the environment in either mitigating or contributing to these problems. We examined the association of parental socio-economic status (SES) with cognition and behavior in children with 22q11DS (n = 65) and matched healthy control subjects (n = 52), since SES is a component of family resources. We found that in children with 22q11DS, higher SES correlated with better overall functioning (p < .01) and social skills (p < .01), and less frequent oppositional defiant behavior (p < .001). These findings were in contrast to the control subjects in whom SES correlated with cognition and achievement, but not behavior. Our results indicate that environmental factors influence the behavioral phenotype in children with 22q11DS, providing a framework for developing appropriate interventions. As such, genetic counseling for families with 22q11DS may include consideration of family resources and inclusion of other health professionals, such as social workers, to explore with the family available social supports and resources.


Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2.
MicroRNAs (miRNAs) are genomically encoded small RNAs used by organisms to regulate the expression of proteins generated from messenger RNA transcripts. The in vivo requirement of specific miRNAs in mammals through targeted deletion remains unknown, and reliable prediction of mRNA targets is still problematic. Here, we show that miRNA biogenesis in the mouse heart is essential for cardiogenesis. Furthermore, targeted deletion of the muscle-specific miRNA, miR-1-2, revealed numerous functions in the heart, including regulation of cardiac morphogenesis, electrical conduction, and cell-cycle control. Analyses of miR-1 complementary sequences in mRNAs upregulated upon miR-1-2 deletion revealed an enrichment of miR-1 "seed matches" and a strong tendency for potential miR-1 binding sites to be located in physically accessible regions. These findings indicate that subtle alteration of miRNA dosage can have profound consequences in mammals and demonstrate the utility of mammalian loss-of-function models in revealing physiologic miRNA targets.


Single-Cell Transcriptomics of a Human Kidney Allograft Biopsy Specimen Defines a Diverse Inflammatory Response.
Background Single-cell genomics techniques are revolutionizing our ability to characterize complex tissues. By contrast, the techniques used to analyze renal biopsy specimens have changed little over several decades. We tested the hypothesis that single-cell RNA-sequencing can comprehensively describe cell types and states in a human kidney biopsy specimen.Methods We generated 8746 single-cell transcriptomes from a healthy adult kidney and a single kidney transplant biopsy core by single-cell RNA-sequencing. Unsupervised clustering analysis of the biopsy specimen was performed to identify 16 distinct cell types, including all of the major immune cell types and most native kidney cell types, in this biopsy specimen, for which the histologic read was mixed rejection.Results Monocytes formed two subclusters representing a nonclassical CD16+ group and a classic CD16- group expressing dendritic cell maturation markers. The presence of both monocyte cell subtypes was validated by staining of independent transplant biopsy specimens. Comparison of healthy kidney epithelial transcriptomes with biopsy specimen counterparts identified novel segment-specific proinflammatory responses in rejection. Endothelial cells formed three distinct subclusters: resting cells and two activated endothelial cell groups. One activated endothelial cell group expressed Fc receptor pathway activation and Ig internalization genes, consistent with the pathologic diagnosis of antibody-mediated rejection. We mapped previously defined genes that associate with rejection outcomes to single cell types and generated a searchable online gene expression database.Conclusions We present the first step toward incorporation of single-cell transcriptomics into kidney biopsy specimen interpretation, describe a heterogeneous immune response in mixed rejection, and provide a searchable resource for the scientific community.


Addressing inequities in alcohol consumption and related harms.
Social determinants, or the conditions in which individuals are born, grow, live, work and age, can result in inequities in health and well-being. However, to-date little research has examined alcohol use and alcohol-related problems from an inequities and social determinants perspective. This study reviewed the evidence base regarding inequities in alcohol consumption and alcohol-related health outcomes in Australia and identified promising approaches for promoting health equity. Fair Foundations: the VicHealth framework for health equity was used as an organizing schema. The review found that social determinants can strongly influence inequities in alcohol consumption and related harms. In general, lower socioeconomic groups experience more harm than wealthier groups with the same level of alcohol consumption. While Australia has implemented numerous alcohol-related interventions and policies, most do not explicitly aim to reduce inequities, and some may inadvertently exacerbate existing inequities. Interventions with the greatest potential to decrease inequities in alcohol consumption and alcohol-related harms include town planning, zoning and licensing to prevent disproportionate clustering of outlets in disadvantaged areas; interventions targeting licensed venues; and interventions targeting vulnerable populations. Interventions that may worsen inequities include national guidelines, technological interventions and public drinking bans. There is a need for further research into the best methods for reducing inequities in alcohol consumption and related harms.


Evaluation of red cell distribution width in dogs with pulmonary hypertension.
To compare red cell distribution width (RDW) between dogs with different causes of pulmonary hypertension (PH) and a control dog population to determine whether RDW was correlated with severity of PH as measured by echocardiography. A further aim was to determine the prognostic significance of increased RDW for dogs with PH. Forty-four client-owned dogs with PH and 79 control dogs presented to a single tertiary referral institution. Signalment, clinical pathological and echocardiographic data were obtained retrospectively from the medical records of dogs with PH, and RDW measured on a Cell-Dyn 3500 was compared between dogs with pre- and post-capillary PH and a control population. Referring veterinary surgeons were contacted for follow-up information and Kaplan-Meier analysis was conducted to investigate differences in survival time between affected dogs with different RDW values. The RDW was significantly greater in dogs with pre-capillary PH compared to control dogs. There was no difference in median survival times between dogs with PH divided according to RDW values. The RDW was positively correlated with mean corpuscular volume and haematocrit in dogs with PH, but did not correlate with echocardiographic variables. An association was found between dogs with PH and increased RDW; however there was considerable overlap in values between control dogs and dogs with PH. The RDW was not associated with survival in this study.


Sexual violence and reproductive health outcomes among South African female youths: a contextual analysis.
We studied whether female youths from communities with higher sexual violence were at greater risk of negative reproductive health outcomes. We used data from a 2003 nationally representative household survey of youths aged 15-24 years in South Africa. The key independent variable was whether a woman had ever been threatened or forced to have sex. We aggregated this variable to the community level to determine, with control for individual-level experience with violence, whether the community-level prevalence of violence was associated with HIV status and adolescent pregnancy among female, sexually experienced, never-married youths. Youths from communities with greater sexual violence were significantly more likely to have experienced an adolescent pregnancy or to be HIV-positive than were youths from communities experiencing lower sexual violence. Youths from communities with greater community-level violence were also less likely to have used a condom at their last sexual encounter. Individual-level violence was only associated with condom nonuse. Programs to reduce adolescent pregnancies and HIV risk in South Africa and elsewhere in sub-Saharan Africa must address sexual violence as part of effective prevention strategies.


Self-harm in laboratory-housed primates: where is the evidence that the Animal Welfare Act amendment has worked?
The 1985 amendment to the United States Animal Welfare Act (AWA) to promote psychological well being of primates in the laboratory represents an acknowledgment of an important welfare problem concerning nonhuman animals. How effective has this amendment been? Perhaps the best-known contributor to psychological distress in primates in the laboratory is nonsocial housing; yet, available analyses suggest that little progress has been made in avoiding single-caging of these animals. Another way to assess psychological well being is to examine rates of self-abusive behavior in laboratory primates. If the AWA has been effective, then post-AWA self-harm rates might be lower than pre-AWA rates. However, when we attempted to determine those rates from published studies, data were too sparse to allow a rigorous statistical analysis; of 139 studies reporting primate self-harming behavior, only 9 contained data allowing estimation of self-harming behavior rates. We conclude that the current system of laboratory animal care and record keeping is inadequate to properly assess AWA impacts on primate psychological well being and that more is required to ensure the psychological well being of primates.


Proteome Analysis Database: online application of InterPro and CluSTr for the functional classification of proteins in whole genomes.
The SWISS-PROT group at EBI has developed the Proteome Analysis Database utilising existing resources and providing comparative analysis of the predicted protein coding sequences of the complete genomes of bacteria, archaea and eukaryotes (http://www.ebi.ac. uk/proteome/). The two main projects used, InterPro and CluSTr, give a new perspective on families, domains and sites and cover 31-67% (InterPro statistics) of the proteins from each of the complete genomes. CluSTr covers the three complete eukaryotic genomes and the incomplete human genome data. The Proteome Analysis Database is accompanied by a program that has been designed to carry out InterPro proteome comparisons for any one proteome against any other one or more of the proteomes in the database.


Correlation of BK Virus Neutralizing Serostatus With the Incidence of BK Viremia in Kidney Transplant Recipients.
BK virus (BKV)-associated nephropathy is the second leading cause of graft loss in kidney transplant recipients. Due to the high prevalence of persistent infection with BKV in the general population, it is possible that either the transplant recipient or donor may act as the source of virus resulting in viruria and viremia. Although several studies suggest a correlation between donor-recipient serostatus and the development of BK viremia, specific risk factors for BKV-related complications in the transplant setting remain to be established. We retrospectively determined the pretransplant BKV neutralizing serostatus of 116 donors (D)-recipient (R) pairs using infectious BKV neutralization assays with representatives from the 4 major viral serotypes. The neutralizing serostatus of donors and recipients was then correlated with the incidence of BK viremia during the first year posttransplantation. There were no significant differences in baseline demographics or transplant data among the 4 neutralizing serostatus groups, with the exception of calculated panel-reactive antibody which was lowest in the D+/R- group. Recipients of kidneys from donors with significant serum neutralizing activity (D+) had elevated risk for BK viremia, regardless of recipient serostatus (D+ versus D-: odd ratio, 5.0; 95% confidence interval, 1.9-12.7]; P = 0.0008). Furthermore, donor-recipient pairs with D+/R- neutralizing serostatus had the greatest risk for BK viremia (odds ratio, 4.9; 95% confidence interval, 1.7-14.6; P = 0.004). Donor neutralizing serostatus correlates significantly with incidence of posttransplant BK viremia. Determination of donor-recipient neutralizing serostatus may be useful in assessing the risk of BKV infection in kidney transplant recipients.


Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018).
A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a H1-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance.


Band bending and dipole effect at interface of metal-nanoparticles and TiO2 directly observed by angular-resolved hard X-ray photoemission spectroscopy.
This paper describes the observation of band bending and band edge shifts at the interfaces between nanoscale metals and TiO2 film over a wide depth range by angular-resolved hard X-ray photoemission spectroscopy (HAXPES). The HAXPES results indicate strong electrostatic interactions between the TiO2 semiconductor and metal nanoparticles, while density functional theory (DFT) calculations suggest that these interactions are primarily associated with charge transfer leading to electric dipole moments at the interface in the ground state. The effects of these dipole moments are not limited to the surface but also occur deep in the bulk of the semiconductor, and are highly dependent on the coverage of the metal nanoparticles on the semiconductor species.


Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation.
Proper regulation of nuclear factor κB (NF-κB) transcriptional activity is required for normal lymphocyte function, and deregulated NF-κB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB-inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-κB pathway in B lymphoproliferative disease.


Integrative Bioinformatics Analysis Reveals Potential Long Non-Coding RNA Biomarkers and Analysis of Function in Non-Smoking Females with Lung Cancer.
BACKGROUND Lung cancer is the most lethal cancer worldwide. The aim of this study was to identify the tumor-related lncRNAs and explore their functions in female non-smokers with lung cancer. MATERIAL AND METHODS The gene expression microarray datasets GSE19804, GSE31210, and GSE31548 were downloaded from the Gene Expression Omnibus database. The differentially-expressed lncRNAs between non-smoking female lung cancer samples and non-tumor lung tissues were identified using GEO2R. RESULTS In total, 25, 40, and 15 differentially-expressed lncRNAs were obtained from GSE19804, GSE31210, and GSE31548 datasets (|logFC| >1, adj. P<0.05), respectively. Eight lncRNAs were screened out in all 3 datasets. Of these, 5 lncRNAs were up-regulated and 3 lncRNAs were down-regulated in lung cancer tissues compared to non-tumor lung tissues. Then, the target miRNAs of aberrantly expressed lncRNAs and target mRNAs corresponding to miRNAs were predicted. Subsequently, the ceRNA network with 8 key lncRNAs, 20 miRNAs, and 38 mRNAs were constructed. Functional and pathway enrichment analysis showed these target genes were mainly enriched in biological processes associated with protein binding, nucleus, metal ion binding, regulation of transcription from RNA polymerase II promoter, nucleic acid binding, cell differentiation, microRNAs in cancer, and the hippo signaling pathway. Survival analysis of these lncRNAs revealed that low LINC00968 (P=0.0067) and TBX5-AS1 (P=0.0028) expression were associated with unfavorable prognosis in never-smoking female lung cancer patients. CONCLUSIONS The present study promotes understanding of the molecular mechanism of the pathogenesis of non-smoking female lung cancer and provides potential biomarkers for diagnosis and treatment.


Regulation of lymphocyte traffic by adhesion molecules.
Lymphocytes are antigen specific cells whose effector function is acquired through complex differentiation pathways. This implies, firstly, antigen encounter and recognition at specific sites, and, subsequently, the transition from a naive to a memory/effector phenotype. Clonotypically expanded cells must then be capable of recirculating to the tissue where their effector function is needed. To this aim, defined receptor-counter receptor pairs are expressed on lymphocytes versus endothelial cells. Extravasation is therefore a key-process in this scenario. Indeed, different lymphocyte subsets display distinct recirculation patterns and capability to migrate into lymphoid and non-lymphoid tissues. As a general rule, naive lymphocytes preferentially migrate into secondary lymphoid organs, where all the requirements for effective antigen presentation and differentiation are available; in contrast, memory/effector lymphocytes preferentially migrate to peripheral tissues, such as skin and mucosa. We review here the molecular events that regulate leukocyte extravasation and the specific migration properties acquired by both naive and memory/effector lymphocytes under physiological and pathological conditions.


Just because we can, should we? A discussion of treatment withdrawal.
Children's nurses are vocationally committed to promoting the health of children, relieving their suffering, enhancing their development, helping them to achieve a sense of worth and a confidence in their future. Supporting parents and medical colleagues while the decision is made to withdraw or withhold life-sustaining treatment is one of the most difficult aspects of children's nursing practice. Current guidelines support the withholding or withdrawing of life-sustaining treatment from children in brain death, permanent vegetative state, and no chance, no purpose or unbearable situations. Societal and professional attitudes to euthanasia and assisted suicide may be changing and this could lead to changes in legislation and guidelines. However, nurses must be clear about the differences: currently any measure, practice or treatment administered with the primary intention to cause death is not allowed. This is not the same as any measure, practice or treatment administered with the intent to relieve suffering and promote comfort, that can cause or hasten death.


[Accident prevention in agriculture in the ASL1 Abruzzo Local Health Service: protection facilities for tractors].
The ASL1 workplace prevention and safety service in Abruzzo has been conducting workplace inspections on agricultural and livestock farms in the province of L'Aquila since 2011, mainly in the areas of Avezzano, Sulmona and L'Aquila. The agricultural sector in Abruzzo is characterized by high rates of accidents and the ratio of fatal injuries/total injuries is higher than the industry and services sector. To evaluate the presence or absence of safety devices , i.e. compliance or otherwise with regulations for tractors, and of any variable factor that could be associated with the safety of the vehicle. Between 2011 and 2013, 98 farms in the province of L'Aquila were inspected. The data resulting from the inspections was collected by the use of a checklist. An univariate logistic regression analysis was conducted in which the vehicles that complied with regulations were considered as the dependant variable, and the age of the tractor owner, the acres of worked land and the type of farm were considered as explanatory variables. Statistical elaboration was carried out using the Stata 12 programme. Out of a total of 298 tractors that were checked, 64.8% did not comply with regulations due to absence or unsuitability of one or more safety devices such as: a protective device in case of overturning; retention system of the driver; mounting and dismounting from the vehicle; protection of moving parts and hot parts; PTO (Power Take Off) protection device. A significant association between non-compliance of vehicles and the age of the owner and acres worked was observed, whereas no statistical significance was observed for the association with the farm type variable. Our study showed that farms where the owner's age is between 50 and 64 years and where more acres of land are worked are those where the agricultural or forestry tractors had lower levels of compliance with regulations.


Comparison of Nondiabetic Retinal Findings Identified With Nonmydriatic Fundus Photography vs Ultrawide Field Imaging in an Ocular Telehealth Program.
Ultrawide field imaging (UWFI) is increasingly being used in teleophthalmology settings. Given the greater area of the retina imaged, we evaluated the ability of UWFI vs nonmydriatic fundus photography (NMFP) to detect nondiabetic retinal findings in a teleophthalmology program. We conducted a retrospective single-center comparative cohort study from January 1, 2011, to June 30, 2013, imaging 3864 and 3971 consecutive teleophthalmology patients (7728 and 7942 eyes) using NMFP and UWFI, respectively. Standard diabetic retinopathy evaluation and nondiabetic findings were compared between the 2 imaging modalities. In patients without diabetic retinopathy (2243 by NMFP and 2252 by UWFI), the rate of identification of nondiabetic findings by NMFP (451 patients [20.1%]) and UWFI (490 [21.8%]) were comparable (P = .19). Ultrawide field imaging increased the identification of choroidal nevi by 27% (406 eyes [5.3%] by NMFP vs 545 eyes [6.9%] by UWFI; P < .001) and chorioretinal atrophy or scarring by 116% (50 eyes [0.6%] by NMFP vs 101 eyes [1.3%] by UWFI; P < .001). No peripheral retinal findings were identified with NMFP, while UWFI detected 25 retinal tears (0.3%; P < .001), 54 lattice and peripheral degenerations (0.7%; P < .001), and 142 cases of vitreous detachment or floaters (1.8%; P < .001). Data analysis was performed from November 1, 2013, to May 1, 2014. In eyes without diabetic retinopathy, approximately 20% may have ocular findings identified on retinal imaging, which emphasizes the role of retinal imaging in patients with diabetes mellitus type 1 and type 2 regardless of the severity of retinopathy. In this cohort, UWFI increased the identification of peripheral retinal and vitreous pathologic findings.


Mapping single molecule sequencing reads using basic local alignment with successive refinement (BLASR): application and theory.
Recent methods have been developed to perform high-throughput sequencing of DNA by Single Molecule Sequencing (SMS). While Next-Generation sequencing methods may produce reads up to several hundred bases long, SMS sequencing produces reads up to tens of kilobases long. Existing alignment methods are either too inefficient for high-throughput datasets, or not sensitive enough to align SMS reads, which have a higher error rate than Next-Generation sequencing. We describe the method BLASR (Basic Local Alignment with Successive Refinement) for mapping Single Molecule Sequencing (SMS) reads that are thousands of bases long, with divergence between the read and genome dominated by insertion and deletion error. The method is benchmarked using both simulated reads and reads from a bacterial sequencing project. We also present a combinatorial model of sequencing error that motivates why our approach is effective. The results indicate that it is possible to map SMS reads with high accuracy and speed. Furthermore, the inferences made on the mapability of SMS reads using our combinatorial model of sequencing error are in agreement with the mapping accuracy demonstrated on simulated reads.


