Thalamic activation in the Kleine-Levin syndrome.
The objective of this study was to investigate if combined measures of activation in the thalamus and working memory capacity could guide the diagnosis of Kleine-Levin Syndrome (KLS). A second objective was to obtain more insight into the neurobiological causes of KLS. Matched group and consecutive recruitment. University hospital neurology department and imaging center. Eighteen patients with KLS diagnosed according to the International Classification of Sleep Disorders and 26 healthy controls were included. N/A. Working memory capacity was assessed by the listening span task. A version of this task (reading span) was presented to the participants during functional magnetic resonance imaging (fMRI). Activation in the thalamus was measured in a region of interest analysis. A combination of the working memory capacity and the thalamic activation measures resulted in 80% prediction accuracy, 81% sensitivity, and 78% specificity regarding the ability to separate KLS patients from healthy controls. The controls had an inverse relation between working memory capacity and thalamic activation; higher performing participants had lower thalamic activation (r = -0.41). KLS patients showed the opposite relationship; higher performing participants had a tendency to higher thalamic activation (r = -0.35). This study shows that functional neuroimaging of the thalamus combined with neuropsychological assessment of working memory function provides a means to guide diagnosis of Kleine-Levin Syndrome. Results in this study also indicate that imaging of brain function and evaluation of cognitive capacity can give insights into the neurobiological mechanisms of Kleine-Levin Syndrome.


Risk factors for HCV acquisition among HIV-positive MSM in Belgium.
To better understand risk factors for the sexual transmission of hepatitis C viral (HCV) infection among men who have sex with men (MSM). Case-control study among HIV-infected MSM, attending AIDS Reference Centers in Belgium. Cases were HIV-infected MSM who were diagnosed with HCV between January 2010 and December 2013. For each case, 2 controls were randomly selected among the HIV-positive MSM who tested negative for HCV around the same time as the cases were identified. Consenting participants were interviewed with a questionnaire on risk factors. Medical records were abstracted to document past episodes of sexually transmitted infections (STIs). Associations between HCV infection and risk factors were explored using bivariate analysis followed by multiple logistic regression analysis. A total of 52 cases and 90 controls were recruited. In multivariate analysis, douching before anal intercourse [adjusted odds ratio (AOR) = 9.84, 95% CI: 2.26 to 42.78], fisting (AOR = 3.54, 95% CI: 1.31 to 9.57), having intercourse with HIV-positive men (AOR = 5.51, 95% CI: 1.87 to 16.20), and a documented gonorrhoea or chlamydial infection in the year before inclusion in the study (AOR = 4.50, 95% CI: 1.11 to 18.31) were independently associated with incident HCV infection. Our study confirmed fisting and suffering from other STIs as risk factors for HCV and suggested an increased risk of HCV associated with serosorting. Furthermore, we identified anal douching as being associated with HCV infection. The role that douching plays in the acquisition of HCV infection and other STIs requires further research, as well as the effect of serosorting on STI transmission.


Opioid Misuse among Smokers with Chronic Pain: Relations with Substance Use and Mental Health.
Opioid misuse is a significant public health concern with substantial medical, social, and economic costs. Cross cutting the personal and societal effects of this current crisis, opioid misuse is associated with poorer physical and mental health outcomes that impair function across numerous life domains. Importantly, opioid misuse disproportionately affects persons with chronic pain and individuals who smoke tobacco. Despite the higher risk for smokers with chronic pain to engage in opioid misuse, little work has examined how opioid misuse may be related to mental health problems, including other substance use, among this vulnerable group. The current study examined opioid misuse as a predictor of substance use and mental health problems among 187 (Mage = 39.02, SD = 9.94, 74.9% female) daily cigarette smokers with chronic pain who currently use opioids. Results indicated that opioid misuse is associated with greater tobacco (13% of variance), alcohol (27% of variance), and cannabis (22% of variance) problems, as well as anxiety (26% of variance) and depressive symptoms (26% of variance). These results highlight the potential importance of opioid misuse in terms of concurrent substance and mental health problems among smokers with chronic pain. Future work is needed to explicate directionality and temporal ordering in the observed relations.


SIDATRAT: informatics to improve HIV/AIDS care.
AIDS is a major cause of death in the Caribbean, a region with a high prevalence of HIV. However, prevalence in Cuba's population aged 15 to 49 years, despite a slight increase in recent years, is considered extremely low (0.1%). At the close of 2010, 5692 Cuban patients were receiving antiretroviral therapy. SIDATRAT, an informatics system, was developed at the Pedro Kourí Tropical Medicine Institute in Havana to ensure proper monitoring and followup of drug administration. Functioning on a web platform utilizing an Apache server, PHP and MySQL, it records patients' general information, CD4 counts, viral load and data from other laboratory tests, as well as endoscopic and imaging studies. It also compiles information on their AIDS classification, opportunistic infections, HIV subtype and resistance studies, followup consultations, drug regimen, adverse reactions to medications, changes in drug combinations, and survival; and tracks total number of individuals under treatment. SIDATRAT follows the client-server philosophy and enables access by authorized users throughout Cuba via the health informatics network. SIDATRAT has been found effective in supporting quality care for persons living with HIV/AIDS and universal access to antiretroviral therapy, compiling most of the information needed for decisionmaking on patient health and therapies. SIDATRAT has been offered to the UNDP office in Havana for sharing with other developing countries that may wish to adapt or implement it.


The interface between assisted reproductive technologies and genetics: technical, social, ethical and legal issues.
The interface between assisted reproductive technologies (ART) and genetics comprises several sensitive and important issues that affect infertile couples, families with severe genetic diseases, potential children, professionals in ART and genetics, health care, researchers and the society in general. Genetic causes have a considerable involvement in infertility. Genetic conditions may also be transmitted to the offspring and hence create transgenerational infertility or other serious health problems. Several studies also suggest a slightly elevated risk of birth defects in children born following ART. Preimplantation genetic diagnosis (PGD) has become widely practiced throughout the world for various medical indications, but its limits are being debated. The attitudes towards ART and PGD vary substantially within Europe. The purpose of the present paper was to outline a framework for development of guidelines to be issued jointly by European Society of Human Genetics and European Society of Human Reproduction and Embryology for the interface between genetics and ART. Technical, social, ethical and legal issues of ART and genetics will be reviewed.


Acylthioureas as anion transporters: the effect of intramolecular hydrogen bonding.
Small molecule synthetic anion transporters may have potential application as therapeutic agents for the treatment of diseases including cystic fibrosis and cancer. Understanding the factors that can dictate the anion transport activity of such transporters is a crucial step towards their application in biological systems. In this study a series of acylthiourea anion transporters were synthesised and their anion binding and transport properties in POPC bilayers have been investigated. The transport activity of these receptors is dominated by their lipophilicity, which is in turn dependent on both substituent effects and the formation and strength of an intramolecular hydrogen bond as inferred from DFT calculations. This is in contrast to simpler thiourea systems, in which the lipophilicity depends predominantly on substituent effects alone.


Lactobacillus acidophilus JCM 1132 Strain and Its Mutant with Different Bacteriocin-Producing Behaviour Have Various in Situ Effects on the Gut Microbiota of Healthy Mice.
The production of bacteriocin is considered to be a probiotic trait of lactic acid bacteria (LAB). However, not all strains of LAB harbour bacteriocin genes, even within the same species. Moreover, the effects of bacteriocins on the host gut microbiota and on host physiological indicators are rarely studied. This study evaluated the effects of the bacteriocin-producing Lactobacillus acidophilus strain JCM1132 and its non-producing spontaneous mutant, L. acidophilus CCFM720, on the physiological statuses and gut microbiota of healthy mice. Mice that received the bacteriocin-producing strain JCM1132 exhibited reduced water and food intake. Furthermore, the administration of these strains induced significant changes in the compositional abundance of faecal microbiota at the phylum and genus levels, and some of these changes were more pronounced after one week of withdrawal. The effects of CCFM720 treatment on the gut microbiota seemed to favour the prevention of metabolic diseases to some extent. However, individuals that received JCM1132 treatment exhibited weaker inflammatory responses than those that received CCFM720 treatment. Our results indicate that treatment with bacteriocin-producing or non-producing strains can have different effects on the host. Accordingly, this trait should be considered in the applications of LAB.


Large electro-optic beam steering with nematicons.
We analyze the angular steering of self-confined light beams, i.e., spatial solitons, in nematic liquid crystals exploiting both their electro-optic response and reorientational nonlinearity. A bias-induced interface is obtained with comb electrodes in a planar cell, applying two distinct voltages to control the spatial distribution of the optic axis. The configuration allows spatial solitons to propagate in a plane and maximize their deflection via refraction and total internal reflection, with an overall deflection of 70° in standard E7.


The effects of growth hormone deficiency and growth hormone replacement therapy on intellectual ability, personality and adjustment in children.
Traditionally, it has been assumed that intellectual development in children with growth hormone deficiency (GHD) is distributed between ranges of a normal population based on the observation that it does not differ substantially from that of children of the same age. Nevertheless, few studies have investigated this assumption. This Spanish Collaborative study was prospectively planned with two main purposes: to study a possible influence of GHD on intelligence quotient (IQ), personality traits and adaptative capacity and to study the evolution of these parameters during substitution therapy with growth hormone (GH). Although the overall intellectual ability of children with GHD is comparable to that of a normal reference population, some areas such the motor-component scale (evaluated by McCarthy test) and performance IQ (evaluated by WISC-R) were below the mean at the beginning of the study, showing significant improvement during therapy. Emotional adjustment (normal at study start) also improved significantly during treatment. Females showed better adjustment capacity before and during GH therapy. Longer studies with an increased number of cases are needed to confirm these effects of GHD and its treatment in children.


