Premature ovarian insufficiency and neurological function.
Premature ovarian insufficiency (POI) involves loss of ovarian function before age 40. POI has been associated with neurological dysfunction and an increased risk of dementia, perhaps due to depletion in estrogen levels. The present review discusses the effects of POI caused by genetic disorder, natural premature menopause, surgical menopause, breast cancer treatment and gonadotropin-releasing hormone (GnRH) agonist treatment. Overall, data suggest an increased risk of neurological disorder where POI is due to premature menopause or induced from surgery. This increased risk appears to be most apparent on domains of global cognitive and verbal memory tests. Where POI is caused by genetic disorder, observed cognitive deficiencies may be more likely to have a genetic basis rather than being due to the effects of sex steroids on the brain. Findings related to loss of cognitive function after chemotherapy or GnRH treatments are mixed. There are also discrepant data related to use of hormone therapy after POI (particularly after surgical menopause). After surgery, hormone treatment appears to be most beneficial if initiated close to the average natural age of menopause.


Transcriptome analysis reveals unique metabolic features in the Cryptosporidium parvum Oocysts associated with environmental survival and stresses.
Cryptosporidium parvum is a globally distributed zoonotic parasite and an important opportunistic pathogen in immunocompromised patients. Little is known on the metabolic dynamics of the parasite, and study is hampered by the lack of molecular and genetic tools. Here we report the development of the first Agilent microarray for C. parvum (CpArray15K) that covers all predicted ORFs in the parasite genome. Global transcriptome analysis using CpArray15K coupled with real-time qRT-PCR uncovered a number of unique metabolic features in oocysts, the infectious and environmental stage of the parasite. Oocyst stage parasites were found to be highly active in protein synthesis, based on the high transcript levels of genes associated with ribosome biogenesis, transcription and translation. The proteasome and ubiquitin associated components were also highly active, implying that oocysts might employ protein degradation pathways to recycle amino acids in order to overcome the inability to synthesize amino acids de novo. Energy metabolism in oocysts was featured by the highest level of expression of lactate dehydrogenase (LDH) gene. We also studied parasite responses to UV-irradiation, and observed complex and dynamic regulations of gene expression. Notable changes included increased transcript levels of genes involved in DNA repair and intracellular trafficking. Among the stress-related genes, TCP-1 family members and some thioredoxin-associated genes appear to play more important roles in the recovery of UV-induced damages in the oocysts. Our observations also suggest that UV irradiation of oocysts results in increased activities in cytoskeletal rearrangement and intracellular membrane trafficking. CpArray15K is the first microarray chip developed for C. parvum, which provides the Cryptosporidium research community a needed tool to study the parasite transcriptome and functional genomics. CpArray15K has been successfully used in profiling the gene expressions in the parasite oocysts as well as their responses to UV-irradiation. These observations shed light on how the parasite oocysts might adapt and respond to the hostile external environment and associated stress such as UV irradiation.


Attached biofilms and suspended aggregates are distinct microbial lifestyles emanating from differing hydraulics.
Small-scale hydraulics affects microbial behaviour at the cell level1, trophic interactions in marine aggregates2 and the physical structure and function of stream biofilms3,4. However, it remains unclear how hydraulics, predictably changing from small streams to large rivers, impacts the structure and biodiversity of complex microbial communities in these ecosystems. Here, we present experimental evidence unveiling hydraulics as a hitherto poorly recognized control of microbial lifestyle differentiation in fluvial ecosystems. Exposing planktonic source communities from stream and floodplain ecosystems to different hydraulic environments revealed strong selective hydraulic pressures but only minor founder effects on the differentiation of attached biofilms and suspended aggregates and their biodiversity dynamics. Key taxa with a coherent phylogenetic underpinning drove this differentiation. Only a few resident and phylogenetically related taxa formed the backbone of biofilm communities, whereas numerous resident taxa characterized aggregate communities. Our findings unveil fundamental differences between biofilms and aggregates and build the basis for a mechanistic understanding of how hydraulics drives the distribution of microbial diversity along the fluvial continuum5-7.


Stromal-derived factor 1 signalling regulates radial and tangential migration in the developing cerebral cortex.
Stromal-derived factor 1 (SDF-1), a known chemoattractant, and its receptor CXCR4 are widely expressed in the developing and adult cerebral cortex. Recent studies have highlighted potential roles for SDF-1 during early cortical development. In view of the current findings, our histological analysis has revealed a distinct pattern of SDF-1 expression in the developing cerebral cortex at a time when cell proliferation and migration are at peak. To determine the role of chemokine signalling during early cortical development, embryonic rat brain slices were exposed to a medium containing secreted SDF-1 to perturb the endogenous levels of chemokine. Alternatively, brain slices were treated with 40 muM of T140 or AMD3100, known antagonists of CXCR4. Using these experimental approaches, we demonstrate that chemokine signalling is imperative for the maintenance of the early cortical plate. In addition, we provide evidence that both neurogenesis and radial migration are concomitantly regulated by this signalling system. Conversely, interneurons, although not dependent on SDF-1 signalling to transgress the telencephalic boundary, require the chemokine to maintain their tangential migration. Collectively, our results demonstrate that SDF-1 with its distinct pattern of expression is essential and uniquely positioned to regulate key developmental events that underlie the formation of the cerebral cortex.


Dorsally placed commercially available subpalpebral lavage systems have low complication rates in horses.
To retrospectively evaluate the complication rate following dorsal placement of a commercially available 1-hole subpalpebral lavage system (SPL) at a veterinary teaching hospital. 102 client-owned horses with ophthalmic disease. Medical records of horses (2010 to 2020) with ophthalmic disease were reviewed to determine whether a commercially available SPL system was dorsally placed. Data collected from the medical record included signalment, presenting complaint(s), diagnosis, ophthalmic procedures performed, SPL laterality, hospital service that placed the SPL, anesthetic technique for placement (general anesthesia or sedation with local nerve blocks), duration of SPL management while hospitalized or at home, type of enclosure for the horse, use of eye protection, duration of time the SPL was in place, location of SPL management (home vs hospital), types and numbers of medications administered, recorded complications, and outcome of the globe. Complications experienced during treatment were categorized as either ocular or nonocular. The χ2 test for independence test and Fisher exact test were performed to examine the relationship between the department that placed the SPL, method of anesthesia, antimicrobial administration, type of facial protection used, and complication type and rate. Overall complication rate for SPL systems was 29.1% (37/127), with 21.2% (27/127) being ocular complications and 7.9% (10/127) being nonocular complications. SPL complication rate was not affected by any variable that was examined. Commercially available SPL systems placed dorsally have a low ocular complication rate. These SPL systems may be placed by veterinarians with varied training backgrounds and managed at home without significantly increasing complication rate.


Mechanical Properties and Applications of Recycled Polycarbonate Particle Material Extrusion-Based Additive Manufacturing.
Past work has shown that particle material extrusion (fused particle fabrication (FPF)/fused granular fabrication (FGF)) has the potential for increasing the use of recycled polymers in 3D printing. This study extends this potential to high-performance (high-mechanical-strength and heat-resistant) polymers using polycarbonate (PC). Recycled PC regrind of approximately 25 mm2 was 3D printed with an open-source Gigabot X and analyzed. A temperature and nozzle velocity matrix was used to find useful printing parameters, and a print test was used to maximize the output for a two-temperature stage extruder for PC. ASTM type 4 tensile test geometries as well as ASTM-approved compression tests were used to determine the mechanical properties of PC and were compared with filament printing and the bulk virgin material. The results showed the tensile strength of parts manufactured from the recycled PC particles (64.9 MPa) were comparable to that of the commercial filament printed on desktop (62.2 MPa) and large-format (66.3 MPa) 3D printers. Three case study applications were investigated: (i) using PC as a rapid molding technology for lower melting point thermoplastics, (ii) printed parts for high temperature applications, and (iii) printed parts for high-strength applications. The results show that recycled PC particle-based 3D printing can produce high-strength and heat-resistant products at low costs.


Escherichia albertii sp. nov., a diarrhoeagenic species isolated from stool specimens of Bangladeshi children.
The taxonomic position of a group of five D-sorbitol- and lactose-negative enterobacterial isolates recovered from diarrhoeal stools of children at the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), was investigated by DNA-DNA hybridization, phenotypic characterization and 16S rDNA sequencing. These strains were originally identified as 'Hafnia alvei-like' with the API 20E system but, in fact, show more phenotypic and genotypic resemblance to members of the genus Escherichia. By 16S rDNA sequencing, one representative strain of the ICDDR,B group was shown to be closely affiliated to the genera Escherichia and Shigella. Using the fluorimetric microplate hybridization method, the diarrhoeagenic ICDDR,B isolates were found to constitute a homogeneous taxon (> or = 82% internal DNA relatedness), with the closest affiliation to the type strains of Escherichia coli (55-64%) and Shigella flexneri (54-60%). The DNA-DNA hybridization levels were much lower with members of other described Escherichia species (16-45%) and with the type strain of H. alvei (9-17%). The G + C content of the ICDDR,B strains ranged from 50.5 to 50.7 mol%. Together with the diagnostic characteristics reported previously, including the presence of the eaeA gene of enteropathogenic E. coli and of the E. coli and Shigella-specific phoE gene, it is concluded that the ICDDR,B strains represent a novel taxon in the genus Escherichia, for which the name Escherichia albertii sp. nov. is proposed. Its type strain is Albert 19982(T) (= LMG 20976(T) = CCUG 46494(T)).