Intelligent artifact classification for ambulatory physiological signals.
Connected health represents an increasingly important model for health-care delivery. The concept is heavily reliant on technology and in particular remote physiological monitoring. One of the principal challenges is the maintenance of high quality data streams which must be collected with minimally intrusive, inexpensive sensor systems operating in difficult conditions. Ambulatory monitoring represents one of the most challenging signal acquisition challenges of all in that data is collected as the patient engages in normal activities of everyday living. Data thus collected suffers from considerable corruption as a result of artifact, much of it induced by motion and this has a bearing on its utility for diagnostic purposes. We propose a model for ambulatory signal recording in which the data collected is accompanied by labeling indicating the quality of the collected signal. As motion is such an important source of artifact we demonstrate the concept in this case with a quality of signal measure derived from motion sensing technology viz. accelerometers. We further demonstrate how different types of artifact might be tagged to inform artifact reduction signal processing elements during subsequent signal analysis. This is demonstrated through the use of multiple accelerometers which allow the algorithm to distinguish between disturbance of the sensor relative to the underlying tissue and movement of this tissue. A brain monitoring experiment utilizing EEG and fNIRS is used to illustrate the concept.


Ras-GAP SH3 domain binding protein (G3BP) is a modulator of USP10, a novel human ubiquitin specific protease.
Degradation of cellular proteins through ubiquitination is a fundamental strategy for regulating biological pathways. De-ubiquitination, i.e. the removal of ubiquitin from proteins and peptides to which ubiquitin is attached, is catalyzed by processing proteases known as de-ubiquitinating enzymes. We are studying the biology of a family of de-ubiquitinating enzymes, the mammalian ubiquitin-specific proteases (USPs), some of which appear to play a role in growth control. Given the fact that the modes of regulation of USPs and of their substrate specificity are poorly understood, we decided to attempt the identification of USP interacting proteins. Using the yeast two-hybrid system (2HS), we have isolated a cDNA clone whose product specifically interacts with USP10 but not with other USP baits tested. The isolated clone encodes a protein known to interact with the Ras-GTPase activating protein (G3BP). This interaction was further confirmed by performing a 2HS with G3BP, which led to the isolation of USP10 encoding cDNAs. We validated the interaction between the two proteins by performing in vitro binding assays and immunoprecipitations in human cells. G3BP does not appear to be a substrate of USP10; it rather inhibits the ability of USP10 to disassemble ubiquitin chains. The USP10/G3BP complex appears to co-immunoprecipitate with ubiquitinated species that could be substrates of USP10.


Rational design of a new Trypanosoma rangeli trans-sialidase for efficient sialylation of glycans.
This paper reports rational engineering of Trypanosoma rangeli sialidase to develop an effective enzyme for a potentially important type of reactivity: production of sialylated prebiotic glycans. The Trypanosoma cruzi trans-sialidase and the homologous T. rangeli sialidase has previously been used to investigate the structural requirements for trans-sialidase activity. We observed that the T. cruzi trans-sialidase has a seven-amino-acid motif (197-203) at the border of the substrate binding cleft. The motif differs substantially in chemical properties and substitution probability from the homologous sialidase, and we hypothesised that this motif is important for trans-sialidase activity. The 197-203 motif is strongly positively charged with a marked change in hydrogen bond donor capacity as compared to the sialidase. To investigate the role of this motif, we expressed and characterised a T. rangeli sialidase mutant, Tr13. Conditions for efficient trans-sialylation were determined, and Tr13's acceptor specificity demonstrated promiscuity with respect to the acceptor molecule enabling sialylation of glycans containing terminal galactose and glucose and even monomers of glucose and fucose. Sialic acid is important in association with human milk oligosaccharides, and Tr13 was shown to sialylate a number of established and potential prebiotics. Initial evaluation of prebiotic potential using pure cultures demonstrated, albeit not selectively, growth of Bifidobacteria. Since the 197-203 motif stands out in the native trans-sialidase, is markedly different from the wild-type sialidase compared to previous mutants, and is shown here to confer efficient and broad trans-sialidase activity, we suggest that this motif can serve as a framework for future optimization of trans-sialylation towards prebiotic production.


Guide for protein fold change and p-value calculation for non-experts in proteomics.
Proteomics studies generate tables with thousands of entries. A significant component of being a proteomics scientist is the ability to process these tables to identify regulated proteins. Many bioinformatics tools are freely available for the community, some of which within reach for scientists with limited or no background in programming and statistics. However, proteomics has become popular in most other biological and biomedical disciplines, resulting in more and more studies where data processing is delegated to specialists that are not lead authors of the scientific project. This creates a risk or at least a limiting factor, as the biological interpretation of a dataset is contingent of a third-party specialist transforming data without the input of the project leader. We acknowledge in advance that dedicated scripts and software have a higher level of sophistication; but we hereby claim that the approach we describe makes proteomics data processing immediately accessible to every scientist. In this paper, we describe key steps of the typical data transformation, normalization and statistics in proteomics data analysis using a simple spreadsheet. This manuscript aims to demonstrate to those who are not familiar with the math and statistics behind these workflows that a proteomics dataset can be processed, simplified and interpreted in software like Microsoft Excel. With this, we aim to reach the community of non-specialists in proteomics to find a common language and illustrate the basic steps of -omics data processing.


Screening mammography: a missed clinical opportunity? Results of the NCI Breast Cancer Screening Consortium and National Health Interview Survey Studies.
Data from seven studies sponsored by the National Cancer Institute (NCI) were used to determine current rates of breast cancer screening and to identify the characteristics of and reasons for women not being screened. All seven studies were population-based surveys of women aged 50 to 74 years without breast cancer. While over 90% of non-Hispanic white respondents had regular sources of medical care, 46% to 76% had had a clinical breast examination within the previous year, and only 25% to 41% had had a mammogram. Less educated and poorer women had had fewer mammograms. The two most common reasons women gave for never having had a mammogram were that they did not know they needed it and that their physician had not recommended it. Many physicians may have overlooked the opportunity to recommend mammography for older women when performing a clinical breast examination and to educate their patients about the benefit of screening mammography.


Variable relationship between chimerism and tolerance after hematopoietic cell transplantation without myelosuppressive conditioning.
We have previously described a mixed chimerism protocol that avoids myelosuppressive conditioning and permits hematopoietic cell transplantation across MHC barriers without the need for whole body irradiation in miniature swine. Here, we report our current experience including animals conditioned without thymic irradiation, and we attempt to define the relationship between long-term chimerism and stable tolerance in these animals. Recipient swine received in vivo T-cell depletion, with or without thymic irradiation on day -2. Cyclosporine was administered for 30 to 60 days beginning on day -1. A total of 1 to 2 x 10(10) /kg cytokine-mobilized donor hematopoietic cells were infused during 3 days. Chimerism was determined by flow cytometry. In vitro tolerance assays and donor-matched kidney transplantation were performed after cessation of cyclosporine. Most recipients maintained stable chimerism (26 of 35) and were specifically tolerant to donor-matched cells in vitro regardless of whether they received thymic irradiation. Donor-matched kidney transplantations performed in chimeric animals without in vitro antidonor immune responses were accepted without immunosuppression. Some animals developed in vitro evidence of antidonor MHC responsiveness despite the persistence of donor cells in the peripheral blood. Donor-matched kidney transplantations performed in the face of these responses were rejected. These data indicate that this nonmyelosuppressive protocol can induce stable chimerism and robust tolerance even in animals conditioned without thymic irradiation. However, the data also demonstrate that macrochimerism does not always correlate with tolerance. Lack of in vitro antidonor immune responses in chimeric animals is an important predictor of renal allograft acceptance in this model.


Nonfamilial cutaneous melanoma incidence in women associated with sun exposure before 20 years of age.
Despite strong evidence that sun exposure causes malignant melanoma, the details of this relation remain unclear. A nested case-control analysis was conducted within the Nurses' Health Study cohort to examine the relation between timing of severe sun exposure and incidence of melanoma. The subjects were 130 white women aged 38 to 65 years with confirmed cutaneous melanoma (other than acral lentigenous) who reported no history of melanoma in first-degree relatives. The control subjects were 300 women matched by race, date of birth, and cycle of questionnaire who also reported no history of melanoma in first-degree relatives. We used conditional logistic regression to evaluate the relation of sun damage after 30 years of age and sun damage from 15 to 20 years of age to the incidence of melanoma. Blistering sunburns between 15 to 20 years of age were associated with risk of melanoma (relative risk = 2.2 for five or more burns vs none, 95% confidence interval 1.2 to 3.8). This association persisted when a history of burns after 30 years of age was controlled in the analysis. No material association was found between blistering sunburns after 30 years of age and melanoma. Similarly, a more equatorial latitude of residence between 15 and 20 years of age was positively associated with melanoma; latitude after 30 years of age was less strongly and not significantly related to melanoma risk. Sun exposure prior to 20 years of age is more closely associated with melanoma risk than sun exposure after 30 years of age.


Efficacy and safety of cannabidiol followed by an open label add-on of tetrahydrocannabinol for the treatment of chronic pain in patients with rheumatoid arthritis or ankylosing spondylitis: protocol for a multicentre, randomised, placebo-controlled study.
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic, systemic, inflammatory diseases, primarily in the musculoskeletal system. Pain and fatigue are key symptoms of RA and AS. Treatment presents a clinical challenge for several reasons, including the progressive nature of the diseases and the involvement of multiple pain mechanisms. Moreover, side effects of pain treatment pose an implicit risk. Currently, no well-controlled studies have investigated how medical cannabis affects pain and cognitive functions in RA and AS. The present study aims to evaluate the efficacy and safety of medical cannabis in the treatment of persistent pain in patients with RA and AS with low disease activity. A double-blinded, randomised, placebo-controlled study of cannabidiol (CBD), followed by an open label add-on of tetrahydrocannabinol (THC) with collection of clinical data and biological materials in RA and AS patients treated in routine care. The oral treatment with CBD in the experimental group is compared with placebo in a control group for 12 weeks, followed by an observational 12-week period with an open label add-on of THC in the primary CBD non-responders. Disease characteristics, psychological parameters, demographics, comorbidities, lifestyle factors, blood samples and serious adverse events are collected at baseline, after 12 and 24 weeks of treatment, and at a follow-up visit at 36 weeks. Data will be analysed in accordance with a predefined statistical analysis plan. The Danish Ethics Committee (S-20170217), the Danish Medicines Agency (S-2018010018) and the Danish Data Protection Agency approved the protocol. The project is registered in the European Clinical Trials Database (EudraCT 2017-004226-15). All participants will give written informed consent to participate prior to any study-related procedures. The results will be presented at international conferences and published in peer-reviewed journals.