Cytodiagnosis in the management of extrahepatic biliary stricture.
A total of 117 patients presenting with extrahepatic biliary strictures between 1981 and 1989 had 206 cytological examinations of the bile duct or bile (153 non-operative, 53 intraoperative) to establish the presence of malignancy. A final diagnosis of cholangiocarcinoma was made in 88 patients, with 29 patients having benign biliary strictures. The cytological techniques used were fine needle aspiration (n = 102) or brushing (n = 24) of the bile duct, or exfoliative cytology of bile (n = 80). Forty one patients with malignancy had two or more examinations with differing results between samples in 20 cases. The overall sensitivity was 72%. There was only one false positive result, giving a patient predictive value of positive cytology of 98%. Intraoperative cytology was more sensitive than non-operative examination (80% v 42%). Overall, the sensitivity of fine needle aspiration (67%) was greater than that of brush cytology (40%) or exfoliative cytology (30%). No complications were encountered. Cytodiagnosis of extrahepatic biliary strictures is a safe procedure which is not technically demanding, and as it has a high sensitivity and predictive value for positive cytology, cytological confirmation of malignancy should be sought in all clinically and radiologically suspicious cases.


Anterior cervical decompression and fusion accelerates adjacent segment degeneration: comparison with asymptomatic volunteers in a ten-year magnetic resonance imaging follow-up study.
Prospective 10-year follow-up magnetic resonance imaging (MRI) study of patients who underwent anterior cervical decompression and fusion (ACDF) and healthy control subjects. To clarify the incidence of adjacent segment degeneration during 10 years after ACDF. There have been few studies which investigated incidence of progression of degenerative changes at adjacent segments in patients treated by ACDF comparing with healthy subjects. Sixty-four patients who underwent ACDF (48 males, 16 females, mean age 47.3 years, mean follow-up 12.1 year) and 201 asymptomatic volunteers who underwent MRI in our previous study (113 males, 88 females, mean age; 41.1 year, mean follow-up; 11.7 years) were included in this study. The patients and control subjects underwent follow-up MRI in this study. Following MR findings were evaluated using a numerical grading system from C2-C3-C7-T1: (1) Decrease in signal intensity of disc (DSI), (2) Posterior disc protrusion (PDP), (3) Disc space narrowing, and (4) Foraminal stenosis. When an increase in at least one grade in any of the radiographic parameters was detected between the 2 time points, progression of disc degeneration was judged as present at the level of interest. Progression of DSI was significantly more frequent in ACDF group than in control group at C4-C5, while progression of PDP was significantly more frequent in ACDF group than in control group at all levels except for C5-C6. Progression of disc space narrowing and foraminal stenosis was significantly more frequent in ACDF group at C3-C4 and at C6-C7, respectively. Although both ACDF patients and control subjects demonstrated progression of disc degeneration during 10 years, ACDF patients had significantly higher incidence of progression of disc degeneration at adjacent segments than control subjects, while progression of disc degeneration at adjacent segments was not always related to development of clinical symptoms.


Impact of oxide and electrode materials on the switching characteristics of oxide ReRAM devices.
Resistive switching random-access memory (ReRAM) is one of the most promising technologies for non-volatile memories. Thanks to the low power and high speed operation, the high density CMOS-compatible integration, and the high cycling endurance, the ReRAM technology is becoming a strong candidate for high-density storage arrays and novel in-memory computing systems. However, ReRAM suffers from cycle-to-cycle switching variability and noise-induced resistance fluctuations, leading to insufficient read margin between the programmed resistive states. To overcome the existing challenges, a deep understanding of the roles of the ReRAM materials in the device characteristics is essential. To better understand the role of the switching layer material in controlling ReRAM performance and reliability, this work compares SiOx- and HfO2-based ReRAM at fixed geometry and electrode materials. Ti/HfO2/C and Ti/SiOx/C devices are compared from the point of view of the forming process, switching characteristics, resistance variability, and temperature stability of the programmed states. The results show clear similarities for the two different oxides, including a similar resistance window and stability at high temperatures, thus suggesting a common nature of the switching mechanism, highlighting the importance of the electrodes. On the other hand, the oxide materials play a clear role in the forming, breakdown, and variability characteristics. The discrimination between the role of the oxide and the electrode materials in the ReRAM allows ReRAM optimization via materials engineering to be better explored for future memory and computing applications.


A role for gelsolin in actuating epidermal growth factor receptor-mediated cell motility.
Phospholipase C-gamma (PLC gamma) is required for EGF-induced motility (Chen, P., H. Xie, M.C. Sekar, K.B. Gupta, and A. Wells. J. Cell Biol. 1994. 127:847-857); however, the molecular basis of how PLC gamma modulates the actin filament network underlying cell motility remains undetermined. We propose that one connection to the actin cytoskeleton is direct hydrolysis of PIP2 with subsequent mobilization of membrane-associated actin modifying proteins. We used signaling-restricted EGFR mutants expressed in receptor-devoid NR6 fibroblast cells to investigate whether EGFR activation of PLC causes gelsolin mobilization from the cell membrane in vivo and whether this translocation facilitates cell movement. Gelsolin anti-sense oligonucleotide (20 microM) treatment of NR6 cells expressing the motogenic full-length (WT) and truncated c'1000 EGFR decreased endogenous gelsolin by 30-60%; this resulted in preferential reduction of EGF (25 nM)-induced cell movement by > 50% with little effect on the basal motility. As 14 h of EGF stimulation of cells did not increase total cell gelsolin content, we determined whether EGF induced redistribution of gelsolin from the membrane fraction. EGF treatment decreased the gelsolin mass associated with the membrane fraction in motogenic WT and c'1000 EGFR NR6 cells but not in cells expressing the fully mitogenic, but nonmotogenic c'973 EGFR. Blocking PLC activity with the pharmacologic agent U73122 (1 microM) diminished both this mobilization of gelsolin and EGF-induced motility, suggesting that gelsolin mobilization is downstream of PLC. Concomitantly observed was reorganization of submembranous actin filaments correlating directly with PLC activation and gelsolin mobilization. In vivo expression of a peptide that is reported to compete in vitro with gelsolin in binding to PIP2 dramatically increased basal cell motility in NR6 cells expressing either motogenic (WT and c'1000) or nonmotogenic (c'973) EGFR; EGF did not further augment cell motility and gelsolin mobilization. Cells expressing this peptide demonstrated actin reorganization similar to that observed in EGF-treated control cells; the peptide-induced changes were unaffected by U73122. These data suggest that much of the EGF-induced motility and cytoskeletal alterations can be reproduced by displacement of select actin-modifying proteins from a PIP2-bound state. This provides a signaling mechanism for translating cell surface receptor-mediated biochemical reactions to the cell movement machinery.


High-throughput genome editing and phenotyping facilitated by high resolution melting curve analysis.
With the goal to generate and characterize the phenotypes of null alleles in all genes within an organism and the recent advances in custom nucleases, genome editing limitations have moved from mutation generation to mutation detection. We previously demonstrated that High Resolution Melting (HRM) analysis is a rapid and efficient means of genotyping known zebrafish mutants. Here we establish optimized conditions for HRM based detection of novel mutant alleles. Using these conditions, we demonstrate that HRM is highly efficient at mutation detection across multiple genome editing platforms (ZFNs, TALENs, and CRISPRs); we observed nuclease generated HRM positive targeting in 1 of 6 (16%) open pool derived ZFNs, 14 of 23 (60%) TALENs, and 58 of 77 (75%) CRISPR nucleases. Successful targeting, based on HRM of G0 embryos correlates well with successful germline transmission (46 of 47 nucleases); yet, surprisingly mutations in the somatic tail DNA weakly correlate with mutations in the germline F1 progeny DNA. This suggests that analysis of G0 tail DNA is a good indicator of the efficiency of the nuclease, but not necessarily a good indicator of germline alleles that will be present in the F1s. However, we demonstrate that small amplicon HRM curve profiles of F1 progeny DNA can be used to differentiate between specific mutant alleles, facilitating rare allele identification and isolation; and that HRM is a powerful technique for screening possible off-target mutations that may be generated by the nucleases. Our data suggest that micro-homology based alternative NHEJ repair is primarily utilized in the generation of CRISPR mutant alleles and allows us to predict likelihood of generating a null allele. Lastly, we demonstrate that HRM can be used to quickly distinguish genotype-phenotype correlations within F1 embryos derived from G0 intercrosses. Together these data indicate that custom nucleases, in conjunction with the ease and speed of HRM, will facilitate future high-throughput mutation generation and analysis needed to establish mutants in all genes of an organism.