Therapeutics and Immunoprophylaxis Against Noroviruses and Rotaviruses: The Past, Present, and Future.
Noroviruses and rotaviruses are important viral etiologies of severe gastroenteritis. Noroviruses are the primary cause of nonbacterial diarrheal outbreaks in humans, whilst rotaviruses are a major cause of childhood diarrhea. Although both enteric pathogens substantially impact human health and economies, there are no approved drugs against noroviruses and rotaviruses so far. On the other hand, whilst the currently licensed rotavirus vaccines have been successfully implemented in over 100 countries, the most advanced norovirus vaccine has recently completed phase-I and II trials. We performed a structured search of bibliographic databases for peer-reviewed research literature on advances in the fields of norovirus and rotavirus therapeutics and immunoprophylaxis. Technological advances coupled with a proper understanding of viral morphology and replication over the past decade has facilitated pioneering research on therapeutics and immunoprophylaxis against noroviruses and rotaviruses, with promising outcomes in human clinical trials of some of the drugs and vaccines. This review focuses on the various developments in the fields of norovirus and rotavirus therapeutics and immunoprophylaxis, such as potential antiviral drug molecules, passive immunotherapies (oral human immunoglobulins, egg yolk and bovine colostral antibodies, llama-derived nanobodies, and antibodies expressed in probiotics, plants, rice grains and insect larvae), immune system modulators, probiotics, phytochemicals and other biological substances such as bovine milk proteins, therapeutic nanoparticles, hydrogels and viscogens, conventional viral vaccines (live and inactivated whole virus vaccines), and genetically engineered viral vaccines (reassortant viral particles, virus-like particles (VLPs) and other subunit recombinant vaccines including multi-valent viral vaccines, edible plant vaccines, and encapsulated viral particles). This review provides important insights into the various approaches to therapeutics and immunoprophylaxis against noroviruses and rotaviruses.


The alpha-3 domain of class I MHC proteins influences cytotoxic T lymphocyte recognition of antigenic determinants located within the alpha-1 and alpha-2 domains.
An interspecies class I MHC molecule, Kb1+2/A2 (in which the alpha-1 and alpha-2 domains of the H-2Kb molecule have been linked to the alpha-3, transmembrane and intracytoplasmic domains of the HLA-A2 molecule) has been expressed on both human and mouse target cells by gene transfer. Maintenance of serologic determinants has been demonstrated. However, decreased lysis by allospecific CTL populations of cell lines that expressed a hybrid interspecies class I molecule, Kb1+2/A2, as compared with lines that expressed the native Ag, H-2Kb, has been described. An analysis with a limited panel of H-2Kb allospecific clones demonstrated that not all H-2Kb-specific CTL can lyse cells that express Kb1+2/A2 Ag. This suggested that the reduction of lysis by CTL populations was due to the loss of specific alloreactive clones in the population. Each clone used in this study was then defined as having high or low affinity characteristics. No correlation between the affinity of the CTL and the ability to recognize the interspecies hybrid molecule could be shown. Rather, these data suggest that antigenic determinants that are located within the polymorphic domains, alpha-1 and alpha-2, may be conformationally influenced by the alpha-3 domain.


Psychopathic Personality Traits Scale (PPTS): Construct Validity of the Instrument in a Sample of U.S. Prisoners.
The Psychopathic Personality Traits Scale (PPTS; Boduszek et al., 2016) is a personality-based psychopathy assessment tool consisting of four subscales: affective responsiveness, cognitive responsiveness, interpersonal manipulation, and egocentricity. Although the measure offers a promising alternative to other, more behaviorally weighted scales, to date the factor structure of the PPTS and differential predictive validity of its dimensions has only been tested in one study. Consequently, the objective of the present research was to assess construct validity, factor structure, and composite reliability of the PPTS within a sample of U.S. male and female incarcerated offenders (N = 772). Another goal was to test the predictive efficiency of the PPTS dimensions for different types of offences (serial killing, homicide, sex crimes, weapon-related crimes, domestic violence, white-collar crimes, property crimes, drug-related crimes), recidivism (i.e., number of incarcerations), time spent in prison, and gender. Dimensionality and construct validity of the PPTS was investigated using traditional CFA techniques, confirmatory bifactor analysis, and multitrait-multimethod modelling (MTMM). Seven alternative models of the PPTS were estimated in Mplus using WLSMV estimator. An MTMM model with four grouping factors (affective responsiveness, cognitive responsiveness, interpersonal manipulation, and egocentricity) while controlling for two method factors (knowledge/skills and attitudes/beliefs) offered the best representation of the data. Good composite reliability and differential predictive validity was reported. The PPTS can be reliably used among prisoners from the United States.


Application of Electric Cell-Substrate Impedance Sensing to Investigate the Cytotoxic Effects of Andrographolide on U-87 MG Glioblastoma Cell Migration and Apoptosis.
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. In recent studies, the efficacy of suberoylanilide hydroxamic acid (SAHA) has been investigated for GBM. We explored the effects of two exploratory compounds, the histone deacetylase SAHA and the natural product andrographolide, on Uppsala 87 Malignant Glioma (U-87 MG) cell migration and viability in comparison with the clinically used therapeutic agent temozolomide (TMZ). We used the electric cell-substrate impedance sensing (ECIS) system to monitor the migration of U-87 MG cells after treatment with various concentrations of these compounds. Moreover, we used the Alamar blue assay and western blotting to observe the concentration-dependent changes in the viability and apoptosis of U-87 MG cells. Our results demonstrated that both SAHA and andrographolide (10-300 μM) significantly inhibited GBM cell migration in a concentration-dependent manner, and 10 μM SAHA and 56 μM andrographolide demonstrated remarkable inhibitory effects on U-87 MG migration. Western blotting indicated that compared with TMZ, both SAHA and andrographolide induced higher expression levels of apoptosis-related proteins, such as caspase-3, BAX, and PARP in U-87 MG cells. Furthermore, all three drugs downregulated the expression of the antiapoptotic protein Bcl-2. In conclusion, SAHA and andrographolide showed exceptional results in inhibiting cell migration and motility. The ECIS wound healing assay is a powerful technique to identify and screen potential therapeutic agents that can inhibit cancer cell migration.


Beclin-1-Dependent Autophagy Protects the Heart During Sepsis.
Cardiac dysfunction is a major component of sepsis-induced multiorgan failure in critical care units. Changes in cardiac autophagy and its role during sepsis pathogenesis have not been clearly defined. Targeted autophagy-based therapeutic approaches for sepsis are not yet developed. Beclin-1-dependent autophagy in the heart during sepsis and the potential therapeutic benefit of targeting this pathway were investigated in a mouse model of lipopolysaccharide (LPS)-induced sepsis. LPS induced a dose-dependent increase in autophagy at low doses, followed by a decline that was in conjunction with mammalian target of rapamycin activation at high doses. Cardiac-specific overexpression of Beclin-1 promoted autophagy, suppressed mammalian target of rapamycin signaling, improved cardiac function, and alleviated inflammation and fibrosis after LPS challenge. Haplosufficiency for beclin 1 resulted in opposite effects. Beclin-1 also protected mitochondria, reduced the release of mitochondrial danger-associated molecular patterns, and promoted mitophagy via PTEN-induced putative kinase 1-Parkin but not adaptor proteins in response to LPS. Injection of a cell-permeable Tat-Beclin-1 peptide to activate autophagy improved cardiac function, attenuated inflammation, and rescued the phenotypes caused by beclin 1 deficiency in LPS-challenged mice. These results suggest that Beclin-1 protects the heart during sepsis and that the targeted induction of Beclin-1 signaling may have important therapeutic potential.


Culture of cryopreserved ovarian tissue: state of the art in 2008.
This paper reviews the most relevant literature from the past 10 years on different techniques for the culture of fresh and cryopreserved ovarian tissue from animals and humans. Information on strategies for culturing whole ovarian tissue and isolated follicles are provided as well as an updated and comprehensive view of the role that growth factors have in mediating and regulating in vitro folliculogenesis.


Mapping of catalytic residues in the RNA polymerase active center.
When the Mg2+ ion in the catalytic center of Escherichia coli RNA polymerase (RNAP) is replaced with Fe2+, hydroxyl radicals are generated. In the promoter complex, such radicals cleave template DNA near the transcription start site, whereas the beta' subunit is cleaved at a conserved motif NADFDGD (Asn-Ala-Asp-Phe-Asp-Gly-Asp). Substitution of the three aspartate residues with alanine creates a dominant lethal mutation. The mutant RNAP is catalytically inactive but can bind promoters and form an open complex. The mutant fails to support Fe2+-induced cleavage of DNA or protein. Thus, the NAD-FDGD motif is involved in chelation of the active center Mg2+.


The Treatment for Adolescents With Depression Study (TADS): long-term effectiveness and safety outcomes.
The Treatment for Adolescents With Depression Study evaluates the effectiveness of fluoxetine hydrochloride therapy, cognitive behavior therapy (CBT), and their combination in adolescents with major depressive disorder. To report effectiveness outcomes across 36 weeks of randomized treatment. Randomized, controlled trial conducted in 13 academic and community sites in the United States. Cognitive behavior and combination therapies were not masked, whereas administration of placebo and fluoxetine was double-blind through 12 weeks, after which treatments were unblinded. Patients assigned to placebo were treated openly after week 12, and the placebo group is not included in these analyses by design. Three hundred twenty-seven patients aged 12 to 17 years with a primary DSM-IV diagnosis of major depressive disorder. All treatments were administered per protocol. The primary dependent measures rated blind to treatment status by an independent evaluator were the Children's Depression Rating Scale-Revised total score and the response rate, defined as a Clinical Global Impressions-Improvement score of much or very much improved. Intention-to-treat analyses on the Children's Depression Rating Scale-Revised identified a significant time x treatment interaction (P < .001). Rates of response were 73% for combination therapy, 62% for fluoxetine therapy, and 48% for CBT at week 12; 85% for combination therapy, 69% for fluoxetine therapy, and 65% for CBT at week 18; and 86% for combination therapy, 81% for fluoxetine therapy, and 81% for CBT at week 36. Suicidal ideation decreased with treatment, but less so with fluoxetine therapy than with combination therapy or CBT. Suicidal events were more common in patients receiving fluoxetine therapy (14.7%) than combination therapy (8.4%) or CBT (6.3%). In adolescents with moderate to severe depression, treatment with fluoxetine alone or in combination with CBT accelerates the response. Adding CBT to medication enhances the safety of medication. Taking benefits and harms into account, combined treatment appears superior to either monotherapy as a treatment for major depression in adolescents.