Predictive value of biochemical, echocardiographic and electrocardiographic markers in non-surviving and surviving asphyxiated full-term newborns.
Severe perinatal asphyxia can cause multiple organ dysfunction and early neonatal mortality. This prospective study was conducted at the Regional University Hospital Neonatology Center in Serbia. The aim of this study was to compare fullterm asphyxiated newborn infants (n=55) with (n=13) and without (n=42) mortality outcome and healthy full-term newborns (n=36) regarding biochemical (cardiac troponin I, creatine kinase (total and MB fraction) and C-reactive protein), echocardiographic (ejection fraction, fractional shortening, mitral regurgitation, significant tricuspid regurgitation, and patent ductus arteriosus) and electrocardiographic (ST segment elevation/depression, T wave inversion and corrected QT interval) markers of myocardial damage in order to assess their predictive value in the clinical outcome. Statistically significant differences in the majority of the tested markers of ischemic myocardial lesion were found between perinatal asphyxia survivors and the control group. However, among the biochemical indicators, only the level of cardiac troponin I was significantly higher in the group of neonates who died compared to the group of asphyxiated neonates who survived (p: 0.000), with an area under the receiver operating characteristic curve of 0.821 and cutoff value for lethal outcome of 0.135 μg/L (sensitivity 0.85; specificity 0.69). In addition, differences in ejection fraction, fractional shortening and significant tricuspid regurgitation (≥2+) were also found between the two subgroups of asphyxiated newborns. Cardiac troponin I is the most sensitive ischemic myocardial lesion biochemical marker in the prediction of early mortality in perinatal asphyxia patients.


Thermo-, photo-, and mechano-responsive liquid crystal networks enable tunable photonic crystals.
Tunable photonic crystals exhibiting optical properties that respond reversibly to external stimuli have been developed using liquid crystal networks (LCNs) and liquid crystal elastomers (LCEs). These tunable photonic crystals possess an inverse opal structure and are photo-responsive, but circumvent the usual requirement to contain dye molecules in the structure that often limit their applicability and cause optical degradation. Herein, we report tunable photonic crystal films that reversibly tune the reflection peak wavelength under thermo-, photo- and mechano-stimuli, through bilayering a stimuli-responsive LCN including azobenzene units with a colourless inverse opal film composed of non-responsive, flexible durable polymers. By mechanically deforming the azobenzene containing LCN via various stimuli, the reflection peak wavelength from the bilayered film assembly could be shifted on demand. We confirm that the reflection peak shift occurs due to the deformation of the stimuli-responsive layer propagating towards and into the inverse opal layer to change its shape in response, and this shift behaviour is repeatable without optical degradation.


New Approach on Quantification of Porosity of Thin Films via Electron-Excited X-ray Spectra.
One of the crucial characteristics of functionalized thin films is their porosity (i.e., the ratio between the pore volume and the volume of the whole film). Due to the very low amount of material per coated area corresponding to thin films, it is a challenge for analytics to measure the film porosity. In this work, we present an approach to determine the porosity of thin films by means of electron probe microanalysis (EPMA) either by wavelength-dispersive X-ray spectrometry (WDX) or by energy-dispersive X-ray spectrometry (EDX) with a scanning electron microscope (SEM). The procedure is based on the calculation of the film mass deposition from electron-excited X-ray spectra. The mass deposition is converted into film density by division of measured film thickness. Finally, the film porosity is calculated from the measured film density and the density of bulk, nonporous film material. The general applicability of the procedure to determine the porosity is demonstrated on thin templated mesoporous TiO2 films, dip-coated on silicon wafer, with controlled porosity in the range of 15 to 50%. The high accuracy of the mass deposition as determined from X-ray spectra was validated with independent methods (ICP-OES and weighing). Furthermore, for the validation of the porosity results, ellipsometry, interference fringes method (IFM), and focused ion beam (FIB) cross sectioning were employed as independent techniques. Hence, the approach proposed in the present study is proven to be suited as a new analytical tool for accurate and relatively fast determination of the porosity of thin films.


Functional analysis of PGRP-LA in Drosophila immunity.
PeptidoGlycan Recognition Proteins (PGRPs) are key regulators of the insect innate antibacterial response. Even if they have been intensively studied, some of them have yet unknown functions. Here, we present a functional analysis of PGRP-LA, an as yet uncharacterized Drosophila PGRP. The PGRP-LA gene is located in cluster with PGRP-LC and PGRP-LF, which encode a receptor and a negative regulator of the Imd pathway, respectively. Structure predictions indicate that PGRP-LA would not bind to peptidoglycan, pointing to a regulatory role of this PGRP. PGRP-LA expression was enriched in barrier epithelia, but low in the fat body. Use of a newly generated PGRP-LA deficient mutant indicates that PGRP-LA is not required for the production of antimicrobial peptides by the fat body in response to a systemic infection. Focusing on the respiratory tract, where PGRP-LA is strongly expressed, we conducted a genome-wide microarray analysis of the tracheal immune response of wild-type, Relish, and PGRP-LA mutant larvae. Comparing our data to previous microarray studies, we report that a majority of genes regulated in the trachea upon infection differ from those induced in the gut or the fat body. Importantly, antimicrobial peptide gene expression was reduced in the tracheae of larvae and in the adult gut of PGRP-LA-deficient Drosophila upon oral bacterial infection. Together, our results suggest that PGRP-LA positively regulates the Imd pathway in barrier epithelia.


Human prenatal exposure to polychlorinated biphenyls (PCBs) and risk behaviors in adolescence.
Polychlorinated biphenyls (PCBs) are chemicals used in a variety of products before they were widely banned due to toxic effects in humans and wildlife. Because of continued persistence and ubiquity of these contaminants, risk of exposure to people living in industrialized countries is still high. Experimental research show that developmental exposure to PCB may alter function of brain pleasure centers and potentially influence disinhibitory behaviors, including tobacco and alcohol use. Yet, the potential effects of developmental PCB exposure on adolescent substance use have not been studied in humans. We used the Child Health and Development Studies (CHDS), a prospective birth cohort study in the Oakland and East Bay areas of California, to investigate associations between prenatal exposure to PCB congeners (66, 74, 99, 118, 138, 153, 170, 180, 187, and 203) and later disinhibitory behaviors in adolescents, specifically alcohol consumption and smoking, in a randomly selected sample (n = 554). Total prenatal PCB exposure was not associated with disinhibitory behaviors, among adolescents. However, the adjusted odds ratio (aOR) for being a current smoker, was higher in subjects within the third quartile of maternal PCB 66 exposure compared to those below the median (aOR = 1.93; 95% CI 1.05, 3.55). The aOR for drinking >2 alcoholic beverages per week, were also higher for adolescents within the third (aOR = 1.46; 95% CI 0.86, 2.47) and fourth quartile of PCB 66 exposure (aOR = 1.39; 95% CI 0.83, 2.35), but the differences did not reach statistical significance. These results suggest that this specific PCB congener may play a role inducing neurodevelopmental alterations that could potentially increase the risk of becoming a long-term user of tobacco and possibly alcohol. There were no notable differences between magnitude or direction of effect between boys and girls. Future replicate analyses with larger longitudinal samples and animal experimental studies of potential underlying mechanisms are warranted.


Moderate alcohol consumption is associated with better endothelial function: a cross sectional study.
Moderate alcohol consumption is protective against coronary artery disease. Endothelial dysfunction contributes to atherosclerosis and the pathogenesis of cardiovascular disease. The effects of alcohol consumption on endothelial function may be relevant to these cardiovascular outcomes, but very few studies have examined the effect of alcohol consumption on endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery in humans. In the population-based Northern Manhattan Study (NOMAS), we performed a cross-sectional analysis of lifetime alcohol intake and brachial artery FMD during reactive hyperemia using high-resolution B-mode ultrasound images among 884 stroke-free participants (mean age 66.8 years, women 56.6%, Hispanic 67.4%, black 17.4%, and white 15.2%). The mean brachial FMD was 5.7% and the median was 5.5%. Compared to non-drinkers, those who drank >1 drink/month to 2 drinks/day were more likely to have FMD above the median FMD (5.5%) (unadjusted OR 1.7, 95% CI 1.2-2.4, p = 0.005). In multivariate analysis, the relationship between moderate alcohol consumption and FMD remained significant after adjusting for multiple traditional cardiovascular risk factors, including sex, race-ethnicity, body mass index, diabetes mellitus, coronary artery disease, Framingham risk score, medication use (adjusted OR 1.8, 95%CI 1.1-3.0, p = 0.03). No beneficial effect on FMD was seen for those who drank more than 2 drinks/day. In conclusion, consumption of up to 2 alcoholic beverages per day was independently associated with better FMD compared to no alcohol consumption in this multiethnic population. This effect on FMD may represent an important mechanism in explaining the protective effect of alcohol intake on cardiovascular disease.