Educating, Enrolling, And Engaging: The State Of Marketplace Consumer Assistance Under The Affordable Care Act.
Programs created under the Affordable Care Act to connect consumers to health care coverage represent an unprecedented public-sector investment. State-level implementation of these programs has varied greatly, making it possible to learn from differences in strategy and performance. In this article we assess the current state of Marketplace enrollment assistance, synthesizing evidence from published evaluations (largely derived from grey literature) and analyses of data from nationwide surveys of assisters. Synthesis of this evidence suggests that assister programs play a vital role supporting consumers in the new Marketplaces, particularly when assisters maintain extended ongoing relationships with consumers; assisters come from and are situated within communities they serve; local programs are well coordinated; and postenrollment issues can be addressed. Stable funding commitments, year-round employment, and enriched training were identified as crucial long-run strategies for building a more professional assister workforce and stronger infrastructure.


Genome-wide association of pericardial fat identifies a unique locus for ectopic fat.
Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7 × 10(-08)). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.


Astragaloside IV inhibits excessive mesangial cell proliferation and renal fibrosis caused by diabetic nephropathy via modulation of the TGF-β1/Smad/miR-192 signaling pathway.
Astragaloside IV (ASI) exhibits a wide variety of pharmacological effects in cardiovascular diseases, hepatitis and kidney disease and due to this, ASI has recently become an attractive research target. The present study aimed to determine the effect of ASI on renal fibrosis and the mechanisms underlying its therapeutic effects in diabetic nephropathy (DN). In vitro, ASI was added to rat mesangial cells (RMCs) and cultured with a high level of glucose (HG) to observe the effects exhibited on proliferation and fibrosis-related mRNA and protein expression. In vivo, a DN model was established using streptozotocin administration in rats, and renal injury was evaluated using renal histological examination. The expression levels of related mRNAs and proteins were analyzed using reverse transcription-quantitative PCR, western blot analysis and immunohistochemistry. ASI was demonstrated to downregulate miR-192 expression and inhibit excessive proliferation of RMCs, which was induced by HG, in a dose-dependent manner. Additionally, ASI exhibited a therapeutic effect on DN rats. ASI was also demonstrated to decrease the miR-192 expression and mRNA and protein expression of transforming growth factor-β1 (TGF-β1), Smad3, α-smooth muscle actin (α-SMA) and collagen type 1 (col1), and increase the mRNA and protein expression of Smad7 in vitro and in vivo. These results suggested that ASI exhibited a therapeutic effect on DN, possibly due to the inhibition of excessive mesangial proliferation and renal fibrosis via the TGF-β1/Smad/miR-192 signaling pathway.


Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation.
Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large-scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews; second, expert opinion was added for specific issues following several rounds of debate; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; and the addition of newer treatment options for resteroid-refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.


A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy.
Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC. This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on days 1-4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue). Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0-120 h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles. NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC.


Human motor endplate remodeling after traumatic nerve injury.
Current management of traumatic peripheral nerve injuries is variable with operative decisions based on assumptions that irreversible degeneration of the human motor endplate (MEP) follows prolonged denervation and precludes reinnervation. However, the mechanism and time course of MEP changes after human peripheral nerve injury have not been investigated. Consequently, there are no objective measures by which to determine the probability of spontaneous recovery and the optimal timing of surgical intervention. To improve guidance for such decisions, the aim of this study was to characterize morphological changes at the human MEP following traumatic nerve injury. A prospective cohort (here analyzed retrospectively) of 18 patients with traumatic brachial plexus and axillary nerve injuries underwent biopsy of denervated muscles from the upper extremity from 3 days to 6 years after injury. Muscle specimens were processed for H & E staining and immunohistochemistry, with visualization via confocal and two-photon excitation microscopy. Immunohistochemical analysis demonstrated varying degrees of fragmentation and acetylcholine receptor dispersion in denervated muscles. Comparison of denervated muscles at different times postinjury revealed progressively increasing degeneration. Linear regression analysis of 3D reconstructions revealed significant linear decreases in MEP volume (R = -0.92, R2 = 0.85, p = 0.001) and surface area (R = -0.75, R2 = 0.56, p = 0.032) as deltoid muscle denervation time increased. Surprisingly, innervated and structurally intact MEPs persisted in denervated muscle specimens from multiple patients 6 or more months after nerve injury, including 2 patients who had presented > 3 years after nerve injury. This study details novel and critically important data about the morphology and temporal sequence of events involved in human MEP degradation after traumatic nerve injuries. Surprisingly, human MEPs not only persisted, but also retained their structures beyond the assumed 6-month window for therapeutic surgical intervention based on previous clinical studies. Preoperative muscle biopsy in patients being considered for nerve transfer may be a useful prognostic tool to determine MEP viability in denervated muscle, with surviving MEPs also being targets for adjuvant therapy.


Integrating nanopore sensors within microfluidic channel arrays using controlled breakdown.
Nanopore arrays are fabricated by controlled dielectric breakdown (CBD) in solid-state membranes integrated within polydimethylsiloxane (PDMS) microfluidic devices. This technique enables the scalable production of independently addressable nanopores. By confining the electric field within the microfluidic architecture, nanopore fabrication is precisely localized and electrical noise is significantly reduced. Both DNA and protein molecules are detected to validate the performance of this sensing platform.


Associations of 25-hydroxyvitamin D with markers of inflammation, insulin resistance and obesity in black and white community-dwelling adults.
Vitamin D is a fat-soluble vitamin classically known for its role in calcium absorption and bone health. Growing evidence indicates that vitamin D deficiency may be associated with inflammation, insulin resistance, and obesity. However, prior studies examining the association of vitamin D with metabolic risk factors had relatively low representation of individuals of black race, limiting their ability to characterize associations of vitamin D and parameters of metabolic health in black vs. white individuals. We examined associations of 25-hydroxyvitamin D (25(OH)D) concentrations with markers of inflammation (interleukin [IL]-6, IL-10, high sensitivity C-reactive protein [hsCRP]), insulin sensitivity (adiponectin, resistin, HOMA-IR), and obesity (body mass index [BMI], waist circumference) in 1,042 participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a large national cohort of black and white adults 45 years or older. In unadjusted analyses, lower 25(OH)D concentrations were associated with higher IL-6 and hsCRP concentrations; lower adiponectin concentrations; higher HOMA-IR; and higher BMI and waist circumference (P<0.05 for all). After adjustment for sociodemographic, clinical, lifestyle, and laboratory variables, lower 25(OH) D concentrations remained associated with lower adiponectin concentrations, higher IL-6 concentrations, higher HOMA-IR, and higher BMI and waist circumference (P <0.05 for all). The magnitude of these associations did not differ by race (Pinteraction>0.1). Lower 25(OH)D concentrations are associated with disturbances in metabolic health in both blacks and whites. Whether correcting vitamin D deficiency could offer a beneficial therapy for additional disease prevention requires further study.


Bi-compartmental elderly or adult dynamic digestion models applied to interrogate protein digestibility.
The world's population is inevitably ageing thanks to modern progress; however, the development of food and oral formulations tailored to the needs of the elderly is still in its infancy. In vitro digestion models offer high throughput, robust and practically ethics free evaluation of the digestive fate of ingested products. To date, no data have been made publicly available to facilitate the development or application of an in vitro model mirroring the physicochemical conditions of the elderly gastrointestinal system. This study reports the development of a novel and highly bio-relevant in vitro model based on two serially connected bioreactors recreating the dynamic conditions of the adult or elderly alimentary canal. This report and its supplementary material describe in detail the set-up of the system, the applied physicochemical parameters and the development of the controlling software. These are intended to openly depict a versatile platform, which could assist future efforts to develop age-tailored oral formulations. SDS-PAGE analyses of samples collected from the in vitro digestion of β-lactoglobulin, α-lactalbumin and lactoferrin suggest the bioaccessibility of "slow digesting" and "fast digesting" proteins identified in adult models do not necessarily maintain this trait under elderly gastro-intestinal conditions. Overall, this study brings forward a new generic yet advanced model that could facilitate age-tailoring the digestive fate of liquid formulations.


Spectroelectrochemical studies of hole percolation on functionalised nanocrystalline TiO2 films: a comparison of two different ruthenium complexes.
We report the application of spectroelectrochemical techniques to compare the hole percolation dynamics of molecular networks of two ruthenium bipyridyl complexes adsorbed onto mesoporous, nanocrystalline TiO(2) films. The percolation dynamics of the ruthenium complex cis-di(thiocyanato)(2,2'-bipyridyl-4,4'-dicarboxylic acid)-(2,2'-bipyridyl-4,4'-tridecyl) ruthenium(II), N621, is compared with those observed for an analogous dye with an additional tri-phenyl amine (TPA) donor moiety, cis-di(thiocyanato)(2,2'-bipyridyl-4,4'-dicarboxylic acid)-(2,2'-bipyridyl-4,4'-bis(vinyltriphenylamine)) ruthenium(II), HW456. The in situ oxidation of these ruthenium complexes adsorbed to the TiO(2) films is monitored by cyclic voltammetry and voltabsorptometry, whilst the dynamics of hole (cation) percolation between adsorbed ruthenium complexes is monitored by potentiometric spectroelectrochemistry and chronoabsorptometry. The hole diffusion coefficient, D(eff), is shown to be dependent on the dye loading on the nanocrystalline TiO(2) film, with a threshold observed at ∼60% monolayer surface coverage for both dyes. The hole diffusion coefficient of HW456 is estimated to be 2.6 × 10(-8) cm(2)/s, 20-fold higher than that obtained for the control N621, attributed to stronger electronic coupling between the TPA moieties of HW456 accelerating the hole percolation dynamics. The presence of mercuric ions, previously shown to bind to the thiocyanates of analogous ruthenium complexes, resulted in a quenching of the hole percolation for N621/TiO(2) films and an enhancement for HW456/TiO(2) films. These results strongly suggest that the hole percolation pathway is along the overlapped neighbouring -NCS groups for the N621 molecules, whereas in HW456 molecules cation percolation proceeds between intermolecular TPA ligands. These results are discussed in the context of their relevance to the process of dye regeneration in dye sensitised solar cells, and to the molecular wiring of wide bandgap inorganic materials for battery and sensing applications.