Connexin 32 mutation in a Turkish family with X-linked Charcot-Marie-Tooth disease.
In the present work, we describe a large Turkish family (N=39) with Charcot-Marie-Tooth disease, which is the most commonly inherited peripheral neuropathy. The subjects were from four generations, including six hemizygote patients and nine heterozygote carrier females. Symptoms appeared in late childhood in males (mean age=13.5) but later in carrier females (mean age=33.5). The peripheral nerve conduction was more severely affected in males than females. Genomic DNA was isolated from peripheral white blood cells. Using SSCP technique (single strand conformation polymorphism analysis), abnormal patterns of migration were observed in 15 subjects: 6 of them were hemizygote males and 9 were heterozygote carrier females. We identified a mutation of the Cx32 gene, consisting of a guanine to adenine transition at position 271 (271G-A). The results suggested relations between degenerative processes and position of Cx32 mutations.


Using EQ-5D-3L and OAB-5D to assess changes in the health-related quality of life of men with lower urinary tract symptoms associated with benign prostatic hyperplasia.
To assess changes in the health status of men with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) using the EQ-5D-3L and OAB-5D instruments and to evaluate the sensitivity of the instruments. Data were available from a large randomised phase III trial of men with moderate-to-severe storage and voiding LUTS/BPH (NEPTUNE). Men received a fixed-dose combination of solifenacin 6 mg plus oral controlled absorption system (OCAS™) formulation of tamsulosin (TOCAS, 0.4 mg), TOCAS monotherapy or placebo and completed the EQ-5D-3L and OAB-5D at baseline and weeks 4, 8 and 12. Analysis of covariance was used to estimate changes in EQ-5D-3L Index, EQ-VAS and OAB-5D. Changes in dimension level were summarised using the Paretian Classification of Health Change (PCHC). Improved health-related quality of life from baseline was seen in all treatment arms on EQ-5D-3L and OAB-5D at week 12, although only OAB-5D showed statistically significant differences between active treatment and placebo, both on the index score and using the PCHC approach. Effect sizes in the active treatment groups were large (>0.8) on OAB-5D but small (≈0.2) on EQ-5D-3L. EQ-5D-3L showed a very high ceiling effect (45% of men reported full health at baseline) and a substantial proportion of these men reported improvements at week 12 in several dimensions of OAB-5D. A large ceiling effect on EQ-5D-3L substantially limited its sensitivity in this population. OAB-5D proved more sensitive to changes in health status and could be considered a complement to ED-5D-3L as a source of utilities for health economic modelling.


The control of reproductive physiology and behavior by gonadotropin-inhibitory hormone.
Gonadotropin-releasing hormone (GnRH) controls the reproductive physiology and behavior of vertebrates by stimulating synthesis and release of gonadotropin from the pituitary gland. In 2000, another hypothalamic neuropeptide, gonadotropin-inhibitory hormone (GnIH), was discovered in quail and found to be an inhibiting factor for gonadotropin release. GnIH homologs are present in the brains of vertebrates, including birds, mammals, amphibians, and fish. These peptides, categorized as RF amide-related peptides (RFRPs), possess a characteristic LPXRF-amide (X = L or Q) motif at their C-termini. GnIH/RFRP precursor mRNA encodes a polypeptide that is possibly cleaved into three mature peptides in birds and two in mammals. The names of these peptides are GnIH, GnIH-related peptide-1 (GnIH-RP-1) and GnIH-RP-2 in birds, and RFRP-1 and RFRP-3 in mammals. GnIH/RFRP is synthesized in neurons of the paraventricular nucleus of the hypothalamus in birds and the dorsomedial hypothalamic area in mammals. GnIH neurons project to the median eminence, thus providing a functional neuroanatomical infrastructure to regulate anterior pituitary function. In quail, GnIH inhibits gonadal activity by decreasing synthesis and release of gonadotropin. The widespread distribution of GnIH/RFRP immunoreactive fibers in all animals tested suggests various actions within the brain. In accordance, GnIH/RFRP receptor mRNA is also expressed widely in the brain and the pituitary. GnIH/RFRP immunoreactive axon terminals are in probable contact with GnRH neurons in birds and mammals, and we recently demonstrated expression of GnIH receptor mRNA in GnRH-I and GnRH-II neurons in European starlings. Thus, GnIH/RFRP may also inhibit gonadotropin synthesis and release by inhibiting GnRH neurons in addition to having direct actions on the pituitary gland. Intracerebroventricular administration of GnIH/RFRP further inhibits reproductive behaviors in songbirds and rodents, possibly via direct actions on the GnRH system. The expression of GnIH/RFRP is regulated by melatonin which is an internal indicator of day length in vertebrates. Stress stimuli also regulate the expression of GnIH/RFRP in songbirds and rodents. Accordingly, GnIH/RFRP may serve as a transducer of environmental information and social interactions into endogenous physiology and behavior of the animal. Recently, it was shown that GnIH/RFRP and its receptor are also expressed in the gonads of birds, rodents and primates. In sum, the existing data suggest that GnIH/RFRP is an important mediator of reproductive function acting at the level of the brain, pituitary, and the gonad in birds and mammals.


Unicompartmental knee arthroplasty in patients sixty years of age or younger.
Unicompartmental knee arthroplasty has been used to treat elderly, low-demand patients, but the literature is sparse regarding the use of this procedure for younger, active patients. The purpose of the present retrospective study was to evaluate the results of unicompartmental knee arthroplasty in younger, more active patients. Forty-one patients underwent forty-six consecutive unicompartmental knee arthroplasties with use of the Miller-Galante system between 1988 and 1996. All of the patients were sixty years of age or younger and all were physically active. The Hospital for Special Surgery knee score and the University of California at Los Angeles activity assessment were used to rate the function and to determine the activity level of each patient, respectively. Serial radiographs were used to evaluate the status of prosthetic fixation, femorotibial alignment, and the progression of arthrosis in the unreplaced compartment. Long-term survivorship was calculated with use of Kaplan-Meier analysis. The mean duration of follow-up was eleven years. Of the forty-five knees that were available for follow-up, three had been revised. The Hospital for Special Surgery score was excellent for thirty-nine (93%) of the remaining forty-two knees and good for three. The University of California at Los Angeles activity assessment score was 6.6 +/- 1.4 for the knees in which the original prosthesis had been retained and 7.3 +/- 1.5 for those in which it had been revised. Two asymptomatic patients had revision of a modular tibial component because of substantial radiographic evidence of polyethylene wear; one of these patients had exchange of the polyethylene insert and the tibial tray, and the other had exchange of the polyethylene insert only. A third patient underwent revision total knee arthroplasty because of continuing knee pain and a progressive tibial radiolucent line that was >2 mm in width. The average postoperative femorotibial alignment was 5 degrees of valgus. Nine knees had progression of arthritis in the unresurfaced compartment; none of these knees were revised, and none of the patients had deterioration in the Hospital for Special Surgery score. Kaplan-Meier analysis demonstrated an eleven-year survivorship of 92%. At an average duration of follow-up of eleven years, unicompartmental knee arthroplasty was associated with pain relief and excellent function in a cohort of patients who had been sixty years of age or younger and active at the time of surgery.


Imaging textural variation in the acoustoelastic coefficient of aluminum using surface acoustic waves.
Much interest has arisen in nonlinear acoustic techniques because of their reported sensitivity to variations in residual stress, fatigue life, and creep damage when compared to traditional linear ultrasonic techniques. However, there is also evidence that the nonlinear acoustic properties are also sensitive to material microstructure. As many industrially relevant materials have a polycrystalline structure, this could potentially complicate the monitoring of material processes when using nonlinear acoustics. Variations in the nonlinear acoustoelastic coefficient on the same length scale as the microstructure of a polycrystalline sample of aluminum are investigated in this paper. This is achieved by the development of a measurement protocol that allows imaging of the acoustoelastic response of a material across a samples surface at the same time as imaging the microstructure. The development, validation, and limitations of this technique are discussed. The nonlinear acoustic response is found to vary spatially by a large factor (>20) between different grains. A relationship is observed when the spatial variation of the acoustoelastic coefficient is compared to the variation in material microstructure.


Childhood cancer survival rates in two South African units.
Childhood cancer is relatively rare, but there is a very good chance of cure. While overall survival rates of >70% are reported from developed countries, survival is much less likely in developing countries and unknown in many countries in Africa. To analyse survival rates of childhood cancers in two South African paediatric oncology units. This retrospective review included all children (0 - 15 years) admitted with a malignancy at two paediatric oncology units (Universitas Hospital Academic Complex in Bloemfontein, Free State, and Tygerberg Hospital in Cape Town, Western Cape) between 1987 and 2011. The protocols used in the units were similar, and all the diagnoses were confirmed histologically. There were 3 241 children, 53.5% of whom were males. Median follow-up was 17 months. The most common cancers were leukaemia (25.0%), brain tumours (19.5%), lymphoma (13.0%) and nephroblastoma (10.0%). The prevalences of neuroblastoma and retinoblastoma were similar at 5.8% and 5.7%, respectively. Overall survival was calculated to be 52.1%. Lymphoma and nephroblastoma had the highest survival rates at 63.9% and 62.6%, respectively. Brain tumours had the lowest survival rate at 46.4%. A comparison between ethnic groups showed white children to have the highest survival rate (62.8%); the rate for children of mixed racial origin was 53.8% and that for black children 48.5%. Overall survival rates for children admitted to two paediatric cancer units in South Africa were lower than data published from developed countries, because many children presented with advanced disease. New strategies to improve cancer awareness are urgently required.