Definitive Characterization of CA 19-9 in Resectable Pancreatic Cancer Using a Reference Set of Serum and Plasma Specimens.
The validation of candidate biomarkers often is hampered by the lack of a reliable means of assessing and comparing performance. We present here a reference set of serum and plasma samples to facilitate the validation of biomarkers for resectable pancreatic cancer. The reference set includes a large cohort of stage I-II pancreatic cancer patients, recruited from 5 different institutions, and relevant control groups. We characterized the performance of the current best serological biomarker for pancreatic cancer, CA 19-9, using plasma samples from the reference set to provide a benchmark for future biomarker studies and to further our knowledge of CA 19-9 in early-stage pancreatic cancer and the control groups. CA 19-9 distinguished pancreatic cancers from the healthy and chronic pancreatitis groups with an average sensitivity and specificity of 70-74%, similar to previous studies using all stages of pancreatic cancer. Chronic pancreatitis patients did not show CA 19-9 elevations, but patients with benign biliary obstruction had elevations nearly as high as the cancer patients. We gained additional information about the biomarker by comparing two distinct assays. The two CA 9-9 assays agreed well in overall performance but diverged in measurements of individual samples, potentially due to subtle differences in antibody specificity as revealed by glycan array analysis. Thus, the reference set promises be a valuable resource for biomarker validation and comparison, and the CA 19-9 data presented here will be useful for benchmarking and for exploring relationships to CA 19-9.


Synthesis and catalytic application of PVP-coated Ru nanoparticles embedded in a porous metal-organic framework.
A hybrid catalyst consisting of polymer-coated Ru nanoparticles (Ru-PVP, PVP: poly(N-vinyl-2-pyrrolidone)) embedded in a porous metal-organic framework of ZIF-8 (Ru-PVP@ZIF-8) was synthesized by the crystallization of ZIF-8 in a methanol solution of Ru-PVP. The structural properties of Ru-PVP@ZIF-8 were examined by N2 gas adsorption, infrared spectra, and X-ray powder diffraction measurements. We successfully identified the most appropriate pretreatment conditions for surface activation of the Ru nanoparticles in the catalyst. The pretreated Ru-PVP@ZIF-8 was applied for a CO oxidation reaction with H2 gas feeds. Ru-PVP@ZIF-8 was found to exhibit higher catalytic activities and higher CO2 selectivity than those observed on a carbon-supported Ru-PVP (Ru-PVP/C), implying that the pores of the ZIF-8 provide a more suitable environment for the reaction with O2 and CO gases.


Thermoresponsive block copolymer brush for temperature-modulated hepatocyte separation.
Hepatic tissue engineering may be an effective approach for the treatment of liver disease; however, its practical application requires hepatic cell separation technologies that do not involve cell surface modification and maintain cell activity. In this study, we developed hepatocyte cell separation materials using a thermoresponsive polymer and a polymer with high affinity to hepatocytes. A block copolymer of poly(N-p-vinylbenzyl-O-β-D-galactopyranosyl-(1→4)-D-gluconamide) (PVLA) and poly(N-isopropylacrylamide) (PNIPAAm) [PVLA-b-PNIPAAm] was prepared through two steps of atom transfer radical polymerization. On the prepared PVLA-b-PNIPAAm brush, HepG2 cells (model hepatocytes) adhered at 37 °C and detached at 20 °C, attributed to the temperature-modulated affinity between PVLA and HepG2. Cells from the immortalized human hepatic stellate cell line (TWNT-1) did not adhere to the copolymer brush, and RAW264.7 cells (mouse macrophage; model Kupffer cells) adhered to the copolymer brush, regardless of temperature. Using the difference in cell adhesion properties on the copolymer brush, temperature-modulated cell separation was successfully demonstrated. A mixture of HepG2, RAW264.7, and TWNT-1 cells was seeded on the copolymer brush at 37 °C for adherence. By reducing the temperature to 20 °C, adhered HepG2 cells were selectively recovered with a purity of approximately 85% and normal activity. In addition, induced pluripotent stem (iPS) cell-derived hepatocytes adhered on the PVLA-b-PNIPAAm brush at 37 °C and detached from the copolymer brush at 20 °C, whereas the undifferentiated iPS cells did not adhere, indicating that the prepared PVLA-b-PNIPAAm brush could be utilized to separate hepatocyte differentiated and undifferentiated cells. These results indicated that the newly developed PVLA-b-PNIPAAm brush can separate hepatic cells from contaminant cells by temperature modulation, without affecting cell activity or modifying the cell surface. Thus, the copolymer brush is expected to be a useful separation tool for cell therapy and tissue engineering using hepatocytes.


Rituximab for the treatment of relapsed/refractory chronic lymphocytic leukaemia.
This paper presents a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of rituximab with chemotherapy compared to chemotherapy only for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) based on the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. Evidence was available in the form of one open-label, ongoing, unpublished randomised controlled trial (RCT), REACH (Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia), conducted by the manufacturer, which compared rituximab with a fludarabine and cyclophosphamide combination (R-FC) to fludarabine and cyclophosphamide (FC) only. REACH was scheduled to run for 8 years; however, the data provided were immature, with a median observation time at the time of data analysis of 2.1 years. REACH provided evidence of prolonged progression free survival with R-FC compared to FC (10 months, investigators' data), but no evidence of an overall survival benefit with R-FC. Patients refractory to fludarabine and with prior rituximab exposure were excluded from REACH and no controlled studies were identified by the ERG for these patient groups. The ERG had concerns about the structure of the economic model submitted by the manufacturer, which did not allow improvement in quality of life from treatment while in a progressed state. The manufacturer's model further assumed a divergence in cumulative deaths between the R-FC and FC treatment arms from the outset, which did not accord with observed data from REACH. When the survival advantage was removed, the manufacturer's base-case incremental cost-effectiveness ratio (ICER) changed from 15,593 pounds to between 40,000 pounds and 42,000 pounds per quality-adjusted life-year (QALY). With no survival advantage, the ICER became sensitive to changes in utility. There was no good empirical evidence on the utility of CLL patients in different states. Allowing for the possibility of a survival advantage with rituximab (although not supported by current evidence), the ERG performed further modelling, which found that rituximab would be cost-effective at 20,000 pounds/QALY (30,000 pounds/QALY) if a reduction in survival advantage relative to the manufacturer's base case of 40% (80%) was assumed. The guidance issued by NICE in July 2010 as a result of the STA recommends rituximab with FC for people with relapsed or refractory chronic lymphocytic leukaemia, except when the condition is refractory to fludarabine or where there has been previous treatment with rituximab.


Human trophoblast and the choriocarcinoma cell line BeWo express a truncated HLA Class I molecule.
Extravillous trophoblast from normal human placenta has been shown previously to express an unusual form of HLA class I molecule, as does a choriocarcinoma cell line, BeWo. This molecule has a H chain of approximately 40 kDa and appears to be nonpolymorphic. We have isolated and sequenced a HLA class I cDNA clone, which probably corresponds to this molecule, from a library derived from BeWo. The nucleotide sequence shows a high degree of homology with the published sequence of a genomic clone, HLA 6.0, which is the product of a class I locus other than A, B, or C, (provisionally designated "HLA G"). The expressed product of this locus has not previously been localized. We have used the polymerase chain reaction to demonstrate the presence of similar HLA class I sequences in cDNA from normal extravillous trophoblast. Although there is some nucleotide sequence polymorphism the amino acid sequence of this molecule is conserved. It is therefore unlikely to provoke immune responses even though it is found at the fetal-maternal interface.


Description and analysis of three Homo naledi incudes from the Dinaledi Chamber, Rising Star cave (South Africa).
This study describes three incudes recovered from the Dinaledi Chamber in the Rising Star cave system in South Africa. All three bones were recovered during sieving of excavated sediments and likely represent three Homo naledi individuals. Morphologically and metrically, the Dinaledi ossicles resemble those of chimpanzees and Paranthropus robustus more than they do later members of the genus Homo, and fall outside of the modern human range of variation in several dimensions. Despite this, when overall size is considered, the functional lengths in H. naledi and P. robustus are very similar to those predicted for a human with a similar-sized incus. In this sense, both taxa seem to show a relatively elongated functional length, distinguishing them from chimpanzees. The functional length in H. naledi is slightly longer in absolute terms than in P. robustus, suggesting H. naledi may already show a slight increase in functional length compared with early hominins. While H. naledi lacks the more open angle between the long and short processes found in modern humans, considered a derived feature within the genus Homo, the value in H. naledi is similar to that predicted for a hominoid with a similar-sized incus. Principal components analysis of size-standardized variables shows H. naledi falling outside of the recent human range of variation, but within the confidence ellipse for gorillas. Phylogenetic polarity is complicated by the absence of incus data from early members of the genus Homo, but the generally primitive nature of the H. naledi incudes is consistent with other primitive features of the species, such as the very small cranial capacity. These ossicles add significantly to the understanding of incus variation in hominins and provide important new data on the morphology and taxonomic affinities of H. naledi.


Implicit expectations influence target detection in children and adults.
When a sound occurs at a predictable time, it gets processed more efficiently. Predictability of the temporal structure of acoustic inflow has been found to influence the P3b of event-related potentials in young adults, such that highly predictable compared to less predictable input leads to earlier P3b peak latencies. In our study, we wanted to investigate the influence of predictability on target processing indexed by the P3b in children (10-12 years old) and young adults. To do that, we used an oddball paradigm with two conditions of predictability (high and low). In the High-predictability condition, a high-pitched target tone occurred most of the time in the fifth position of a five-tone pattern (after four low-pitched non-target sounds), whereas in the Low-predictability condition, no such rule was implemented. The target tone occurred randomly following 2, 3, 4, 5, or 6 non-target tones. In both age groups, reaction time to predictable targets was faster than to non-predictable targets. Remarkably, this effect was largest in children. Consistent with the behavioral responses, the onset latency of the P3b response elicited by targets in both groups was earlier in the predictable than the unpredictable conditions. However, only the children had significantly earlier peak latency responses for predictable targets. Our results demonstrate that target stimulus predictability increases processing speed in children and adults even when predictability was only implicitly derived by the stimulus statistics. Children did have larger effects of predictability, seeming to benefit more from predictability for target detection.