A systematic review of quality of life in sickle cell disease and thalassemia after stem cell transplant or gene therapy.
Patients with sickle cell disease (SCD) and thalassemia experience several complications across their lifespan that lead to impairment in different health-related quality of life (HRQOL) domains. There is increasing interest in curative therapies for patients with SCD and thalassemia, including hematopoietic stem cell transplant (HSCT) and gene therapy; however, the effect of these therapies on various HRQOL domains remains unclear. Our objective was to systematically evaluate the most recent evidence for the effect of HSCT and gene therapy on HRQOL in patients with SCD and thalassemia. A systematic search of medical literature databases was conducted. A total of 16 studies (thalassemia, n = 9; SCD, n = 6; both, n = 1) involving 517 participants met inclusion criteria (thalassemia, n = 416; SCD, n = 101). HSCT was associated with a small to large positive effects in most HRQOL domains (Cohen's d; mean = 0.47; median = 0.37; range, 0.27-2.05). In thalassemia, HSCT was frequently associated with large positive effects in physical and emotional HRQOL domains (median d = 0.79 and d = 0.57, respectively). In SCD, HSCT was associated with large positive effects in all HRQOL domains. Emerging data suggest improvement in HRQOL outcomes across different domains following gene therapy in thalassemia and SCD. The quality of evidence was moderate in 13 studies (81%). HSCT has a positive impact on several HRQOL domains in patients with SCD and thalassemia; however, more longitudinal studies are warranted to assess the sustainability of these effects. Reporting HRQOL outcomes from ongoing gene therapy or gene-editing trials in SCD and thalassemia is key to better understand the benefits of such therapies.


Cost effectiveness of medical devices to diagnose pre-eclampsia in low-resource settings.
Maternal mortality remains a major health challenge facing developing countries, with pre-eclampsia accounting for up to 17 percent of maternal deaths. Diagnosis requires skilled health providers and devices that are appropriate for low-resource settings. This study presents the first cost-effectiveness analysis of multiple medical devices used to diagnose pre-eclampsia in low- and middle-income countries (LMICs). Blood pressure and proteinuria measurement devices, identified from compendia for LMICs, were included. We developed a decision tree framework to assess the cost-effectiveness of each device using parameter values that reflect the general standard of care based on a survey of relevant literature and expert opinion. We examined the sensitivity of our results using one-way and second-order probabilistic multivariate analyses. Because the disability-adjusted life years (DALYs) averted for each device were very similar, the results were influenced by the per-use cost ranking. The most cost-effective device combination was a semi-automatic blood pressure measurement device and visually read urine strip test with the lowest combined per-use cost of $0.2004 and an incremental cost effectiveness ratio of $93.6 per DALY gained relative to a baseline with no access to diagnostic devices. When access to treatment is limited, it is more cost-effective to improve access to treatment than to increase testing rates or diagnostic device sensitivity. Our findings were not sensitive to changes in device sensitivity, however they were sensitive to changes in the testing rate and treatment rate. Furthermore, our results suggest that simple devices are more cost-effective than complex devices. The results underscore the desirability of two design features for LMICs: ease of use and accuracy without calibration. Our findings have important implications for policy makers, health economists, health care providers and engineers.


Sleep-Wake Cycle in Young and Older Mice.
Sleep plays a key role in multiple cognitive functions and sleep pattern changes with aging. Human studies revealed that aging decreases sleep efficiency and reduces the total sleep time, the time spent in slow-wave sleep (SWS), and the delta power (1-4 Hz) during sleep; however, some studies of sleep and aging in mice reported opposing results. The aim of our work is to estimate how features of sleep-wake state in mice during aging could correspond to age-dependent changes observed in human. In this study, we investigated the sleep/wake cycle in young (3 months old) and older (12 months old) C57BL/6 mice using local-field potentials (LFPs). We found that older adult mice sleep more than young ones but only during the dark phase of sleep-wake cycle. Sleep fragmentation and sleep during the active phase (dark phase of cycle), homologous to naps, were higher in older mice. Older mice show a higher delta power in frontal cortex, which was accompanied with similar trend for age differences in slow wave density. We also investigated regional specificity of sleep-wake electrographic activities and found that globally posterior regions of the cortex show more rapid eye movement (REM) sleep whereas somatosensory cortex displays more often SWS patterns. Our results indicate that the effects of aging on the sleep-wake activities in mice occur mainly during the dark phase and the electrode location strongly influence the state detection. Despite some differences in sleep-wake cycle during aging between human and mice, some features of mice sleep share similarity with human sleep during aging.


Predictors of Specialized Pediatric Palliative Care Involvement and Impact on Patterns of End-of-Life Care in Children With Cancer.
Purpose The impact of specialized pediatric palliative care (SPPC) teams on patterns of end-of-life care is unknown. We sought to determine (1) which children with cancer access SPPC and (2) the impact of accessing SPPC on the risk of experiencing high-intensity end-of-life care (intensive care unit admission, mechanical ventilation, or in-hospital death). Methods Using a provincial childhood cancer registry, we assembled a retrospective cohort of Ontario children with cancer who died between 2000 and 2012 and received care through pediatric institutions with an SPPC team. Patients were linked to population-based administrative data capturing inpatient, outpatient, and emergency visits. Children were classified as having SPPC, general palliative care, or no palliative care on the basis of SPPC clinical databases, physician billing codes, or inpatient diagnosis codes. Results Of the 572 children, 166 (29%) received care from an SPPC team for at least 30 days before death, and 100 (17.5%) received general palliative care. SPPC involvement was significantly less likely for children with hematologic cancers (OR, 0.3; 95% CI, 0.3 to 0.4), living in the lowest income areas (OR, 0.4; 95% CI, 0.2 to 0.8), and living further from the treatment center (OR, 0.5; 95% CI, 0.4 to 0.5). SPPC was associated with a five-fold decrease in odds of intensive care unit admission (OR, 0.2; 95% CI, 0.1 to 0.4), whereas general palliative care had no impact. Similar associations were seen with all secondary indicators. Conclusion When available, SPPC, but not general palliative care, is associated with lower intensity care at the end of life for children with cancer. However, access remains uneven. These results provide the strongest evidence to date supporting the creation of SPPC teams.


Muscle physiology changes induced by every other day feeding and endurance exercise in mice: effects on physical performance.
Every other day feeding (EOD) and exercise induce changes in cell metabolism. The aim of the present work was to know if both EOD and exercise produce similar effects on physical capacity, studying their physiological, biochemical and metabolic effects on muscle. Male OF-1 mice were fed either ad libitum (AL) or under EOD. After 18 weeks under EOD, animals were also trained by using a treadmill for another 6 weeks and then analyzed for physical activity. Both, EOD and endurance exercise increased the resistance of animals to extenuating activity and improved motor coordination. Among the groups that showed the highest performance, AL and EOD trained animals, ALT and EODT respectively, only the EODT group was able to increase glucose and triglycerides levels in plasma after extenuating exercise. No high effects on mitochondrial respiratory chain activities or protein levels neither on coenzyme Q levels were found in gastrocnemius muscle. However, exercise and EOD did increase β-oxidation activity in this muscle accompanied by increased CD36 levels in animals fed under EOD and by changes in shape and localization of mitochondria in muscle fibers. Furthermore, EOD and training decreased muscle damage after strenuous exercise. EOD also reduced the levels of lipid peroxidation in muscle. Our results indicate that EOD improves muscle performance and resistance by increasing lipid catabolism in muscle mitochondria at the same time that prevents lipid peroxidation and muscle damage.


What failure in collective decision-making tells us about metacognition.
Condorcet (1785) proposed that a majority vote drawn from individual, independent and fallible (but not totally uninformed) opinions provides near-perfect accuracy if the number of voters is adequately large. Research in social psychology has since then repeatedly demonstrated that collectives can and do fail more often than expected by Condorcet. Since human collective decisions often follow from exchange of opinions, these failures provide an exquisite opportunity to understand human communication of metacognitive confidence. This question can be addressed by recasting collective decision-making as an information-integration problem similar to multisensory (cross-modal) perception. Previous research in systems neuroscience shows that one brain can integrate information from multiple senses nearly optimally. Inverting the question, we ask: under what conditions can two brains integrate information about one sensory modality optimally? We review recent work that has taken this approach and report discoveries about the quantitative limits of collective perceptual decision-making, and the role of the mode of communication and feedback in collective decision-making. We propose that shared metacognitive confidence conveys the strength of an individual's opinion and its reliability inseparably. We further suggest that a functional role of shared metacognition is to provide substitute signals in situations where outcome is necessary for learning but unavailable or impossible to establish.