The concentration of three anti-seizure medications in hair: the effects of hair color, controlling for dose and age.
This paper assess the relationship between the quantity of three anti-seizure medications in hair and the color of the analyzed hair, while controlling for the effects of dose, dose duration, and patient age for 140 clinical patients undergoing anti-seizure therapy. Three drugs are assessed: carbamazepine (40 patients), valproic acid (40 patients), and phenytoin (60 patients). The relationship between hair assay results, hair color, dose, dose duration, and age is modeled using an analysis of covariance. The covariance model posits the hair assay results as the dependent variable, the hair color as the qualitative categorical independent variable, and dose, dose duration, and age as covariates. The null hypothesis assessed is that there is a no relationship between hair color and the quantity of analyte determined by hair assay such that darker colored hair will demonstrate higher concentrations of analyte than lighter colored hair. The analysis reveals that there is a significant relationship between dose and concentration for all hair color categories independent of the other covariates or the categorical independent variable. There does not appear to be any relationship between carbamazepine concentration and hair color. There is a weak relationship between hair color and valproic acid concentration, which the data suggest may be mediated by age. There is a significant, moderate relationship between phenytoin concentration and hair color such that darker colored hair has greater concentration values than lighter colored hair.


SigFuge: single gene clustering of RNA-seq reveals differential isoform usage among cancer samples.
High-throughput sequencing technologies, including RNA-seq, have made it possible to move beyond gene expression analysis to study transcriptional events including alternative splicing and gene fusions. Furthermore, recent studies in cancer have suggested the importance of identifying transcriptionally altered loci as biomarkers for improved prognosis and therapy. While many statistical methods have been proposed for identifying novel transcriptional events with RNA-seq, nearly all rely on contrasting known classes of samples, such as tumor and normal. Few tools exist for the unsupervised discovery of such events without class labels. In this paper, we present SigFuge for identifying genomic loci exhibiting differential transcription patterns across many RNA-seq samples. SigFuge combines clustering with hypothesis testing to identify genes exhibiting alternative splicing, or differences in isoform expression. We apply SigFuge to RNA-seq cohorts of 177 lung and 279 head and neck squamous cell carcinoma samples from the Cancer Genome Atlas, and identify several cases of differential isoform usage including CDKN2A, a tumor suppressor gene known to be inactivated in a majority of lung squamous cell tumors. By not restricting attention to known sample stratifications, SigFuge offers a novel approach to unsupervised screening of genetic loci across RNA-seq cohorts. SigFuge is available as an R package through Bioconductor.


Fractures during growth: potential role of a milk-free diet.
Dietary calcium deficiency may increase fracture risk. In girls, 29.4% of fracture cases and 11.8% of controls without fracture had a history of milk-free diet. The odds ratio (OR) for fracture with a milk-free diet in girls was 4.6, p < 0.01. In boys, 23% of cases and 19% of controls had a history of a milk-free diet; OR = 1.3, NS). A milk-free diet due to cow's milk allergy is associated with increased fracture risk in girls. An intake of calcium below the reference daily intake (RDI) of 800-1200 mg/day during growth is thought to increase fracture risk even though convincing evidence for this view is scarce. The paucity of evidence may be partly due to many trial participants being calcium replete. Children and adolescents with cow's milk allergy (CMA) avoid milk and have a calcium intake below the RDI. The aim of this study was to examine the association between consumption of a milk-free diet and fracture risk. In this case-control study conducted in Poland, 57 boys and 34 girls aged 2.5-20 years with fractures (cases) were randomly matched by age and sex with 171 boys and 102 girls without fractures (controls). Weight and height were examined using standard methods. Bone mineral density (BMD) and body composition were measured using dual-energy X-ray absorptiometry. Conditional logistic regression and Bayesian analyses were used to determine the proportion of the fracture risk attributable to a milk-free diet. In girls, 29.4% of cases and 11.8% of controls had a history of milk-free diet producing an odds ratio (OR) for fracture associated with a milk-free diet of 4.6 (95% confidence interval [CI]: 1.4-15.5, p < 0.01). In boys, 23% of cases and 19% of controls had a history of a milk-free diet; OR = 1.3 (95% CI: 0.6-2.7, NS). If the prevalence of CMA in the population is 5%, only 6.7% of the fractures occurring are attributable to CMA and the associated nutritional deficit. Cow's milk allergy is associated with increased fracture risk in girls. Whether this association is due to the illness, calcium deficit or a deficit in other milk nutrients is uncertain. These data suggest that the contribution of milk-free diet to fracture liability among children and adolescents is modest.


A para-nitrophenol phosphonate probe labels distinct serine hydrolases of Arabidopsis.
Activity-based protein profiling represents a powerful methodology to probe the activity state of enzymes under various physiological conditions. Here we present the development of a para-nitrophenol phosphonate activity-based probe with structural similarities to the potent agrochemical paraoxon. We demonstrate that this probes labels distinct serine hydrolases with the carboxylesterase CXE12 as the predominant target in Arabidopsis thaliana. The designed probe features a distinct labeling pattern and therefore represents a promising chemical tool to investigate physiological roles of selected serine hydrolases such as CXE12 in plant biology.


Compact Shape Morphing Tensegrity Robots Capable of Locomotion.
Robustness, compactness, and portability of tensegrity robots make them suitable candidates for locomotion on unknown terrains. Despite these advantages, challenges remain relating to ease of fabrication, shape morphing (packing-unpacking), and locomotion capabilities. The paper introduces a design methodology for fabricating tensegrity robots of varying morphologies with modular components. The design methodology utilizes perforated links, coplanar (2D) alignment of components and individual cable tensioning to achieve a 3D tensegrity structure. These techniques are utilized to fabricate prism (three-link) tensegrity structures, followed by tensegrity robots in icosahedron (six-link), and shpericon (curved two-link) formation. The methodology is used to explore different robot morphologies that attempt to minimize structural complexity (number of elements) while facilitating smooth locomotion (impact between robot and surface). Locomotion strategies for such robots involve altering the position of center-of-mass (referred to as internal mass shifting) to induce "tip-over." As an example, a sphericon formation comprising of two orthogonally placed circular arcs with conincident center illustrates smooth locomotion along a line (one degree of freedom). The design of curved links of tensegrity mechanisms facilitates continuous change of the point of contact (along the curve) that results from the tip-over. This contrasts to the sudden and piece-wise continuous change for the case of robots with traditional straight links which generate impulse reaction forces during locomotion. The two resulting robots-the Icosahedron and the Sphericon Tensegrity Robots-display shape morphing (packing-unpacking) capabilities and achieve locomotion through internal mass-shifting. The presented static equilibrium analysis of sphericon with mass is the first step in the direction of dynamic locomotion control of these curved link robots.


Adherence and acceptability in MTN 001: a randomized cross-over trial of daily oral and topical tenofovir for HIV prevention in women.
We compared adherence to and acceptability of daily topical and oral formulations of tenofovir (TFV) used as pre-exposure prophylaxis (PrEP) for HIV prevention among women in South Africa, Uganda and the United States. 144 sexually active, HIV-uninfected women participated in a cross-over study of three regimens: oral tablet, vaginal gel, or both. We tested for differences in adherence and evaluated product acceptability. Self-reported adherence for all regimens was high (94 %), but serum TFV concentrations indicated only 64 % of participants used tablets consistently. Most women in the U.S. (72 %) favored tablets over gel; while preferences varied at the African sites (42 % preferred gel and 40 % tablets). Findings indicate a role for oral and vaginal PrEP formulations and highlight the importance of integrating pharmacokinetics-based adherence assessment in future trials. Biomedical HIV prevention interventions should consider geographic and cultural experience with product formulations, partner involvement, and sexual health benefits that ultimately influence use.


Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.


Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response.
Astrocytes are the most abundant cell type in the human brain and are important regulators of several critical cellular functions, including synaptic transmission. Although astrocytes are known to play a central role in the etiology and pathophysiology of schizophrenia, little is known about their potential involvement in clinical response to the antipsychotic clozapine. Moreover, astrocytes display a remarkable degree of morphological diversity, but the potential contribution of astrocytic subtypes to disease biology and drug response has received little attention. Here, we used state-of-the-art human induced pluripotent stem cell (hiPSC) technology to derive a morphological subtype of astrocytes from healthy individuals and individuals with schizophrenia, including responders and nonresponders to clozapine. Using functional assays and transcriptional profiling, we identified a distinct gene expression signature highly specific to schizophrenia as shown by disease association analysis of more than 10 000 diseases. We further found reduced levels of both glutamate and the NMDA receptor coagonist d-serine in subtype astrocytes derived from schizophrenia patients, and that exposure to clozapine only rescued this deficiency in cells from clozapine responders, providing further evidence that d-serine in particular, and NMDA receptor-mediated glutamatergic neurotransmission in general, could play an important role in disease pathophysiology and clozapine action. Our study represents a first attempt to explore the potential contribution of astrocyte diversity to schizophrenia pathophysiology using a human cellular model. Our findings suggest that specialized subtypes of astrocytes could be important modulators of disease pathophysiology and clinical drug response, and warrant further investigations.