Transitions in care during the end of life: changes experienced following enrolment in a comprehensive palliative care program.
BACKGROUND: Transitions in the location of care and in who provides such care can be extremely stressful for individuals facing death and for those close to them. The objective of this study was to describe the distribution of transitions in care experienced by palliative care patients following admission to a comprehensive palliative care program (PCP). A better understanding of these transitions may aid in reducing unnecessary change, help predict care needs, enhance transitions that improve quality of life, guide health care system communication links and maximize the cost-effective utilization of different care settings and providers. METHODS: Transition and demographic information pertaining to all patients registered in the PCP at the Queen Elizabeth II Health Sciences Centre (QEII), Halifax, Nova Scotia, Canada between January 1, 1998 and December 31, 2002 and who died on or prior to December 31, 2002 was extracted from the PCP database and examined. A transition was defined as either: (1) a change in location of where the patient was cared for by the PCP or, (2) a change in which clinical service provided care. Descriptive analysis provided frequencies and locations of transitions experienced from time of PCP admission to death and during the final two and four weeks of life, an examination of patient movement and a summary of the length of stay spent by patients at each care location. RESULTS: Over the five year period, 3974 adults admitted to the QEII PCP experienced a total of 5903 transitions (Mean 1.5; standard deviation 1.8; median 1). Patients with no transitions (28%) differed significantly from those who had experienced at least one transition with respect to survival time, age, location of death and diagnosis (p < 0.0001). The majority of patients were admitted to the PCP from various acute care units (66%). Although 54% of all transitions were made to the home, only 60% of these moves included care provided by PCP staff. During the last four weeks of life, 47% of patients experienced at least one transition; 36% during the final two weeks of life. Shorter stays in each location were evident when care was actively provided by the PCP. CONCLUSION: A relatively small number of patients under the care of the PCP at the end of life, made several transitions in care setting or service provider. These particular patients need closer scrutiny to understand why such transitions take place so that clinical programs may be designed or modified to minimize the transitions themselves or the impact transitions have on patients and families.


Effects and correction of magneto-optic spatial light modulator phase errors in an optical correlator.
Here we study the optical phase errors introduced into an optical correlator by the input and filter plane magneto-optic spatial light modulators. We measure and characterize the magnitude of these phase errors, evaluate their effects on the correlation results, and present a means of correction by a design modification of the binary phase-only optical-filter function. The efficacy of the phase-correction technique is quantified and is found to restore the correlation characteristics to those obtained in the absence of errors, to a high degree. The phase errors of other correlator system elements are also discussed and treated in a similar fashion.


Diabetes-Multimorbidity Combinations and Disability Among Middle-aged and Older Adults.
Older adults with diabetes rarely have only one chronic disease. As a result, there is a need to re-conceptualize research and clinical practice to address the growing number of older Americans with diabetes and concurrent chronic diseases (diabetes-multimorbidity). To identify prevalent multimorbidity combinations and examine their association with poor functional status among a nationally representative sample of middle-aged and older adults with diabetes. A prospective cohort study of the 2012-2014 Health and Retirement Study (HRS) data. We identified the most prevalent diabetes-multimorbidity combinations and estimated negative binomial models of diabetes-multimorbidity on prospective disability. Analytic sample included 3841 HRS participants with diabetes, aged 51 years and older. The main outcome measure was the combined activities of daily living (ADL)-instrumental activities of daily living (IADL) index (range 0-11; higher index denotes higher disability). The main independent variables were diabetes-multimorbidity combination groups, defined as the co-occurrence of diabetes and at least one of six somatic chronic diseases (hypertension, cardiovascular disease, lung disease, cancer, arthritis, and stroke) and/or two mental chronic conditions (cognitive impairment and high depressive symptoms (CESD score ≥ 4). The three most prevalent multimorbidity combinations were, in rank-order diabetes-arthritis-hypertension (n = 694, 18.1%); diabetes-hypertension (n = 481, 12.5%); and diabetes-arthritis-hypertension-heart disease (n = 383, 10%). Diabetes-multimorbidity combinations that included high depressive symptoms or stroke had significantly higher counts of ADL-IADL limitations compared with diabetes-only. In head-to-head comparisons of diabetes-multimorbidity combinations, high depressive symptoms or stroke added to somatic multimorbidity combinations was associated with a higher count of ADL-IADL limitations (diabetes-arthritis-hypertension-high depressive symptoms vs. diabetes-arthritis-hypertension: IRR = 1.95 [1.13, 3.38]; diabetes-arthritis-hypertension-stroke vs. diabetes-arthritis-hypertension: IRR = 2.09 [1.15, 3.82]) even after adjusting for age, gender, education, race/ethnicity, BMI, baseline ADL-IADL, and diabetes duration. Coefficients were robust to further adjustment for diabetes treatment. Depressive symptoms or stroke added onto other multimorbidity combinations may pose a substantial functional burden for middle-aged and older adults with diabetes.


Genome-scale metabolic reconstructions of multiple Escherichia coli strains highlight strain-specific adaptations to nutritional environments.
Genome-scale models (GEMs) of metabolism were constructed for 55 fully sequenced Escherichia coli and Shigella strains. The GEMs enable a systems approach to characterizing the pan and core metabolic capabilities of the E. coli species. The majority of pan metabolic content was found to consist of alternate catabolic pathways for unique nutrient sources. The GEMs were then used to systematically analyze growth capabilities in more than 650 different growth-supporting environments. The results show that unique strain-specific metabolic capabilities correspond to pathotypes and environmental niches. Twelve of the GEMs were used to predict growth on six differentiating nutrients, and the predictions were found to agree with 80% of experimental outcomes. Additionally, GEMs were used to predict strain-specific auxotrophies. Twelve of the strains modeled were predicted to be auxotrophic for vitamins niacin (vitamin B3), thiamin (vitamin B1), or folate (vitamin B9). Six of the strains modeled have lost biosynthetic pathways for essential amino acids methionine, tryptophan, or leucine. Genome-scale analysis of multiple strains of a species can thus be used to define the metabolic essence of a microbial species and delineate growth differences that shed light on the adaptation process to a particular microenvironment.


Effects of music intervention with nursing presence and recorded music on psycho-physiological indices of cancer patient caregivers.
To compare the effects of music intervention with nursing presence and recorded music on blood volume pulse amplitude, the low/high frequency ratio component of heart rate variability, depression, anxiety and sleep quality in cancer patient caregivers; to compare the participants evaluation of these two forms of musical intervention. Presence is one of the activities of caring. However, little is known about the effect of music intervention with nursing presence on psycho-physiological indices. Randomised crossover controlled trial. Thirty-four female participants were randomly assigned to a music intervention with nursing presence/recorded music sequence or recorded music/music intervention with nursing presence sequence. Each intervention lasted 30 minutes and was held at the participant's home. The music intervention with nursing presence consisted of an erhu and recorder performance. In the recorded music session, participants listened to prerecorded music for 30 minutes. Continuous measurements of blood volume pulse and low/high frequency ratio were taken throughout the procedure. Depression, anxiety and sleep quality were measured before and after each intervention. Both music intervention with nursing presence and recorded music interventions had beneficial effects on anxiety, depression and blood volume pulse amplitude. Significant differences between the two interventions were also observed for anxiety. Music intervention with nursing presence was more effective in lessening anxiety and on improving the ease of getting to sleep compared with recorded music (p < 0·05). All participants reported that they preferred music intervention with nursing presence to recorded music. Significant differences were found in music evaluation scores between the two interventions in terms of harmony and friendliness (p < 0·05). Both music interventions were beneficial, as measured on psycho-physiological indices. The music intervention with nursing presence provided a more friendly music experience to the listeners. The findings provide evidence for nurses that the therapeutic use of music and nursing presence as a research-based nursing intervention for the welfare of caregivers.


Ixodes scapularis does not harbor a stable midgut microbiome.
Hard ticks of the order Ixodidae serve as vectors for numerous human pathogens, including the causative agent of Lyme Disease Borrelia burgdorferi. Tick-associated microbes can influence pathogen colonization, offering the potential to inhibit disease transmission through engineering of the tick microbiota. Here, we investigate whether B. burgdorferi encounters abundant bacteria within the midgut of wild adult Ixodes scapularis, its primary vector. Through the use of controlled sequencing methods and confocal microscopy, we find that the majority of field-collected adult I. scapularis harbor limited internal microbial communities that are dominated by endosymbionts. A minority of I. scapularis ticks harbor abundant midgut bacteria and lack B. burgdorferi. We find that the lack of a stable resident midgut microbiota is not restricted to I. scapularis since extension of our studies to I. pacificus, Amblyomma maculatum, and Dermacentor spp showed similar patterns. Finally, bioinformatic examination of the B. burgdorferi genome revealed the absence of genes encoding known interbacterial interaction pathways, a feature unique to the Borrelia genus within the phylum Spirochaetes. Our results suggest that reduced selective pressure from limited microbial populations within ticks may have facilitated the evolutionary loss of genes encoding interbacterial competition pathways from Borrelia.


Evaluation of the etiology of ocular globe atrophy or loss.
This survey investigated the etiology of atrophy or loss of the ocular globe in patients assisted at the Maxillofacial Prosthetics Clinic of two Schools of Dentistry in São Paulo State, Brazil. A total of 238 patients were examined and their clinical files were reviewed. The etiology of eyeball atrophy/loss was assessed with respect to gender, age group, affected side and type ophthalmologic surgery performed. The greatest incidence of ocular globe loss was due to traumatic etiology (57.14%), followed by pathogenic (36.13%) and congenital (5.04%) etiologies. Comparing the genders, a predominance of male patients was observed (61.76%; p<0.01). The age group most frequently affected was between 21 and 40 years (42.01%; p<0.01). For all types of etiologies investigated in this study, enucleation was the most commonly used surgical procedure for removal of the ocular globe (66.38%; p<0.01). Loss of the left eye was predominantly seen (55.04%), even though no statistically significant difference was found between sides (p>0.01).