An evolutionarily 'young' lysine residue in histone H3 attenuates transcriptional output in Saccharomyces cerevisiae.
The DNA entry and exit points on the nucleosome core regulate the initial invasion of the nucleosome by factors requiring access to the underlying DNA. Here we describe in vivo consequences of eliminating a single protein-DNA interaction at this position through mutagenesis of histone H3 Lys 42 to alanine. This substitution has a dramatic effect on the Saccharomyces cerevisiae transcriptome in both the transcriptional output and landscape of mRNA species produced. We attribute this in part to decreased histone H3 occupancy at transcriptionally active loci, leading to enhanced elongation. Additionally we show that this lysine is methylated in vivo, and genetic studies of methyl-lysine mimics suggest that this modification may be crucial in attenuating gene expression. Interestingly, this site of methylation is unique to Ascomycota, suggesting a recent evolutionary innovation that highlights the evolvability of post-translational modifications of chromatin.


Quick change: post-transcriptional regulation in Pseudomonas.
Pseudomonas species have evolved dynamic and intricate regulatory networks to fine-tune gene expression, with complex regulation occurring at every stage in the processing of genetic information. This approach enables Pseudomonas to generate precise individual responses to the environment in order to improve their fitness and resource economy. The weak correlations we observe between RNA and protein abundance highlight the significant regulatory contribution of a series of intersecting post-transcriptional pathways, influencing mRNA stability, translational activity and ribosome function, to Pseudomonas environmental responses. This review examines our current understanding of three major post-transcriptional regulatory systems in Pseudomonas spp.; Gac/Rsm, Hfq and RimK, and presents an overview of new research frontiers, emerging genome-wide methodologies, and their potential for the study of global regulatory responses in Pseudomonas.


Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina.
Vascular/parenchymal crosstalk is increasingly recognized as important in the development and maintenance of healthy vascularized tissues. The retina is an excellent model in which to study the role of cell type-specific contributions to the process of blood vessel and neuronal growth. During retinal vascular development, glial cells such as astrocytes provide the template over which endothelial cells migrate to form the retinal vascular network, and hypoxia-regulated vascular endothelial growth factor (VEGF) has been demonstrated to play a critical role in this process as well as pathological neovascularization. To investigate the nature of cell-specific contributions to this process, we deleted VEGF and its upstream regulators, the hypoxia-inducible transcription factors HIF-1 alpha and HIF-2 alpha, and the negative regulator of HIF alpha, von Hippel-Lindau protein (VHL), in astrocytes. We found that loss of hypoxic response and VEGF production in astrocytes does not impair normal development of retinal vasculature, indicating that astrocyte-derived VEGF is not essential for this process. In contrast, using a model of oxygen-induced ischemic retinopathy, we show that astrocyte-derived VEGF is essential for hypoxia-induced neovascularization. Thus, we demonstrate that astrocytes in the retina have highly divergent roles during developmental, physiological angiogenesis, and ischemia-driven, pathological neovascularization.


"Most people are simply not designed to eat pasta": evolutionary explanations for obesity in the low-carbohydrate diet movement.
Low-carbohydrate diets, notably the Atkins Diet, were particularly popular in Britain and North America in the late 1990s and early 2000s. On the basis of a discourse analysis of bestselling low-carbohydrate diet books, I examine and critique genetic and evolutionary explanations for obesity and diabetes as they feature in the low-carbohydrate literature. Low-carbohydrate diet books present two distinct neo-Darwinian explanations of health and body-weight. First, evolutionary nutrition is based on the premise that the human body has adapted to function best on the diet eaten in the Paleolithic era. Second, the thrifty gene theory suggests that feast-or-famine conditions during human evolutionary development naturally selected for people who could store excess energy as body fat for later use. However, the historical narratives and scientific arguments presented in the low-carbohydrate literature are beset with generalisations, inconsistencies and errors. These result, I argue, from the use of the primitive as a discursive "blank slate" onto which to project ideals perceived to be lacking in contemporary industrialised life.


Site-directed cleavage of RNA.
Using complementary chimeric oligonucleotides containing deoxyribonucleotides and 2'-O-methylribonucleotides (1), enzymatically synthesized RNA (90 mer) were cleaved at a single site with Escherichia coli RNaseH, either at a hairpin loop or at a stem region. Especially, site-specific cleavage occurred in even the target region being enclosed within a stable, base-paired stem. The method is proved to be generally applicable to RNA containing secondary structures.


Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials.
Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS) metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors. Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data. With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001) from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018). Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001) but bore a higher incidence of CNS recurrence (P = 0.010), while statistical significance failed to be discerned for either overall survival (P = 0.069) or CNS metastasis (P = 0.374) between the sequential and observation arms. This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation.


Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies.
Ki67 index is now an essential part of classification of pancreatic neuroendocrine tumors. However, its adaptation into daily practice has been fraught with challenges related to counting methodology. In this study, three reviewers used four counting methodologies to calculate Ki67 index in 68 well-differentiated pancreatic neuroendocrine tumors: (1) 'eye-ball' estimation, which has been advocated as reliable and is widely used; (2) automated counting by image analyzer; (3) manual eye-counting (eye under a microscope without a grid); and (4) manual count of camera-captured/printed image. Pearson's correlation (R) was used to measure pair-wise correlation among three reviewers using all four methodologies. Average level of agreement was calculated using mean of R values. The results showed that: (1) 'eye-balling' was least expensive and fastest (average time <1 min) but had poor reliability and reproducibility. (2) Automated count was the most expensive and least practical with major impact on turnaround time (limited by machine and personnel accessibility), and, more importantly, had inaccuracies in overcounting unwanted material. (3) Manual eye count had no additional cost, averaged 6 min, but proved impractical and poorly reproducible. (4) Camera-captured/printed image was most reliable, had highest reproducibility, but took longer than 'eye-balling'. In conclusion, based on its comparatively low cost/benefit ratio and reproducibility, camera-captured/printed image appears to be the most practical for calculating Ki67 index. Although automated counting is generally advertised as the gold standard for index calculation, in this study it was not as accurate or cost-effective as camera-captured/printed image and was highly operator-dependent. 'Eye-balling' produces highly inaccurate and unreliable results, and is not recommended for routine use.


Retarded formation of the hippocampal commissure in embryos from mouse strains lacking a corpus callosum.
A precise description of the timing and route traveled by axons traversing the telencephalic midline through the ventral hippocampal commissure (HC) is essential for understanding the role it plays in the formation of the corpus callosum (CC). A normal baseline of HC development was described in B6D2F2 hybrid mice and then compared with two inbred strains of mice displaying callosal agenesis, BALB/cWah1 (50% CC defect) and 129/J (70% CC defect), their F2 hybrid (C129F2-33% CC defect), and a recombinant inbred strain (RI-1-100% CC defect) derived from pairs of C129F2 mice. Embryos weighing from 0.25 g to 0.70 g (E14.5-E17) were collected and fixed by perfusion. Axon tracts were labeled using crystals of the lipophilic dyes DiI and DiA inserted into the hippocampal fimbria and cerebral cortex. HC axons in B6D2F2 mice first cross the midline at about 0.350 g body weight (E14.8) by traveling over the dorsal septum and along the pia membrane lining the longitudinal fissure. Earlier crossing was prevented by the presence of a deep cleft formed by the longitudinal fissure extending down into the septal region. Subsequent axons fasciculated along existing axons, gradually building the dorsoventral height of the HC to about 200 microns by 0.600 g. The earliest callosal axons from frontal cortex crossed the midline at 0.620 g and were clearly seen fasciculating along and between existing hippocampal axons at the dorsal surface of the HC as they crossed. In the acallosal strains, HC formation was delayed by the continued presence of the cleft deep in the septal region. This delay in time of crossing was correlated with later CC defect expression. Initial HC crossing occurred at about 0.470 g (E16.25) in BALB mice and about 0.520 g (E16.5) in 129 mice. In the RI-1 embryos, first HC crossing was estimated at about 0.750 g (E17.5), although several older embryos showed no crossing. These results show the importance of the HC for successful CC formation and suggest that absent CC arises as a consequence of a developmental defect which affects the formation of the hippocampal commissure prior to arrival of CC axons at midplane.


Frequency and variation of the posterior pituitary bright signal on MR images.
Sagittal T1-weighted series with 3-mm sections have routinely been used for all cranial MR studies at our institution. It was apparent from examining these studies that the rate of occurrence of a normal posterior pituitary bright signal was lower than has been previously reported, particularly in older patients. This prompted both a retrospective and a prospective review and analysis of the posterior lobe bright signal in three patient categories. The overall frequency of posterior pituitary bright signal and the influence of sex and age were evaluated in one category. An age-related statistically significant decline in the frequency of posterior pituitary bright signal was found, with a decline rate of approximately 1% per year. An evaluation of the occurrence of anatomic variation in the location of posterior lobe bright signal was made in a second group of 1500 patients. Abberrant location of the posterior lobe was found to be uncommon and was seen most frequently in patients with a sellar fossula. Temporal variation in the presence or absence and size of the posterior lobe bright signal was evaluated in a third group of 36 patients who had at least two MR examinations available for review. Follow-up MR study showed an obvious posterior lobe bright signal in 8% of these patients for whom no bright signal was apparent at the time of initial examination. Loss of the posterior lobe bright signal was apparent in another 25% of patients. A significant change in size of the bright signal was apparent in 19% of patients within this category. Our results indicate that variation in the bright signal of the posterior pituitary lobe should be expected as a normal physiological occurrence.