Comparison of optimised endovaginal vs external array coil T2-weighted and diffusion-weighted imaging techniques for detecting suspected early stage (IA/IB1) uterine cervical cancer.
To compare sensitivity and specificity of endovaginal versus external-array coil T2-W and T2-W + DWI for detecting and staging small cervical tumours. Optimised endovaginal and external array coil MRI at 3.0-T was done prospectively in 48 consecutive patients with stage Ia/Ib1 cervical cancer. Sensitivity/specificity for detecting tumour and parametrial extension against histopathology for a reading radiologist were determined on coronal T2-W and T2W + DW images. An independent radiologist also scored T2-W images without and with addition of DWI for the external-array and endovaginal coils on separate occasions >2 weeks apart. Cohen's kappa assessed inter- and intra-observer agreement. Median tumour volume in 19/38 cases positive on subsequent histology was 1.75 cm(3). Sensitivity, specificity, PPV, NPV were: reading radiologist 91.3 %, 89.5 %, 91.3 %, 89.5 %, respectively; independent radiologist T2-W 82.6 %, 73.7 %, 79.1 %, 77.8 % for endovaginal, 73.9 %, 89.5 %, 89.5 %, 73.9 % for external-array coil. Adding DWI improved sensitivity and specificity of endovaginal imaging (78.2 %, 89.5 %); adding DWI to external-array imaging improved specificity (94.7 %) but reduced sensitivity (66.7 %). Inter- and intra-observer agreement on T2-W + DWI was good (kappa = 0.67 and 0.62, respectively). Endovaginal coil T2-W MRI is more sensitive than external-array coil for detecting tumours <2 cm(3); adding DWI improves specificity of endovaginal imaging but reduces sensitivity of external-array imaging. • Endovaginal more accurate than external-array T2-W MRI for detecting small cervical cancers. • Addition of DWI improves sensitivity and specificity of endovaginal T2-W imaging. • Addition of DWI substantially reduces sensitivity of external-array T2-W imaging.


Hepatitis B small surface antigen particles are octahedral.
The infectious component of hepatitis B (HB) virus (HBV), the Dane particle, has a diameter of approximately 44 nm and consists of a double-layered capsid particle enclosing a circular, incomplete double-stranded DNA genome. The outer capsid layer is formed from the HB surface antigen (HBsAg) and lipid, whereas the inner layer is formed from the HB core Ag assembled into an icosahedral structure. During chronic infection HBsAg is expressed in large excess as noninfectious quasispherical particles and tubules with approximately 22-nm diameter. Here, we report cryo-EM reconstructions of spherical HBsAg particles at approximately 12-A resolution. We show that the particles possess different diameters and have separated them into two predominant populations, both of which have octahedral symmetry. Despite their differing diameters, the two forms of the particle have the same mass and are built through conformational switching of the same building block, a dimer of HBsAg. We propose that this conformational switching, combined with interactions with the underlying core, leads to the formation of HBV Dane particles of different sizes, dictated by the symmetry of the icosahedral core.


What determines gender inequalities in social capital in Ukraine?
Social capital is a social determinant of health that has an impact on equity and well-being. It may be unequally distributed among any population. The aims of this study are to investigate the distribution of different forms of social capital between men and women in Ukraine and analyse how potential gender inequalities in social capital might be explained and understood in the Ukrainian context. The national representative cross-sectional data from the European Social Survey (wave 6) was used with a sample of 1377 women and 797 men. Seven outcomes that represent cognitive and structural social capital were constructed i.e. institutional trust, generalised trust, reciprocity, safety, as well as bonding, bridging and linking forms. Multivariate logistic regression and post-regression Fairlies decompositions were used for the analyses. There are several findings that resulted from the analyses i), access to institutional trust, linking and bridging social capital is very limited; ii), the odds for almost all forms of social capital (besides safety) are lower for men; iii), feeling about income and age explain most of the gender differences and act positively, as well as offsetting the differences. Social capital is unequally distributed between different population groups. Some forms of social capital have a stronger buffering effect on women than on men in Ukraine. Reducing gender and income inequalities would probably influence the distribution of social capital within the society.


Evaluation by quantitative image analysis of anticancer drug activity on multicellular spheroids grown in 3D matrices.
Pharmacological evaluation of anticancer drugs using 3D in vitro models provides invaluable information for predicting in vivo activity. Artificial matrices are currently available that scale up and increase the power of such 3D models. The aim of the present study was to propose an efficient and robust imaging and analysis pipeline to assess with quantitative parameters the efficacy of a particular cytotoxic drug. HCT116 colorectal adenocarcinoma tumor cell multispheres were grown in a 3D physiological hyaluronic acid matrix. 3D microscopy was performed with structured illumination, whereas image processing and feature extraction were performed with custom analysis tools. This procedure makes it possible to automatically detect spheres in a large volume of matrix in 96-well plates. It was used to evaluate drug efficacy in HCT116 spheres treated with different concentrations of topotecan, a DNA topoisomerase inhibitor. Following automatic detection and quantification, changes in cluster size distribution with a topotecan concentration-dependent increase of small clusters according to drug cytotoxicity were observed. Quantitative image analysis is thus an effective means to evaluate and quantify the cytotoxic and cytostatic activities of anticancer drugs on 3D multicellular models grown in a physiological matrix.


Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial.
Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.


Rational design, synthesis, biophysical and antiproliferative evaluation of fluorenone derivatives with DNA G-quadruplex binding properties.
Molecular modeling studies carried out with experimental DNA models with the sequence d[AG(3)(T(2)AG(3))(3)] suggest that the introduction of a net positive charge onto the side chain of a series of fluorenone carboxamides can improve G-quadruplex binding. The terminal morpholino moiety was replaced with a novel N-methylmorpholinium cation starting from two 4-carboxamide compounds. A different substitution on the fluorenone ring was also investigated and submitted to the same quaternarization process. All compounds were analyzed for their DNA binding properties by competition dialysis methods. In vitro antiproliferative tests were carried out against two different tumor cell lines. Docking experiments were conducted by including all four known human repeat unit G-quadruplex DNA sequences (27 experimentally determined conformations) against the most active fluorenone derivatives. The results of theoretical, biophysical, and in vitro experiments indicate two novel derivatives as lead compounds for the development of a new generation of G-quadruplex ligands with greater potency and selectivity.


Use of Sports Supplements in Competitive Handball Players: Sex and Competitive Level Differences.
Sports supplements are commonly used by elite athletes with the main goal of enhancing sport performance. Supplements use might be substantially different depending on the sport discipline, sex, and competitive level. To date, data about prevalence and the most-commonly used supplements in handball are scarce. Thus, the aim of this investigation was to determine the patterns of supplements use by handball players of both sexes and with different competitive levels: One hundred and eighty-seven handball players (112 men and 75 women) of different competitive levels (106 professional and 81 amateur) completed a validated self-administered questionnaire about supplements use. Supplements were classified according to the categorization of the Australian Institute of Sport (AIS). Overall, 59.9% of the handball players (n = 112) declared the use of at least one supplement and there were no significant differences between men and women (58.9% vs. 61.3%, p = 0.762) nor between professional vs. amateur handball players (67.1% vs. 53.8%, p = 0.074). The most prevalent supplements were sports drinks (42.2%), followed by energy bars (35.3%) and caffeine-containing products (31.6%). However, a greater consumption of group A supplements (those with strong scientific evidence; p = 0.029) and group B supplements (those with emerging scientific support, p = 0.012) was observed in male compared to female handball players. Supplements categorized as medical supplements were more commonly consumed in professional vs. amateur players (0.48 ± 0.80 vs. 0.21 ± 0.44, supplements p < 0.006). Additionally, a higher consumption of group B supplements was observed in professional compared to amateur players (0.58 ± 0.88 vs. 0.33 ± 0.72 supplements, p = 0.015). Handball players revealed a moderate use of supplements while sex and competitive level slighted changed the pattern of supplements use. A high portion of handball players use supplements as fuel during exercise and reported the use of caffeine-containing supplements to enhance performance.


Stand up to action: The postural effect of moral dilemma decision-making and the moderating role of dual processes.
Previous studies have demonstrated the possibility that when people are in standing rather than sitting postures, they have a stronger cognitive control propensity, making them inclined to agree more to sacrificing one innocent person and saving more people. Furthermore, this postural effect can be moderated by dual processes. In three studies, participants read dilemma scenarios followed by a proposed behavior to sacrifice one innocent person and save five or more people. The participants in sitting or standing postures were asked whether the described action was morally acceptable (moral judgment) and whether they would perform the described action (moral action). The results demonstrated that participants were more approving of the behavioral proposal in the moral action perspective than in the moral judgment perspective across the three studies. The hypothesized postural effect was found in a field study (Study 1) and replicated in a preregistered replication study (Study 2), and was further supported in an experimental study (Study 3). Compared with those in sitting postures, participants in standing postures expressed higher approval of the behavioral proposal compared to their sitting counterparts. Furthermore, the postural effect was dismissed when participants made moral decisions with a dual task to increase cognitive load, and it was reversed when they made moral decisions after deliberate consideration of the behavioral proposal (Study 3). The present research supports and extends the dual-process morality theory by demonstrating that body posture can affect moral decision-making; it also offers novel evidence revealing the moderating role of dual process on embodiment effects. It enriches our knowledge that morality is evolutionarily embodied in postures and that the dual process can moderate embodiment effects.


Measuring strategies for learning regulation in medical education: scale reliability and dimensionality in a Swedish sample.
The degree of learners' self-regulated learning and dependence on external regulation influence learning processes in higher education. These regulation strategies are commonly measured by questionnaires developed in other settings than in which they are being used, thereby requiring renewed validation. The aim of this study was to psychometrically evaluate the learning regulation strategy scales from the Inventory of Learning Styles with Swedish medical students (N = 206). The regulation scales were evaluated regarding their reliability, scale dimensionality and interrelations. The primary evaluation focused on dimensionality and was performed with Mokken scale analysis. To assist future scale refinement, additional item analysis, such as item-to-scale correlations, was performed. Scale scores in the Swedish sample displayed good reliability in relation to published results: Cronbach's alpha: 0.82, 0.72, and 0.65 for self-regulation, external regulation and lack of regulation scales respectively. The dimensionalities in scales were adequate for self-regulation and its subscales, whereas external regulation and lack of regulation displayed less unidimensionality. The established theoretical scales were largely replicated in the exploratory analysis. The item analysis identified two items that contributed little to their respective scales. The results indicate that these scales have an adequate capacity for detecting the three theoretically proposed learning regulation strategies in the medical education sample. Further construct validity should be sought by interpreting scale scores in relation to specific learning activities. Using established scales for measuring students' regulation strategies enables a broad empirical base for increasing knowledge on regulation strategies in relation to different disciplinary settings and contributes to theoretical development.