Essential elements of the capsid protein for self-assembly into empty virus-like particles of hepatitis E virus.
Hepatitis E virus (HEV) is a noncultivable virus that causes acute liver failure in humans. The virus's major capsid protein is encoded by an open reading frame 2 (ORF2) gene. When the recombinant protein consisting of amino acid (aa) residues 112 to 660 of ORF2 is expressed with a recombinant baculovirus, the protein self-assembles into virus-like particles (VLPs) (T.-C. Li, Y. Yamakawa, K. Suzuki, M. Tatsumi, M. A. Razak, T. Uchida, N. Takeda, and T. Miyamura, J. Virol. 71:7207-7213, 1997). VLPs can be found in the culture medium of infected Tn5 cells but not in that of Sf9 cells, and the major VLPs have lost the C-terminal 52 aa. To investigate the protein requirement for HEV VLP formation, we prepared 14 baculovirus recombinants to express the capsid proteins truncated at the N terminus, the C terminus, or both. The capsid protein consisting of aa residues 112 to 608 formed VLPs in Sf9 cells, suggesting that particle formation is dependent on the modification process of the ORF2 protein. In the present study, electron cryomicroscopy and image processing of VLPs produced in Sf9 and Tn5 cells indicated that they possess the same configurations and structures. Empty VLPs were found in both Tn5 and Sf9 cells infected with the recombinant containing an N-terminal truncation up to aa residue 125 and C-terminal to aa residue 601, demonstrating that the aa residues 126 to 601 are the essential elements required for the initiation of VLP assembly. The recombinant HEV VLPs are potential mucosal vaccine carrier vehicles for the presentation of foreign antigenic epitopes and may also serve as vectors for the delivery of genes to mucosal tissue for DNA vaccination and gene therapy. The results of the present study provide useful information for constructing recombinant HEV VLPs having novel functions.


Genetic variance components and heritability of multiallelic heterozygosity under inbreeding.
The maintenance of genetic diversity in fitness-related traits remains a central topic in evolutionary biology, for example, in the context of sexual selection for genetic benefits. Among the solutions that have been proposed is directional sexual selection for heterozygosity. The importance of such selection is highly debated. However, a critical evaluation requires knowledge of the heritability of heterozygosity, a quantity that is rarely estimated in this context, and often assumed to be zero. This is at least partly the result of the lack of a general framework that allows for its quantitative prediction in small and inbred populations, which are the focus of most empirical studies. Moreover, while current predictors are applicable only to biallelic loci, fitness-relevant loci are often multiallelic, as are the neutral markers typically used to estimate genome-wide heterozygosity. To this end, we first review previous, but little-known, work showing that under most circumstances, heterozygosity at biallelic loci and in the absence of inbreeding is heritable. We then derive the heritability of heterozygosity and the underlying variances for multiple alleles and any inbreeding level. We also show that heterozygosity at multiallelic loci can be highly heritable when allele frequencies are unequal, and that this heritability is reduced by inbreeding. Our quantitative genetic framework can provide new insights into the evolutionary dynamics of heterozygosity in inbred and outbred populations.


CD45 variant alleles: possibly increased frequency of a novel exon 4 CD45 polymorphism in HIV seropositive Ugandans.
The CD45 (leucocyte common) antigen is a haemopoietic cell specific tyrosine phosphatase essential for antigen receptor signalling in lymphocytes, and expression of different CD45 isoforms is associated with distinct functions. Here we describe a novel polymorphism in exon 4 (A54G) of the gene encoding CD45 (PTPRC) that results in an amino acid substitution of Thr-19 to Ala in exon 4. The 54G allele was identified in African Ugandan populations and was found with a suggestive but not statistically significant increase in frequency amongst HIV-seropositive Ugandans. This suggests that the 54G variant and CD45 splicing abnormalities might be associated with HIV infection.


Disaster response team FAST skills training with a portable ultrasound simulator compared to traditional training: pilot study.
Pre-hospital focused assessment with sonography in trauma (FAST) has been effectively used to improve patient care in multiple mass casualty events throughout the world. Although requisite FAST knowledge may now be learned remotely by disaster response team members, traditional live instructor and model hands-on FAST skills training remains logistically challenging. The objective of this pilot study was to compare the effectiveness of a novel portable ultrasound (US) simulator with traditional FAST skills training for a deployed mixed provider disaster response team. We randomized participants into one of three training groups stratified by provider role: Group A. Traditional Skills Training, Group B. US Simulator Skills Training, and Group C. Traditional Skills Training Plus US Simulator Skills Training. After skills training, we measured participants' FAST image acquisition and interpretation skills using a standardized direct observation tool (SDOT) with healthy models and review of FAST patient images. Pre- and post-course US and FAST knowledge were also assessed using a previously validated multiple-choice evaluation. We used the ANOVA procedure to determine the statistical significance of differences between the means of each group's skills scores. Paired sample t-tests were used to determine the statistical significance of pre- and post-course mean knowledge scores within groups. We enrolled 36 participants, 12 randomized to each training group. Randomization resulted in similar distribution of participants between training groups with respect to provider role, age, sex, and prior US training. For the FAST SDOT image acquisition and interpretation mean skills scores, there was no statistically significant difference between training groups. For US and FAST mean knowledge scores, there was a statistically significant improvement between pre- and post-course scores within each group, but again there was not a statistically significant difference between training groups. This pilot study of a deployed mixed-provider disaster response team suggests that a novel portable US simulator may provide equivalent skills training in comparison to traditional live instructor and model training. Further studies with a larger sample size and other measures of short- and long-term clinical performance are warranted.


Treatment of localized primary non-Hodgkin's lymphoma of bone in children: a Pediatric Oncology Group study.
The treatment of primary lymphoma of bone (PLB) in children has traditionally included radiotherapy to the primary site; more recently, it has included systemic chemotherapy. Because of concern about the untoward effects of treatment in a disease that is curable, we attempted to determine whether radiotherapy can be safely excluded from treatment. The results of three consecutive Pediatric Oncology Group (POG) studies were examined to determine the impact on outcome of radiotherapy as adjunctive treatment in children and adolescents receiving chemotherapy for early-stage primary lymphoma of bone. From 1983 to 1997, 31 patients with localized PLB were entered onto POG studies of early-stage non-Hodgkin's lymphoma (NHL). Between 1983 and 1986, seven patients were treated with 8 months of chemotherapy with irradiation (XRT) of the primary site. After 1986, patients were treated without XRT; four received 8 months of chemotherapy, and 20 received 9 weeks of chemotherapy. Primary sites were the femur (nine), tibia (eight), mandible (five), mastoid (one), maxilla (one), zygomatic arch (one), rib (one), clavicle (one), scapula (one), ulna (one), talus (one), and calcaneous (one). Histologic classification revealed 21 cases of large cell lymphoma, five cases of lymphoblastic lymphoma, two cases of small, noncleaved-cell lymphoma, and three cases of NHL that could not be classified further. One patient relapsed at a distant site 22 months after completion of therapy. There have been no deaths. Localized PLB is curable in most children and adolescents with a 9-week chemotherapy regimen of modest intensity, and radiotherapy is an unnecessary adjunct.


Temporal changes in cardiorespiratory fitness and risk of dementia incidence and mortality: a population-based prospective cohort study.
Cardiorespiratory fitness is associated with risk of dementia, but whether temporal changes in cardiorespiratory fitness influence the risk of dementia incidence and mortality is still unknown. We aimed to study whether change in estimated cardiorespiratory fitness over time is associated with change in risk of incident dementia, dementia-related mortality, time of onset dementia, and longevity after diagnosis in healthy men and women at baseline. We linked data from the prospective Nord-Trøndelag Health Study (HUNT) done in Nord-Trøndelag, Norway with dementia data from the Health and Memory Study and cause of death registries (n=30 375). Included participants were apparently healthy individuals for whom data were available on estimated cardiorespiratory fitness and important confounding factors. Datasets were matched to each participant through their 11-digit personal identification number. Cardiorespiratory fitness was estimated on two occasions 10 years apart, during HUNT1 (1984-86) and HUNT2 (1995-97). HUNT2 was used as the baseline for follow-up. Participants were classified into two sex-specific estimated cardiorespiratory fitness groups according to their age (10-year categories): unfit (least fit 20% of participants) and fit (most fit 80% of participants). To assess the association between change in estimated cardiorespiratory fitness and dementia, we used four categories of change: unfit at both HUNT1 and HUNT2, unfit at HUNT1 and fit at HUNT2, fit at HUNT1 and unfit at HUNT2, fit at both HUNT1 and HUNT2. Using Cox proportional hazard analyses, we estimated adjusted hazard ratios (AHR) for dementia incidence and mortality related to temporal changes in estimated cardiorespiratory fitness. During a median follow-up of 19·6 years for mortality, and 7·6 years for incidence, there were 814 dementia-related deaths, and 320 incident dementia cases. Compared with participants who were unfit at both assessments, participants who sustained high estimated cardiorespiratory fitness had a reduced risk of incident dementia (AHR 0·60, 95% CI 0·36-0·99) and a reduced risk of dementia mortality (0·56, 0·43-0·75). Participants who had an increased estimated cardiorespiratory fitness over time had a reduced risk of incident dementia (AHR 0·52, 95% CI 0·30-0·90) and dementia mortality (0·72, 0·52-0·99) when compared with those who remained unfit at both assessments. Each metabolic equivalent of task increase in estimated cardiorespiratory fitness was associated with a risk reduction of incident dementia (adjusted HR 0·84, 95% CI 0·75-0·93) and dementia mortality (0·90, 0·84-0·97). Participants who increased their estimated cardiorespiratory fitness over time gained 2·2 (95% CI 1·0-3·5) dementia-free years, and 2·7 (0·4-5·8) years of life when compared with those who remained unfit at both assessments. Change in estimated cardiorespiratory fitness is an independent risk factor for incidence dementia and dementia mortality. Maintaining or improving cardiorespiratory fitness over time may be a target to reduce risk of dementia incidence and mortality, delay onset, and increase longevity after diagnosis. Our data highlight the importance of assessing cardiorespiratory fitness in health risk assessment for people at risk of dementia. The KG Jebsen Foundation, the Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority, and the Norwegian University of Science and Technology.