How I treat newly diagnosed chronic phase CML.
The progress made in the understanding of chronic myeloid leukemia (CML) since the recognition of a common chromosomal abnormality to the introduction of ever more effective tyrosine kinase inhibitors is unprecedented in cancer. The expected survival for patients diagnosed with CML today, if properly managed, is probably similar to that of the general population. When managing patients with CML the goal is to achieve the best long-term outcome and we should base the treatment decisions on the data available. The results from cytogenetic and molecular analyses have to be interpreted judiciously and all available treatment options integrated into the treatment plan properly. The availability of several treatment options in CML is an asset, but the temptation of rapid succession of treatment changes because of perceived suboptimal response or for adverse events that could be managed needs to be avoided. Any decision to change therapy needs to weigh the expected long-term outcome with the current option versus the true expectations with any new option, particularly as it relates to irreversible outcomes, such as transformation to blast phase and death. In this manuscript, we discuss the treatment approach that has helped us manage successfully a large CML population.


Relationship between visceral adiposity and intramyocellular lipid content in two rat models of insulin resistance.
High visceral adiposity and intramyocellular lipid levels (IMCL) are both associated with the development of type 2 diabetes. The relationship between visceral adiposity and IMCL levels was explored in diet- and glucocorticoid-induced models of insulin resistance. In the diet-induced model, lean and fa/fa Zucker rats were fed either normal or high-fat (HF) chow over 4 wk. Fat distribution, IMCL content in the tibialis anterior (TA) muscle (IMCL(TA)), and whole body insulin resistance were measured before and after the 4-wk period. The HF diet-induced increase in IMCL(TA) was strongly correlated with visceral fat accumulation and greater glucose intolerance in both groups. The increase in IMCL(TA) to visceral fat accumulation was threefold greater for fa/fa rats. In the glucocorticoid-induced model, insulin sensitivity was impaired with dexamethasone. In vivo adiposity and IMCL(TA) content measurements were combined with ex vivo analysis of plasma and muscle tissue. Dexamethasone treatment had minimal effects on visceral fat accumulation while increasing IMCL(TA) levels approximately 30% (P < 0.05) compared with controls. Dexamethasone increased plasma glucose by twofold and increased the saturated fatty acid content of plasma lipids [fatty acid (CH2)n/omegaCH3 ratio +15%, P < 0.05]. The lipid composition of the TA muscle was unchanged by dexamethasone treatment, indicating that the relative increase in IMCL(TA) observed in vivo resulted from a decrease in lipid oxidation. Visceral adiposity may influence IMCL accumulation in the context of dietary manipulations; however, a "causal" relationship still remains to be determined. Dexamethasone-induced insulin resistance likely operates under a different mechanism, i.e., independently of visceral adiposity.


A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease.
Creatine and minocycline were prioritized for testing in Phase II clinical trials based on a systematic evaluation of potentially disease modifying compounds for Parkinson disease (PD). To test whether creatine and minocycline alter the course of early PD relative to a predetermined futility threshold for progression of PD in a randomized, double-blind, Phase II futility clinical trial. Agents that do not perform better than the futility threshold are rejected as futile and are not considered for further study. Participants had a diagnosis of PD within 5 years, but did not require medications for the management of symptoms. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score from baseline to either the time when there was sufficient disability to warrant symptomatic therapy for PD or 12 months, whichever came first. Subjects were randomized 1:1:1 to receive creatine 10 g/day, minocycline 200 mg/day, or matching placebo. The futility threshold was set as a 30% reduction in UPDRS progression based on the placebo/tocopherol arm of the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. p values < or = 0.1 indicate futility. Two hundred subjects were randomized to the three groups. Neither creatine (p = 0.96) nor minocycline (p = 0.66) could be rejected as futile based on the DATATOP futility threshold. The rate of progression for the calibration placebo group fell outside the 95% CI for the DATATOP historical control. In a sensitivity analysis, based on the threshold derived from the calibration placebo group, again neither drug could be rejected as futile. Tolerability was 91% in the creatine group and 77% in the minocycline group. Common adverse events included upper respiratory symptoms (26%), joint pain (19%), and nausea (17%). Both creatine and minocycline should be considered for definitive Phase III trials to determine if they alter the long term progression of Parkinson disease (PD). Additional factors must be weighed before selecting agents for Phase III trials, including safety, tolerability, activity, cost, and availability of these two agents in comparison with other agents currently in development for PD.


Antithrombotic effect and mechanism of Rubus spp. Blackberry.
The compounds of Rubus spp. Blackberry (RSB) were isolated and identified by a bioassay-guided method, and their antithrombotic effects and mechanism were investigated with the acute blood stasis rat model. The RSB extract was evaluated by activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), and fibrinogen (FIB) assays in vitro. Results indicated that RSB extract exhibited anticoagulant activity. In addition to compounds 1 and 6, the other compounds also exhibited anticoagulant activity in vitro. Therefore, the in vivo antithrombosis effects of RSB extract were investigated by measuring whole blood viscosity (WBV), plasma viscosity (PV), APTT, PT, TT, and FIB. Meanwhile, the levels of thromboxane B2 (TXB2), 6-keto prostaglandin F1α (6-keto-PGF1α), endothelial nitric oxide synthase (eNOS) and ET-1 (endothelin-1) were measured. Results suggested that RSB extract had inhibitory effects on thrombus formation, and its antithrombotic effects were associated with the regulation of vascular endothelium active substance, activation of blood flow and an anticoagulation effect.


The importance of parental beliefs and support for pedometer-measured physical activity on school days and weekend days among Canadian children.
Parental influences are essential to the behaviours and physical activity of their children. Our study aimed to determine if parental beliefs and support are associated with children's pedometer measured physical activity levels on school days and weekend days. In the spring of 2009 and 2011, we analyzed cross-sectional data from 1,355 grade five students and parents in 30 schools in Alberta, Canada. Parents reported how much they care about exercising, how much they encourage their child to be physically active, and how frequently they engage in physical activities with their child. Physical activity was assessed from step counts obtained from time-stamped pedometers collected over nine consecutive days. Increased parental encouragement was positively associated with boys' and girls' physical activity on school days (Boys: beta = 1373, 95% CI: 606, 2139; Girls: beta = 632, 95% CI: 108, 1155) and girls' physical activity on weekend days (beta = 997, 95% CI: 130, 1864). Increased parental care was positively associated with boys' physical activity on weekend days (beta = 1381, 95% CI: 85, 2676). Increased parental support and engagement was associated with an additional 632-1381 steps/day for children in this study. Parental care, encouragement and engagement are associated with physical activity levels of children 10-11 years of age. Policy makers and researchers should consider the importance of targeting parents when designing strategies to promote physical activity in children. This is particularly relevant to weekends and holidays when children's activity levels are low.


Pneumococcal vaccination and risk of myocardial infarction.
Based on promising results from laboratory studies, we hypothesized that pneumococcal vaccination would protect patients from myocardial infarction. We conducted a hospital-based case-control study that included patients considered to be at risk of myocardial infarction. We used health databases to obtain hospital diagnoses and vaccination status. We compared patients who had been admitted for treatment of myocardial infarction with patients admitted to a surgical department in the same hospital for a reason other than myocardial infarction between 1997 and 2003. We found a total of 43 209 patients who were at risk; of these, we matched 999 cases and 3996 controls according to age, sex and year of hospital admission. Cases were less likely than controls to have been vaccinated (adjusted odds ratio [OR] 0.53, 95% confidence interval [CI] 0.40-0.70). This putative protective role of the vaccine was not observed for patients who had received the vaccine up to 1 year before myocardial infarction (adjusted OR 0.85, 95% CI 0.54-1.33). In contrast, if vaccination had occurred 2 years or more before the hospital admission, the association was stronger (adjusted OR 0.33, 95% CI 0.20-0.46). Pneumococcal vaccination was associated with a decrease of more than 50% in the rate myocardial infarction 2 years after exposure. If confirmed, this association should generate interest in exploring the putative mechanisms and may offer another reason to promote pneumococcal vaccination.


Synthesis, characterization and photoinduced curing of polysulfones with (meth)acrylate functionalities.
The UV-curable telechelic polysulfones with (meth)acrylate functionalities were synthesized by condensation polymerization and subsequent esterification. The final polymers and intermediates at various stages were characterized by ¹H NMR, FT-ATR, and GPC. The oligomeric films prepared from the appropriate solutions containing these telechelics and 2,2-dimethoxy-2-phenylacetophenone (DMPA) as the photoinitiator undergo rapid polymerization upon irradiation forming insoluble networks. The photo-curing behavior was investigated by photo-DSC and the effects of the molecular weight of the polysulfone precursor and type of functionality on the rate of polymerization and conversion were evaluated. Thermal properties of the photochemically cured films were studied by differential scanning calorimeter (DSC) and thermal gravimetric analysis (TGA).