Sequence analysis of PER-1 extended-spectrum beta-lactamase from Pseudomonas aeruginosa and comparison with class A beta-lactamases.
We have determined the nucleotide sequence (EMBL accession number, Z 21957) of the cloned chromosomal PER-1 extended-spectrum beta-lactamase gene from a Pseudomonas aeruginosa RNL-1 clinical isolate, blaPER-1 corresponds to a 924-bp open reading frame which encodes a polypeptide of 308 amino acids. This open reading frame is preceded by a -10 and a -35 region consistent with a putative P. aeruginosa promoter. Primer extension analysis of the PER-1 mRNA start revealed that this promoter was active in P. aeruginosa but not in Escherichia coli, in which PER-1 expression was driven by vector promoter sequences. N-terminal sequencing identified the PER-1 26-amino-acid leader peptide and enabled us to calculate the molecular mass (30.8 kDa) of the PER-1 mature form. Analysis of the percent GC content of blaPER-1 and of its 5' upstream sequences, as well as the codon usage for blaPER-1, indicated that blaPER-1 may have been inserted into P. aeruginosa genomic DNA from a nonpseudomonad bacterium. The PER-1 gene showed very low homology with other beta-lactamase genes at the DNA level. By using computer methods, assessment of the extent of identity between PER-1 and 10 beta-lactamase amino acid sequences indicated that PER-1 is a class A beta-lactamase. PER-1 shares around 27% amino acid identity with the sequenced extended-spectrum beta-lactamases of the TEM-SHV series and MEN-1 from Enterobacteriaceae species. The use of parsimony methods showed that PER-1 is not more closely related to gram-negative than to gram-positive bacterial class A beta-lactamases. Surprisingly, among class A beta-lactamases, PER-1 was most closely related to the recently reported CFXA from Bacteroides vulgatus, with which it shared 40% amino acid identity. This work indicates that non-Enterobacteriaceae species such as P. aeruginosa may possess class A extended-spectrum beta-lactamase genes possibly resulting from intergeneric DNA transfer.


The clinical spectrum of de novo donor-specific antibodies in pediatric renal transplant recipients.
The development of donor-specific HLA antibodies (DSA) is associated with worse renal allograft survival in adult patients. This study assessed the natural history of de novo DSA, and its impact on renal function in pediatric renal transplant recipients (RTR). HLA antibodies were measured prospectively using single-antigen-bead assays at 1, 3, 6 and 12 months posttransplant followed by 12-monthly intervals and during episodes of allograft dysfunction. Of 215 patients with HLA antibody monitoring, 75 (35%) developed DSA at median of 0.25 years posttransplant with a high prevalence of Class II (70%) and HLA-DQ (45%) DSA. DSA resolved in 35 (47%) patients and was associated with earlier detection (median, inter-quartile range 0.14, 0.09-0.33 vs. 0.84, 0.15-2.37 years) and lower mean fluorescence intensity (MFI) (2658, 1573-3819 vs. 7820, 5166-11 990). Overall, DSA positive patients had more rapid GFR decline with a 50% reduction in GFR at mean 5.3 (CI: 4.7-5.8) years versus 6.1 (5.7-6.4) years in DSA negative patients (p = 0.02). GFR decreased by a magnitude of 1 mL/min/1.73 m(2) per log10 increase in Class II DSA MFI (p < 0.01). Using Cox regression, independent factors predicting poorer renal allograft outcome were older age at transplant (hazard ratio 1.1, CI: 1.0-1.2 per year), tubulitis (1.5, 1.3-1.8) and microvasculature injury (2.9, 1.4-5.7). In conclusion, pediatric RTR with de novo DSA and microvasculature injury were at risk of allograft failure.


What is the price of prevention? New evidence from a field experiment.
How does increasing access to treatment affect the demand for preventive testing? In this paper we present results from a field experiment in Nigeria in which we offered cervical cancer screening to women at randomly chosen prices. To test our hypothesis, we also offered women a lottery where the payoff was a subsidy towards the cost of cervical cancer treatment (conditional upon a diagnosis of cervical cancer). We find that women randomly selected to receive the conditional cancer treatment subsidy were about 4 percentage points more likely to take up screening than those in the control group. We also show that reducing the price of screening by 10 cents increased take-up by about 1 percentage point. These results offer compelling evidence that the optimal set of subsidies to increase take-up of preventive testing in developing countries, must include subsidies towards treatment costs (in addition to price subsidies).


Clinical effectiveness of and attitudes and beliefs of health professionals towards the use of health technology in falls prevention among older adults.
To analyse the evidence on the effectiveness, usability and acceptability of health technology in falls detection and prevention among older adults. Five databases were searched from February 2004 to February 2014: PubMed, Medline, Embase, Cochrane and CINAHL, with reference lists reviewed and researchers contacted for additional articles. The interventions were health technology tools used for falls detection and prevention (e.g. computers, mobile phones, motion sensors). The outcomes were effectiveness of, and the attitudes of healthcare staff towards, health technology in preventing falls. Two review authors independently assessed full texts using modified versions of the Joanna Briggs Institute Critical Appraisal Checklists. Full-texts of 51 out of 7927 articles were examined and 17 articles accepted following appraisal using Joanna Briggs Institute modified criteria. These were divided into subheadings of health information technology tool with visual cues (n = 2), sensors (n = 4), Webcam (n = 1) and electronic medical records (n = 3). Three of the seven systematic reviews evaluated sensor technology alone, whereas the remainder examined multicomponent interventions. There is a lack of research into the efficacy of and staff attitudes towards health technology in falls detection and prevention. One study found nurses accepted a health information technology toolkit with visual cues, with a single randomized controlled trial demonstrating a reduction in falls rates. Most studies regarding sensor technology were of low quality and did not find reduced falls rates or number of falls-related injuries. There was also mixed response from healthcare staff and users regarding the use of sensors, with concerns about privacy and false alarms. Video camera surveillance effectively reduced falls rates and was well accepted by nursing staff. However, patients had concerns for their privacy. Electronic medical records have not so far demonstrated a reduction in falls, with ongoing staff concerns about their usability. Good-quality literature regarding the effectiveness and acceptability of health technology in falls detection and prevention is lacking. Further research into both these fields is vital prior to wider implementation of such tools in clinical practice.


Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice.
Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAG(ERT2cre∕+) mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction-mimicking pharmacological inhibition-strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target for the pharmacotherapy of schizophrenia. These results demonstrate how genetic pharmacotherapy can be implemented to test a CNS target in advance of the development of specific neuroactive inhibitors. We discuss further the advantages, limitations, and feasibility of the wider application of genetic pharmacotherapy for neuropsychiatric drug development.


Hypotensive effect of clonidine during sodium depletion in the rat.
Clonidine was nonhypotensive in conscious unrestrained rats maintained on a normal sodium intake. In contradistinction, clonidine caused a dose-related hypotension in conscious unrestrained rats subjected to sodium depletion via furosemide. The plasma renin activity of normal and sodium-depleted rats was reduced after the administration of clonidine (100 mug/kg, iv) by 22.8% and 34.4%, respectively. Intravenous infusion of an angiotensin II antagonist, 1-Sar-8-Ala-angiotensin II, caused a significant reduction of arterial blood pressure in sodium-depleted rats but not in normal rats. Similarly, bilateral nephrectomy reduced arterial blood pressure and completely abolished the hypotensive effect of clonidine in sodium-depleted rats. Subcutaneous administration of chlorisondamine caused a significantly greater reduction of arterial blood pressure in sodium-depleted rats than it did in normal rats. Treatment of normal and sodium-depleted rats with 6-hydroxydopamine reduced the arterial blood pressure of both groups to approximately 85 mm Hg and completely abolished the hypotensive effect of clonidine in the sodium-depleted rats. The data presented in this paper are consistent with the conclusion that clonidine acts at some site in the sympathetic nervous system of sodium-depleted rats to inhibit renal nerve activity with a resultant suppression of renin secretion and a reduction of the angiotensin II-maintained arterial blood pressure. A similar sequence of events occurring in normal rats would not result in hypotension because their arterial blood pressure is not maintained by angiotensin II.


Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease.
The conserved multifunctional protein Gle1 regulates gene expression at multiple steps: nuclear mRNA export, translation initiation, and translation termination. A GLE1 mutation (FinMajor) is causally linked to human lethal congenital contracture syndrome-1 (LCCS1); however, the resulting perturbations on Gle1 molecular function were unknown. FinMajor results in a proline-phenylalanine-glutamine peptide insertion within the uncharacterized Gle1 coiled-coil domain. Here, we find that Gle1 self-associates both in vitro and in living cells via the coiled-coil domain. Electron microscopy reveals that high-molecular-mass Gle1 oligomers form ?26 nm diameter disk-shaped particles. With the Gle1-FinMajor protein, these particles are malformed. Moreover, functional assays document a specific requirement for proper Gle1 oligomerization during mRNA export, but not for Gle1's roles in translation. These results identify a mechanistic step in Gle1's mRNA export function at nuclear pore complexes and directly implicate altered export in LCCS1 disease pathology.