CUTL1 is phosphorylated by protein kinase A, modulating its effects on cell proliferation and motility.
CUTL1, also known as CDP (CCAAT Displacement Protein), Cut, or Cux-1, is a homeodomain transcription factor known to play an essential role in development and cell cycle progression. Previously, we identified CUTL1 as modulator of cell motility and invasiveness. Here we report that protein kinase A (PKA), known to inhibit tumor progression in various tumor types, directly phosphorylates CUTL1 at serine 1215 in NIH3T3 fibroblasts. The PKA-induced phosphorylation results in decreased DNA binding affinity of CUTL1 and diminished CUTL1-mediated cell cycle progression and cell motility. Furthermore, the expression of several CUTL1 target genes involved in proliferation and migration, such as DNA polymerase A and DKK2, was modulated by PKA-induced phosphorylation. These data identify CUTL1 as a novel target of PKA through which this protein kinase can modulate tumor cell motility and tumor progression.


Non-contact photoacoustic imaging using a fiber based interferometer with optical amplification.
In photoacoustic imaging the ultrasonic signals are usually detected by contacting transducers. For some applications contact with the tissue should be avoided. As alternatives to contacting transducers interferometric means can be used to acquire photoacoustic signals remotely. In this paper we report on non-contact three and two dimensional photoacoustic imaging using an optical fiber-based Mach-Zehnder interferometer. A detection beam is transmitted through an optical fiber network onto the surface of the specimen. Back reflected light is collected and coupled into the same optical fiber. To achieve a high signal/noise ratio the reflected light is amplified by means of optical amplification with an erbium doped fiber amplifier before demodulation. After data acquisition the initial pressure distribution is reconstructed by a Fourier domain reconstruction algorithm. We present remote photoacoustic imaging of a tissue mimicking phantom and on chicken skin.


Administration of adrenomedullin into subfornical organ inhibits Na(+),K(+)-ATPase activity in single proximal renal tubule of rats.
The present study was designed to investigate the effect of administration of adrenomedullin (ADM) into subfornical organ (SFO) on renal tubular Na(+),K(+)-ATPase activity in rats. Rats under anesthesia were injected with ADM 0.1 mL (20 ng/mL) via an implanted cannula into SFO (n=6). Plasma ADM and serum endogenous digitalis-like factor (EDLF) levels were assayed with radioimmunoassay, and urine samples were collected via a canoula intubated in bladder. Urinary sodium concentration was assayed with flame spectrophotometry. Single proximal renal tubule segments were obtained by hand under stereomicroscope and its Na(+),K(+)-ATPase activity was measured by liquid scintillation counting. In addition, single proximal renal tubule segments from normal rats (n=6) were incubated with serum from animals administered with ADM into SFO, and then the Na(+),K(+)-ATPase activity was determined. The results showed that both urinary volume and sodium excretion amounted to the peak value at 30 min after ADM administration, and sustained a significant high level at 60 min (P<0.01). At 30 min after ADM administration, there was a significant increase in serum EDLF and a decrease in Na(+),K(+)-ATPase activity of proximal tubule (P<0.01, respectively), but not in plasma ADM level. Na(+),K(+)-ATPase activity was decreased significantly in single proximal renal tubule segments from normal rats incubated with serum from rats administered with ADM into SFO (P<0.01). These results suggest that the diuretic and natriuretic responses following administration of ADM into SFO are associated with the inhibition of renal tubule Na(+),K(+)-ATPase activity. The inhibition of renal tubule Na(+),K(+)-ATPase activity is related to the increase in the serum level of EDLF.


Kikuchi-fujimoto disease from eastern India.
Kikuchi's disease, a rare disorder which usually presents with fever painful lymphadenopathy, rash and arthritis, all of which are close mimickers of infective and immunological disorders. It is essentially a histopathological diagnosis and tests to rule out other connective tissue disorders or infective etiology must be undertaken. We present a series of two cases of kikuchi-fujimoto's disease presenting primarily with lymphadenopathy and fever in all cases. The first is a case of generalized lymphadenopathy and the second case of kikuchi's disease with SLE, a rare association. Lymph node excision biopsy and histopathology documented Kikuchi Fujimoto disease in above cases. All the cases improved on follow up and had no residual stigmata.


Meta-population structure in a coral reef fish demonstrated by genetic data on patterns of migration, extinction and re-colonisation.
Management strategies for coral reefs are dependant on information about the spatial population structure and connectivity of reef organisms. Genetic tools can reveal important information about population structure, however, this information is lacking for many reef species. We used a mitochondrial molecular marker to examine the population genetic structure and the potential for meta-population dynamics in a direct developing coral reef fish using 283 individuals from 15 reefs on the Great Barrier Reef, Australia. We employed a hierarchical sampling design to test genetic models of population structure at multiple geographical scales including among regions, among shelf position and reefs within regions. Predictions from island, isolation-by-distance and meta-population models, including the potential for asymmetric migration, local extinction and patterns of re-colonisation were examined. Acanthochromis polyacanthus displayed strong genetic structure among regions (PhiST = 0.81, P < 0.0001) that supported an equilibrium isolation-by-distance model (r = 0.77, P = 0.001). Significant structuring across the continental shelf was only evident in the northern region (PhiST = 0.31, P < 0.001) and no evidence of isolation-by-distance was found within any region. Pairwise PhiST values indicated overall strong but variable genetic structure (mean PhiST among reefs within regions = 0.28, 0.38, 0.41), and asymmetric migration rates among reefs with low genetic structure. Genetic differentiation among younger reefs was greater than among older reefs supporting a meta-population propagule-pool colonisation model. Variation in genetic diversities, demographic expansion and population growth estimates indicated more frequent genetic bottlenecks/founder effects and subsequent population expansion in the central and southern regions compared to the northern one. Our findings provide genetic evidence for meta-population dynamics in a direct developing coral reef fish and we reject the equilibrium island and isolation-by distance models at local spatial scales. Instead, strong non-equilibrium genetic structure appears to be generated by genetic bottlenecks/founder effects associated with population reductions/extinctions and asymmetric migration/(re)-colonisation of such populations. These meta-population dynamics varied across the geographical range examined with edge populations exhibiting lower genetic diversities and higher rates of population expansion than more central populations. Therefore, coral reef species may experience local population reductions/extinctions that promote overall meta-population genetic differentiation.


Microsurgery for cerebral arteriovenous malformations: postoperative outcomes and predictors of complications in 264 cases.
The authors conducted a study to assess the safety and efficacy of microsurgical resection of arteriovenous malformations (AVMs) and determine predictors of complications. A total of 264 patients with cerebral AVMs were treated with microsurgical resection between 1994 and 2010 at the Jefferson Hospital for Neuroscience. A review of patient data was performed, including initial hemorrhage, clinical presentation, Spetzler-Martin (SM) grade, treatment modalities, clinical outcomes, and obliteration rates. Univariate and multivariate analyses were used to determine predictors of operative complications. Of the 264 patients treated with microsurgery, 120 (45%) patients initially presented with hemorrhage. There were 27 SM Grade I lesions (10.2%), 101 Grade II lesions (38.3%), 96 Grade III lesions (36.4%), 31 Grade IV lesions (11.7%), and 9 Grade V lesions (3.4%). Among these patients, 102 (38.6%) had undergone prior endovascular embolization. In all patients, resection resulted in complete obliteration of the AVM. Complications occurred in 19 (7.2%) patients and resulted in permanent neurological deficits in 5 (1.9%). In multivariate analysis, predictors of complications were increasing AVM size (OR 3.2, 95% CI 1.5-6.6; p = 0.001), increasing number of embolizations (OR 1.6, 95% CI 1.1-2.2; p = 0.01), and unruptured AVMs (OR 2.7, 95% CI 1-7.2; p = 0.05). Microsurgical resection of AVMs is highly efficient and can be undertaken with low rates of morbidity at high-volume neurovascular centers. Unruptured and larger AVMs were associated with higher complication rates.


T3-Ti receptor triggering of T8+ suppressor T cells leads to unresponsiveness to interleukin-2.
T3-associated disulphide linked heterodimers (Tin) comprised of clonally unique alpha-chains of molecular weight (MW) 49,000-54,000 and beta chains of MW 43,000 have been identified as the antigen receptors on human cytotoxic effector and inducer T-lymphocytes. Crosslinking of Ti molecules by either the appropriate nominal antigen/MHC specificity or anti-clonotypic monoclonal antibody results in clonal expansion of such cells via induction of IL-2 receptor expression, endogenous IL-2 release and IL-2-IL-2 receptor interaction. To determine whether analogous antigen receptor molecules and autocrine growth mechanisms are utilized by suppressor T-cells, we produced an anti-clonotypic monoclonal antibody against a non-cytotoxic T8+ suppressor T-cell, T8AC6, which defines a T3-associated disulphide-linked heterodimer of similar molecular weight to the above clonotypes. We find that Te-Ti triggering of suppressor clones (T8AC6, T8AC7 or T8RW) does not result in IL-2 production or T-cell proliferation and in contrast to inducer clones, also leads to a transient IL-2 unresponsive state. We suggest that such T3-Ti receptor mediated autoregulation of suppressor T-cell growth is necessary in the facilitation of initial inducer T-cell activation following antigenic perturbation.