Gaussian mixture model-based noise reduction in resting state fMRI data.
Neuroimaging the default mode network (DMN) in resting state has been of significant interest for investigating pathological conditions as resting state data are less affected by the variability in the subject's performance and movement-related artefacts in the electromagnetic field which are often issues in event-related activation experiments. An issue to be considered with resting state data is the very low amplitude of the activation patterns which are not induced by any stimulation or stimulus paradigm. Though, many studies have suggested that amplitude of low frequency fluctuation (ALFF) analysis is suitable for resting state functional magnetic resonance imaging (fMRI) data analysis, the low signal-to-noise-ratio (SNR) of acquired neuroimaging data poses a significant problem in the accurate analysis of the same. In this work, a Gaussian Mixture Model (GMM) method to suppress the noise during data pre-processing before ALFF is applied (GMM-ALFF) is proposed, where the optimum numbers of Gaussian distributions are fitted to the data using the Bayesian information criterion (BIC). The method has been tested with artificial data as well as real resting state fMRI data collected from Alzheimer's disease patients with different levels of added noise. Improvement of as much as 40% for artificial datasets and at least 3% for real datasets (p<0.05) have been observed when applying the proposed GMM approach prior to the analysis with the existing ALFF approach.


The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy. Results of National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials B-04 and B-06.
In the current study, the authors compared the incidence of subsequent primary lung carcinoma in patients with breast carcinoma who received radiotherapy as part of their treatment and in those patients who did not. The patients were participants in two large National Surgical Adjuvant Breast and Bowel Project (NSABP) breast carcinoma trials, B-04 and B-06, which prospectively randomized women to either undergo surgery alone or to undergo surgery and postoperative radiotherapy. The NSABP trial B-04 (1971-1974) randomized patients to undergo radical mastectomy versus total (simple) mastectomy and radiotherapy to the chest wall, axilla, and supraclavicular and internal mammary lymph node areas. For patients with a clinically uninvolved axilla, there was a third randomization arm: total mastectomy without radiotherapy. The B-06 trial (1976-1984) randomized patients between those undergoing total mastectomy versus lumpectomy versus those undergoing lumpectomy and breast irradiation, with all patients undergoing an axillary lymph node dissection. The records of all patients who developed a recurrence in the lung or a new primary lung tumor were reviewed to determine the incidence and laterality of confirmed and probable primary lung carcinoma. For the 1665 evaluable patients on the NSABP B-04 trial (mean follow-up of 21.4 years), there was a total of 23 subsequent confirmed and probable ipsilateral or contralateral primary lung carcinomas. In those patients who had received comprehensive postmastectomy radiotherapy, there was a statistically significant increase in the incidence of these new primary tumors (P = 0.029). With regard to the development of confirmed new primary ipsilateral lung carcinoma alone, the incidence was statistically significantly increased (P = 0.013) in those patients who had received radiotherapy as part of their treatment, and when confirmed and probable ipsilateral lung carcinomas were analyzed, there was a strong trend toward a statistically significant increase in those patients who had received radiotherapy (P = 0.066). For the 1850 evaluable patients on the NSABP trial B-06 (mean follow-up of 19.0 years), there was a total of 30 second primary lung carcinomas but no increase in either ipsilateral or contralateral primary tumors of the lung in those patients who had received radiotherapy. Extensive postmastectomy irradiation of the chest wall and regional lymphatic node areas, with consequent exposure of a greater volume of lung to higher doses as administered in the NSABP B-04 trial compared with postlumpectomy breast irradiation in the NSABP B-06 trial, was associated with an increased incidence of subsequent primary lung tumors, both ipsilateral and contralateral.


Action of propolis and medications against Escherichia coli and endotoxin in root canals.
This study evaluated the action of propolis and intracanal medications against Escherichia coli and endotoxin. Forty-eight dental roots were contaminated with E. coli. The root canals were instrumented with propolis and divided into groups according to the type of intracanal medication: Ca(OH)(2), polymyxin B, or Ca(OH)(2) + 2% chlorhexidine gel. In the control group, saline solution was used without application of intracanal medication. Counts of colony-forming units were carried out and the endotoxin was quantified by the chromogenic Limulus amobocyte lysate assay. The results were evaluated by analysis of variance and the Dunn test (5%). Root canal irrigation with propolis was effective to completely eliminate E. coli and reduce the amount of endotoxins. All intracanal medications contributed to the significant decrease in endotoxins. Only intracanal medications may reduce the amount of endotoxins in the root canals. The greatest efficacy was observed for medications containing Ca(OH)(2).


[Simultaneous operations on the carotid and coronary arteries - the risk is due to?].
The article deals with the findings of a retrospective study regarding the incidence of risk factors for unfavourable outcomes during interventions on coronary arteries in patients presenting with atherosclerotic lesions of the carotid basin as compared to aortocoronary bypass grafting alone, followed by analysing individual risk factors. Also evaluated herein is the incidence rate of complications after coronary bypass grafting in patients presenting with various concomitant pathology, followed by determining the relative risk influencing hospital mortality both by groups as a whole and with due regard for stratification along the most significant risk factors. The study comprised a total of 74 patients with combined atherosclerotic lesions of carotid and coronary arteries, who were simultaneously subjected to revascularization of the myocardium and carotid basin. The control group was composed of 1,128 patients undergoing coronary bypass grafting alone. All patients were treated at the Federal Centre for Cardiovascular Surgery under the Russian Federation Ministry of Public Health and Social Development (Penza) from October 2008 to December 2011. The obtained findings confirmed the proposition that a simultaneous intervention of the CA does not increase the postoperative complications rate. The method of stratification demonstrated that the risk for the development of lethal outcomes in such patients turned out considerably higher. Patients with CA stenosis run higher risks of operational vascular complications, which is confirmed by a comparable level of mortality, cerebral strokes and myocardial infarction with the stratified group of patients having similar incidence of risk factors. Preventive interventions on the CA are aimed at decreasing operative complications and bring no additional risk to the lethality rate.


Stigma and suicidal ideation among young people at risk of psychosis after one year.
Suicidality is common among individuals at risk of psychosis. Emerging findings suggest that mental illness stigma contributes to suicidality. However, it is unclear whether stigma variables are associated with suicidality among young people at risk of psychosis. This longitudinal study assessed perceived public stigma and the cognitive appraisal of stigma as a stressor (stigma stress) as predictors of suicidal ideation among individuals at risk of psychosis over the period of one year. One hundred and seventy-two participants between 13 and 35 years of age were included who were at high or ultra-high risk of psychosis or at risk of bipolar disorder. At one-year follow-up, data were available from 73 completers. In multiple logistic regressions an increase of stigma stress (but not of perceived stigma) over one year was significantly associated with suicidal ideation at one-year follow-up, controlling for age, gender, symptoms, comorbid depression and suicidal ideation at baseline. Interventions to reduce public stigma and stigma stress could therefore improve suicide prevention among young people at risk of psychosis.


Differential Sensitivities of Fast- and Slow-Cycling Cancer Cells to Inosine Monophosphate Dehydrogenase 2 Inhibition by Mycophenolic Acid.
As uncontrolled cell proliferation requires nucleotide biosynthesis, inhibiting enzymes that mediate nucleotide biosynthesis constitutes a rational approach to the management of oncological diseases. In practice, however, results of this strategy are mixed and thus elucidation of the mechanisms by which cancer cells evade the effect of nucleotide biosynthesis restriction is urgently needed. Here we explored the notion that intrinsic differences in cancer cell cycle velocity are important in the resistance toward inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). In short-term experiments, MPA treatment of fast-growing cancer cells effectively elicited G0/G1 arrest and provoked apoptosis, thus inhibiting cell proliferation and colony formation. Forced expression of a mutated IMPDH2, lacking a binding site for MPA but retaining enzymatic activity, resulted in complete resistance of cancer cells to MPA. In nude mice subcutaneously engrafted with HeLa cells, MPA moderately delayed tumor formation by inhibiting cell proliferation and inducing apoptosis. Importantly, we developed a lentiviral vector-based Tet-on label-retaining system that enables to identify, isolate and functionally characterize slow-cycling or so-called label-retaining cells (LRCs) in vitro and in vivo. We surprisingly found the presence of LRCs in fast-growing tumors. LRCs were superior in colony formation, tumor initiation and resistance to MPA as compared with fast-cycling cells. Thus, the slow-cycling compartment of cancer seems predominantly responsible for resistance to MPA.


The Astrocyte: Powerhouse and Recycling Center.
Brain metabolism is characterized by fuel monodependence, high-energy expenditure, autonomy from the rest of body, local recycling, and marked division of labor between cell types. Although neurons spend most of the brain's energy on signaling, astrocytes bear the brunt of the metabolic load, controlling the composition of the interstitial fluid, supplying neurons with energy substrates and precursors for biosynthesis, and recycling neurotransmitters, oxidized scavengers, and other waste products. Outstanding questions in this field are the role of oligodendrocytes, the metabolic behavior of the different subtypes of astrocytes during development and disease, and the emerging notion that metabolism may participate directly in information processing.