Wide Critical Fluctuations of the Field-Induced Phase Transition in Graphite.
In the immediate vicinity of the critical temperature (T_{c}) of a phase transition, there are fluctuations of the order parameter that reside beyond the mean-field approximation. Such critical fluctuations usually occur in a very narrow temperature window in contrast to Gaussian fluctuations. Here, we report on a study of specific heat in graphite subject to a high magnetic field when all carriers are confined in the lowest Landau levels. The observation of a BCS-like specific heat jump in both temperature and field sweeps establishes that the phase transition discovered decades ago in graphite is of the second order. The jump is preceded by a steady field-induced enhancement of the electronic specific heat. A modest (20%) reduction in the amplitude of the magnetic field (from 33 to 27 T) leads to a threefold decrease of T_{c} and a drastic widening of the specific heat anomaly, which acquires a tail spreading to two times T_{c}. We argue that the steady departure from the mean-field BCS behavior is the consequence of an exceptionally large Ginzburg number in this dilute metal, which grows steadily as the field lowers. Our fit of the critical fluctuations indicates that they belong to the 3DXY universality class as in the case of the ^{4}He superfluid transition.


A nomogram for predicting the likelihood of lymph node metastasis in early gastric patients.
Early gastric cancer is defined as a lesion confined to the mucosa or submucosa, regardless of the size or lymph node metastasis. Treatment methods include endoscopic mucosal resection or endoscopic submucosal dissection, wedge resection, laparoscopically assisted gastrectomy and open gastrectomy. Lymph node metastasis is strong related with survival and recurrence. Therefore, the likelihood of lymph node metastasis is one of the most important factors when determining the most appropriate treatment. We retrospectively analyzed 597 patients who underwent D2 gastrectomy for early gastric cancer. The relationship between lymph node metastasis and clinicopathological features was analyzed. Using multivariate logistic regression analyses, we created a nomogram to predict the lymph node metastasis probability for early gastric cancer. Receiver operating characteristic analyses was performed to assess the predictive value of the model. In the present study, 58 (9.7%) early gastric cancer patients were histologically shown to have lymph node metastasis. The multivariate logistic regression analysis demonstrated that the age at diagnosis, differentiation status, the presence of ulcers, lymphovascular invasion and depth of invasion were independent risk factors for lymph node metastasis in early gastric cancer. Additionally, the tumor macroscopic type, size and histology type significantly correlated with these important independent factors. We constructed a predictive nomogram with these factors for lymph node metastasis in early gastric cancer patients, and the discrimination was good with the AUC of 0.860 (95% CI: 0.809-0.912). We developed an effective nomogram to predict the incidence of lymph node metastasis for early gastric cancer patients.


Rapid and Rigorous IL-17A Production by a Distinct Subpopulation of Effector Memory T Lymphocytes Constitutes a Novel Mechanism of Toxic Shock Syndrome Immunopathology.
Toxic shock syndrome (TSS) is caused by staphylococcal and streptococcal superantigens (SAgs) that provoke a swift hyperinflammatory response typified by a cytokine storm. The precipitous decline in the host's clinical status and the lack of targeted therapies for TSS emphasize the need to identify key players of the storm's initial wave. Using a humanized mouse model of TSS and human cells, we herein demonstrate that SAgs elicit in vitro and in vivo IL-17A responses within hours. SAg-triggered human IL-17A production was characterized by remarkably high mRNA stability for this cytokine. A distinct subpopulation of CD4+ effector memory T (TEM) cells that secrete IL-17A, but not IFN-γ, was responsible for early IL-17A production. We found mouse "TEM-17" cells to be enriched within the intestinal epithelium and among lamina propria lymphocytes. Furthermore, interfering with IL-17A receptor signaling in human PBMCs attenuated the expression of numerous inflammatory mediators implicated in the TSS-associated cytokine storm. IL-17A receptor blockade also abrogated the secondary effect of SAg-stimulated PBMCs on human dermal fibroblasts as judged by C/EBP δ expression. Finally, the early IL-17A response to SAgs was pathogenic because in vivo neutralization of IL-17A in humanized mice ameliorated hepatic and intestinal damage and reduced mortality. Together, our findings identify CD4+ TEM cells as a key effector of TSS and reveal a novel role for IL-17A in TSS immunopathogenesis. Our work thus elucidates a pathogenic, as opposed to protective, role for IL-17A during Gram-positive bacterial infections. Accordingly, the IL-17-IL-17R axis may provide an attractive target for the management of SAg-mediated illnesses.


Atrial fibrillation, not atrial cardiopathy, is associated with stroke: A single center retrospective study.
Atrial fibrillation (AF) increases the risk of thromboembolism. Atrial cardiopathy, defined as structural left atrial enlargement (LAE), has been proposed to be a unifying risk factor for stroke, with or without atrial fibrillation (AF). We sought to understand the relative importance of LAE and AF as risk factors for stroke. We performed a retrospective analysis of all patients who underwent echocardiography within the Henry Ford Health System between March and September 2016. Patients were categorized based on the degree of LAE (none, mild, moderate and severe). The diagnosis of prior stroke or AF was ascertained by the presence of these conditions in the electronic medical record (www.EPIC.com). Total of 8679 cases, 54% were female, 41% were African-American, and mean age was 65 ± 17 years. Fifteen percent had mild, 12% had moderate and 18% had severe LAE; the frequency of AF was 22%; and prior stroke was 18%. In multivariate analysis, the odds of AF increased progressively with severity of LAE (adjusted OR for mild 1.81, moderate 2.13 and severe 4.38, all P < .001) and AF was confirmed as a risk factor for prior stroke (aOR 1.34, CI 1.15-1.56, p < .001). By contrast, there was no association between LAE and stroke (aOR 0.98 CI 0.86-1.12, p = .74), regardless of the severity of LAE, and regardless of whether AF was present or not. Structural LAE, found in almost half of this population, has a significant association with AF. While AF was confirmed to have a significant association with prior stroke, we found no association between stroke and LAE. AF, not LAE, appears to be the true atrial factor associated with stroke.


Buyer beware? Does the information provided with herbal products available over the counter enable safe use?
Herbal products obtained over the counter are commonly used in Europe, North America and Australia. Although there is concern about a lack of information provided to consumers to allow the safe use of these products, there has been no published research to confirm these fears. In this study, we evaluated written information provided with commonly used herbal products in the UK in advance of a European Union Directive issued in April 2011 that tightened regulations for some herbal products, including requirements to provide safety information. Five commonly used herbal products were purchased from pharmacies, health food shops and supermarkets: St John's wort, Asian ginseng, echinacea, garlic and ginkgo. Written information provided with the products (on the package or on a leaflet contained in the package) was evaluated for inclusion of each of the key safety messages included in the monographs of the US National Center for Complementary and Alternative Medicine. Specifically, we looked for information on precautions (such as Asian ginseng not being suitable for people with diabetes), interactions with conventional medicines (such as St John's wort with the contraceptive pill and warfarin) and side effects (such as ginkgo and allergic reactions). Our analysis showed that, overall, 51 (75%) of 68 products contained none of the key safety messages. This included 4 of 12 St John's wort products, 12 of 12 ginkgo products, 6 of 7 Asian ginseng products, 20 of 21 garlic products and 9 of 13 echinacea products. The two products purchased that are registered under the new European Union regulations (for St John's wort) contained at least 85% of the safety messages. Most of the herbal medicine products studied did not provide key safety information which consumers need for their safe use. The new European Union legislation should ensure that St John's wort and echinacea products will include the previously missing information in due course. The legislation does not apply to existing stock. Depending on therapeutic claims made by manufacturers, garlic, ginkgo and Asian ginseng products may not be covered by the legislation and can continue to be bought without the safety information. Also, consumers will still be able to buy products over the internet from locations outside European Union jurisdiction. Potential purchasers need to know, in both the short term and the long term, how to purchase herbal products which provide the information they need for the safe use of these products.


Innate immune activation enhances hiv acquisition in women, diminishing the effectiveness of tenofovir microbicide gel.
The antiretroviral agent, tenofovir, formulated as a vaginal microbicide gel, reduces human immunodeficiency virus (HIV) acquisition by 39% in women. This study assessed the role of preexisting immune activation in HIV acquisition in women from the CAPRISA 004 trial, to identify potential strategies to increase the effectiveness of tenofovir gel. Systemic cytokine and cellular immune mediators (platelets and natural killer [NK] cells) were assessed in women at high risk for HIV assigned to either tenofovir or placebo gel in the CAPRISA 004 trial. Notwithstanding tenofovir gel use, women who acquired HIV had significantly higher systemic innate immune activation prior to infection than women who remained uninfected. Activation of both soluble (cytokine) and cellular (NK cells) immune mediators were associated with HIV acquisition, individually or in combination. Hence, an innate immune activation suppressant could be added to tenofovir gel as a potential combination gel strategy in developing the next generation of higher efficacy antiretroviral microbicides.


MI TKA: a risk factor for early revision surgery.
Minimal incision total knee arthroplasty (MI TKA) was developed with the potential to decrease surgical trauma, pain, and recovery time. While this procedure has increased in popularity, some surgeons have questioned its safety and long-term efficacy. In this study 58 consecutive revision total knee arthroplasties (TKAs) (57 patients) performed at one academic medical center from 2006 to 2008 are reviewed. Prospectively collected clinical and radiographic data included: incision length, gender, age, time to revision surgery, and primary diagnosis at time of revision. Of these, 34 knees involving infection and rerevision were excluded. Of the remaining 24 knees, 11 knees that met inclusion criteria had undergone MI TKA. There were no differences between the groups with regard to age, diagnosis, body mass index, and gender. Average time to revision was shorter for the MI TKA patients (29 vs. 65 months, p < 0.032, odds ratio 14.7). Reasons for revision were aseptic loosening (55%), pain/stiffness (27%), malrotation (9%), and instability (9%) in the MI TKA group and aseptic loosening (53%), instability (15%), pain/stiffness (8%), malrotation (8%), combined malrotation and instability (8%), and polyethylene wear/osteolysis (8%) in the traditional TKA group. These data suggest that MI TKA may be a risk factor for early revision.


Structural Development of Human Fetal and Preterm Brain Cortical Plate Based on Population-Averaged Templates.
We hypothesized that the distinct maturational processes take place across different cortical areas from middle fetal stage to normal time of birth and these maturational processes are altered in late third trimester. Fractional anisotropies (FA) from diffusion tensor imaging (DTI) infer the microstructures of the early developing cortical plate. High-resolution DTI of 11 fetal brain specimens at postmenstrual age of 20 weeks (or simplified as 20 weeks), 19 in vivo brains at 35 weeks, and 17 in vivo brains at normal time of birth at term (40 weeks) were acquired. Population-averaged age-specific DTI templates were established with large deformation diffeomorphic metric mapping for subject groups at 20, 35, and 40 weeks. To alleviate partial volume effects, skeletonized FA values were used for mapping averaged cortical FA to the cortical surface and measuring FA at 12 functionally distinctive cortical regions. Significant and heterogeneous FA decreases take place in distinct cortical areas from 20 to 35 weeks and from 35 to 40 weeks, suggesting differentiated cortical development patterns. Temporally nonuniform FA decrease patterns during 35-40 weeks compared with those during 20-35 weeks were observed in higher-order association cortex. Measured skeletonized FA suggested dissociated changes between cerebral cortex and white matter during 35-40 weeks.


Pediatric orthopedic injuries following an earthquake: experience in an acute-phase field hospital.
Following the 2010 earthquake in Haiti, the Israel Defense Forces Medical Corps deployed a field hospital in Port au Prince. The purpose of this study was to characterize the injuries sustained by the pediatric population treated in the hospital and examine the implications for planning deployment in future similar disasters. Medical records of children treated in the hospital were reviewed and compared with medical records of the adult population. A total of 1,111 patients were treated in the hospital. Thirty-seven percent were aged 0 to 18 years. Earthquake-related injuries were the cause of admission in 47% of children and 66% of adults. Forty-seven percent of children with traumatic injuries sustained fractures. Seventy-two percent were in the lower limbs, 19% were in the upper limbs, and 9% were in the axial skeleton, with the femur being the most common long bone fractured compared with the tibia in adults.There were four functional operating theaters, and treatment guidelines were adjusted to the rapidly changing situation. Soft tissue injuries were treated by aggressive debridement. Fractures were stabilized by external fixation or casting. Amputation was performed only for nonviable limbs or life-threatening sepsis. Children were more likely than adults to undergo surgery (44% vs. 29% of trauma patients). To maximize hospital surge capacity, minor procedures were performed in the wards under sedation, and patients were discharged after an average of 1.4 days, with subsequent follow-up in the clinic. Children constitute a high percentage of patients in a developing country. The epidemiology of pediatric injuries following an earthquake differs significantly from that encountered in everyday practice and compared with that in adults. Children sustain a significantly higher percentage of femoral fractures and are more likely to require surgery. The shift to nontraumatic reasons for admission occurred earlier in the pediatric population than in adults. Organizations providing post-earthquake relief are usually geared toward adult populations and will require supplementation of both manpower and equipment specifically suited for treatment of pediatric patients. Early deployment teams should be adequately staffed with adult and pediatric orthopedists. Epidemiologic study, level IV.


Neonatal bacteriuria: a prospective study in 1,460 infants.
In a prospective study of 1,460 virtually consecutive neonates 14 (1%) were found to have bacteriuria, established by bladder puncture. Eleven were boys and three girls. Five of the infants with bacteriuria had symptoms suggestive of infection and were treated with antibiotics. The remaining nine were asymptomatic and remained so during a period of observation-five cleared their urine of bacteria without treatment, and four received antibiotics. Only one infant with bacteriuria had bacteraemia. Six infants had more than 10 white blood cells per mm(3) in the bladder puncture urine and three had proteinuria. The blood urea was slightly raised in only two of the infants. The intravenous pyelogram was normal in all infants with bacteriuria but eight had slight or moderate vesicoureteric reflux when examined by micturating cystourethrography.


Attenuation of NF-κB in Intestinal Epithelial Cells Is Sufficient to Mitigate the Bone Loss Comorbidity of Experimental Mouse Colitis.
Skeletal abnormalities are common comorbidities of inflammatory bowel disease (IBD). Patients suffering from IBD, including ulcerative colitis and Crohn's disease, present with skeletal complications. However, the mechanism underpinning IBD-associated bone loss remains vague. Intestinal inflammation generates an inflammatory milieu at the intestinal epithelium that leads to dysregulation of mucosal immunity through gut-residing innate lymphoid cells (ILCs) and other cell types. ILCs are recently identified mucosal cells considered as the gatekeeper of gut immunity and their function is regulated by intestinal epithelial cell (IEC)-secreted cytokines in response to the inflammatory microenvironment. We first demonstrate that serum as well as IECs collected from the intestine of dextran sulfate sodium (DSS)-induced colitis mice contain high levels of inflammatory and osteoclastogenic cytokines. Mechanistically, heightened inflammatory response of IECs was associated with significant intrinsic activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in IECs and increased frequency of ILC1, ILC3, and myeloid osteoclast progenitors. Validating the central role of IEC-specific NF-κB activation in this phenomenon, conditional expression of constitutively active inhibitor kappa B kinase 2 (IKK2) in IECs in mice recapitulates the majority of the cellular, inflammatory, and osteolytic phenotypes observed in the chemically induced colitis. Furthermore, conditional deletion of IKK2 from IECs significantly attenuated inflammation and bone loss in DSS-induced colitis. Finally, using the DSS-induced colitis model, pharmacologic inhibition of IKK2 was effective in reducing frequency of ILC1 and ILC3 cells, attenuated circulating levels of inflammatory cytokines, and halted colitis-associated bone loss. Our findings identify IKK2 in IECs as viable therapeutic target for colitis-associated osteopenia.


Repeated access to sucrose augments dopamine turnover in the nucleus accumbens.
Dopamine in the nucleus accumbens has been implicated in motivated behavior, including feeding. Normal feeding occurs in patterns, but little is known about how these schedules influence this neural system. We hypothesized that repeated access to preferred foods would augment dopamine clearance. Rats on a restricted feeding schedule had access to 0.3 M sucrose or water followed 2 h later by chow. The rats were kept on this regimen for 7 days, with microdialysis performed on the last day. During the chow period, dopamine turnover in the nucleus accumbens was higher when preceded by sucrose than by water. This finding suggests that, under some dietary conditions, neuroadaptation occurs in response to feeding and these changes may, in turn, influence future meals.


QuantiFERON conversion following tuberculin administration is common in HIV infection and relates to baseline response.
HIV-1 infection impairs tuberculosis (TB) specific immune responses affecting the diagnosis of latent TB. We aimed to (1) determine the proportion of HIV-1-infected adults with a negative QuantiFERON®-TB Gold in-tube (QFT-GIT) and Tuberculin skin testing (TST) that convert to QFT-GIT positive following TST, and (2) evaluate the relationship between conversion and baseline QFT-GIT results. HIV-1 infected adults being screened for a TB vaccine study in South Africa underwent QFT-GIT followed by TST. As per protocol, QFT-GIT was repeated if randomization was delayed allowing for evaluation of TST boosting in a proportion of participants. Of the 22 HIV-1 infected, TST and QFT-GIT negative adults (median CD4 477/mm3 IQR 439-621) who had QFT-GIT repeated after median 62 days (IQR 49-70), 40.9 % (95 % CI 18.6-63.2 %) converted. Converters had a significantly greater increase in the background subtracted TB antigen response (TBAg-Nil - all units IU/mL) following TST, 0.82 (IQR 0.39-1.28) vs 0.03 (IQR -0.05-0.06), p = 0.0001. Those who converted also had a significantly higher baseline TBAg-Nil 0.21(IQR 0.17-0.26) vs 0.02(IQR 0.01-0.07), p = 0.002. Converters did not differ with regard to CD4 count or ART status. ROC analysis showed a baseline cut off of 0.15 correctly classified 86.4 % of converters with 88.9 % sensitivity. Our findings support the possibility that there are 2 distinct groups in an HIV-1 infected population with negative QFT-GIT and TST; a true negative group and a group showing evidence of a weak Mtb specific immune response that boosts significantly following TST resulting in conversion of the test result that may represent false negatives. Further evaluation of whether a lower cut off may improve sensitivity of QFT-GIT in this population is warranted.


Ulcerative colitis and pregnancy.
A survey has been made of pregnancy occurring in patients who were attending the Ulcerative Colitis Clinic at Oxford during the 20-year period, 1960-79 inclusive. There were 256 married women of child-bearing age who attended during this period. Of these, 100 were excluded from the survey for various reasons, such as that they had completed their family before the onset of the ulcerative colitis, had already had an hysterectomy, or had a proctocolectomy before their first pregnancy. Of the remaining 156 patients, nine could not be traced. Full details were obtained from 147 patients, virtually all of whom were interviewed. The fertility of these patients was normal. Of the 147 women, 119 (81%) had conceived and only 10 (6.8%) were involuntarily infertile. The size of family approximated to that found in the general British population. The overall outcome of the pregnancies was similar to that in the general British population. The patients in whom the disease was quiescent at the start of pregnancy fared particularly well. Those with active disease had a somewhat lower chance of producing a normal live baby. The small group of patients in whom the disease was severe had a much lower chance of a normal outcome. Patients in whom the ulcerative colitis was quiescent at the beginning of pregnancy had a good chance of remaining symptom-free throughout the pregnancy and puerperium. Even if the colitis recurred, it was likely to be mild and responsive to medical treatment. By contrast, when the ulcerative colitis was active at the start of pregnancy, most patients continued to have symptoms in spite of medical treatment. Some patients had their first attack of ulcerative colitis during pregnancy or the puerperium. In contrast to previous experience the attacks were generally mild and responded to medical treatment. Medical treatment with corticosteroids or sulphasalazine appeared to have no obvious deleterious effects on the fetus or new-born child.