The Downrange Acoustic Toolbox: An Active Solution for Combat-Related Acute Acoustic Trauma.
Frontline military personnel are at high risk of acute acoustic trauma (AAT) caused by impulse noise, such as weapon firing or blast. This can result in anatomic disruption of the tympanic membrane and damage to the middle and inner ear, leading to conductive, sensorineural, or mixed hearing loss that may be temporary or permanent. AAT reduces warfighters' operational effectiveness and has implications for future quality of life. Hearing protection devices can mitigate AAT but are not completely protective. Novel therapeutic options now exist; therefore, identification of AAT as soon as possible from point of injury is vital to ensure optimal treatment and fulfillment of the duty of care. Early recognition and treatment of frontline AAT can maintain the deployed team's capabilities, avoid unnecessary case evacuation (CASEVAC), and raise awareness of military occupational AAT. This will help prioritize hearing preservation, maintain the fighting force, and ultimately retain personnel in service. The UK Defence hearWELL research collaboration has developed a frontline protocol for the assessment of AAT utilizing future-facing technology developed by the US Department of Defense: the Downrange Acoustic Toolbox (DAT). The DAT has been operationally deployed since 2019 and has successfully identified AAT requiring treatment, thereby improving casualties' hearing and reducing unnecessary repatriation.


The Role of Psychogeriatrics in Healthy Living and Active Ageing.
A healthy and active life is a key issue for elderly citizens, above all when psychological complications such as depression and anxiety disorders, late delusion or loneliness can be observed. Moreover, medical pathologies in elderly patients often have a multi-factorial etiology and many psychopathological dimensions and psychosocial risk factors are underestimated. From the perspective of clinical health psychology, psychogeriatrics could play an important role in promoting active ageing and a healthy lifestyle in elderly persons through tailored clinical approaches based on specific research and advanced professional training in this area. More research is needed in order to study which determinants affect the process of an active and functional ageing. Possible research ageing areas are: 1) evaluation of psychosocial risk-protective factors related to the individual's biography and personality. 2) Evaluation of enrichment programs and clinical protocols focused on the management of different topics such as health system areas, behavioral areas, social and physical environment areas, psychological factors and economic determinants. The goal of Psychogeriatrics endeavors to develop and evaluate interventions designed to stimulate improvement in friendship, self-esteem and subjective well-being, as well as to reduce loneliness among older citizens. 3) Evaluation of self-management programs in chronic disease conditions (such as obesity, diabetes, hypertension, poor nutrition, physical inactivity, alcohol abuse and tobacco smoking), that could enhance risk factors for health in elderly citizens. Typical key elements of self-management, such as decision making, problem solving, motivation, self-efficacy, resource utilization, and citizen's empowerment have to be studied.


Initiatives and strategies for development of nanotechnology in nations: a lesson for Africa and other least developed countries.
It is a known fact that the progress and development of different nations of the world is strongly connected with the type of materials under their use. This paper highlighted the development of nanotechnology in some selected countries of the world through a careful review of their road maps by way of public and private initiatives, funding/investment profile, human resources development, industrial potentials, and focus in order to draw inferences. The peculiar challenges and opportunities for some African nations and other least developed countries (LDC) were drawn for their economic and technological developments. This investigation was simply based on open access literatures. The review showed that although nanotechnology is new globally, most countries of the world have had growing public and private investments aimed at bringing about new materials and systems that can impact positively on their economy and ensure their global competitiveness and sustainability. The global scenario suggests the crucial role of cooperation in a multidisciplinary collaboration/partnership between government ministries, agencies, institutions, and private sector/donor agencies in order to pool enough resource capital required for activities in nanotechnology.


The prevalence and recognition rate of delirium in hospitalized elderly patients in Turkey.
Delirium is frequently observed, but generally under recognized in elderly hospitalized patients. The aims of this study were to determine the prevalence of delirium in elderly patients hospitalized at a university hospital, and to determine the recognition rate by hospital staff during hospitalization. The study included 108 consecutive patients aged ≥ 65 years that were hospitalized in the medical and surgical inpatient departments at Başkent University Hospital, Ankara, Turkey. All the patients were evaluated using the Mini Mental State Examination (MMSE) upon admission and Confusion Assessment Method (CAM) on a daily basis during hospitalization. Written documents and consultation requests from psychiatry and/or neurology departments were reviewed for recognition of delirium by hospital staff. Among the 108 patients in the study, delirium was noted in 18 (16.7%) during their hospital stay. Consultation from psychiatry or neurology departments was requested for 5 of the 18 patients, only 1 with a delirium diagnosis, indicating that 17 of the cases (94.4%) were not recognized by their primary physicians. The delirium non-recognition rate in elderly hospitalized patients was very high. We think that hospital staff must be trained to recognize the symptoms of delirium and identify high-risk patients.


Idiopathic systemic granulomatous disease and macrophage expression of PTHrP in a miniature pony.
Idiopathic systemic granulomatous disease, which has been reported in horses, cattle and human beings, is characterized by perivascular granulomatous and lymphoplasmacytic inflammation in many organ systems. Diagnosis is based on the exclusion of possible viral, fungal or bacterial causes. The disease was identified in a miniature pony with widespread lymphoplasmacytic and granulomatous inflammation, special staining techniques having revealed no evidence of any aetiological agent. Skin lesions, which were severe, consisted of hyperkeratosis and serocellular crust formation, with inflammatory infiltrates in a perivascular to diffuse pattern in both the superficial and deep dermis. Inflammatory infiltrates were also present in lymph nodes and around the blood vessels in most organs. Immunohistochemically, both CD3-positive T lymphocytes and BLA36-positive B lymphocytes were identified in the inflammatory infiltrates, and macrophages were immunolabelled for parathyroid hormone-related protein, a factor associated with hypercalcaemia in human beings with granulomatous diseases.


Factors influencing householders' access to improved water in low-income urban areas of Accra, Ghana.
We analysed householders' access to improved water for drinking and other domestic uses in five selected low-income urban areas of Accra, Ghana using a survey of 1,500 households. Our definitions of improved water were different from those suggested by the World Health Organization (WHO). The results revealed that only 4.4% of the respondents had access to improved drinking water compared to 40.7% using the WHO definition. However, 88.7% of respondents had access to improved water for domestic uses compared to 98.3% using the WHO definition. Using logistic regression analysis, we established that the significant determinant of householders' access to improved drinking water was income. However, for access to improved water for other domestic uses, the significant factors were education, income and location of the household. Compared to migrants, indigenous people and people from mixed areas were less likely to have access to improved water for other domestic purposes. For the analysis using the WHO definitions, most of the independent variables were not statistically significant in determining householders' access, and those variables that were significant generated parameter estimates inconsistent with evidence from the literature and anecdotal evidence from officials of public health and water supply companies in Ghana.


Screening behaviors among African American women at high risk for breast cancer: do beliefs about god matter?
To examine the relationship between beliefs about God as a controlling force in health and adherence to breast cancer screening among high-risk African American women. Cross-sectional cohort. In-person interviews in rural, southeastern Louisiana and telephone interviews conducted at the University of Utah. 52 females who were members of a large kindred with a BRCA1 mutation; no subjects had breast cancer. Survey through in-person or telephone interviews. Belief in God as a controlling agent over health measured by the God Locus of Health Control (GLHC) scale; screening behaviors measured by self-report. Adherence was based on consensus-approved recommendations for BRCA1 carriers or women at risk of being carriers. Bivariate analysis indicated that presence of a primary care provider and low GLHC scores were associated with seeking clinical breast examination (CBE) and mammography. With the variable "presence of a primary care provider" excluded, GLHC scores were inversely associated with seeking CBE and mammography. African American women at increased risk for breast cancer and with high GLHC scores may have a decreased inclination to adhere to CBE and mammography recommendations. Assessing religious and spiritual beliefs and incorporating belief systems into education and counseling sessions may improve understanding and acceptance of presented material.


Standards of care of diabetic patients in a typical English community.
Poole has a well-established system of sharing care of patients with diabetes between hospital and general practitioners. Very few comprehensive audits of the effectiveness of such a system, which is being adopted in many areas of the UK, have been carried out. A study was set up to survey structure, process and outcome of care for as many diabetic patients in the Poole area as possible, and to feed the results back to individual practices. Structure criteria were assessed by self-completion questionnaire. Process and outcome criteria were assessed by visits to practices and examination of individual patient notes. A total of 37 practices were visited and the notes of 3974 patients reviewed. Results were analysed by practice and for the district as a whole, and were sent to each practice for comparison. The overall prevalence of diabetes in the area was 1.61%, with a marked preponderance of elderly patients (14.1% were over 80). The overall male to female ratio was 1.2:1. The structure questionnaire pinpointed deficiencies in audit facilities, completeness of diabetic registers, and in general use of optometrists and chiropodists. Process criteria analysis showed that, within the last 13 months, 44% of patients under sole care of a general practitioner had undergone full eye examination, cholesterol levels had been checked in 25%, smoking status in 50%, and some foot inspection had been carried out in 57%. Glycaemic control and blood pressure had been measured in over 75% of patients. Outcome analysis showed, in those patients in which they were measured, mean glycosylated haemoglobin (Hba1c) to be 8.07% (upper limit of normal, ULN = 6.5%), some degree of retinopathy to be present in 17.3%, hypertension in 27%, and hypercholesterolaemia in 33%. Standards of care of diabetics by general practitioners in the Poole area are not optimal, although they are as good as those reported for other districts. Glycaemic control was generally poor, especially in those patients needing insulin to control the disease. Vascular disease risk factors need to be targeted, and eye examination systems and chiropody services improved.