Effectiveness and cost of atypical versus typical antipsychotic treatment for schizophrenia in routine care.
In two recent randomised clinical trials, a meta-analysis and in an effectiveness study analysing routine data from the U.S. Veterans Administration the superiority of the newer atypical drugs over typical antipsychotic drugs, concerning both their efficacy and their side-effect profile, has been questioned. To analyse the effectiveness and cost of atypical versus typical antipsychotic treatment for schizophrenia in routine care. Cohort study using routine care data from a statutory sickness fund with 5.4 million insured in Germany. To be included, patients had to be discharged with a diagnosis of schizophrenia in 2003 and fulfil membership criteria. Main outcome measures were rehospitalisation rates, mean hospital bed days, mean length of stay, cost of inpatient and pharmaceutical care to the sickness fund during follow-up and medication used to treat side-effects. 3121 patients were included into the study. There were no statistically significant differences in the effectiveness of atypical and typical antipsychotics on rehospitalisation during follow-up (rehospitalisation rate ratio 1.07, 95% confidence interval 0.86 to 1.33). However, there were consistent observations of atypical antipsychotics being more effective for severe cases of schizophrenia (14.6% of study population; >61 prior bed days per year in 2000-2002) in the follow-up period, whereas for the other severity strata typical antipsychotics seemed more effective in reducing various rehospitalisation outcomes. Patients treated with atypical antipsychotics received significantly less prescriptions for anticholinergics or tiaprid (relative risk 0.26, 95% confidence interval 0.18 to 0.38). The effectiveness of atypical antipsychotics for schizophrenia on rehospitalisation measures appeared similar to that of typical antipsychotics. With the exception of severe cases, the higher costs for atypical antipsychotics were not offset by savings from reduced inpatient care. Major limitations include the lack of statistical power for subgroup analyses, the lack of clinical severity scale data and of life-course medical history data which both increase the risk of residual confounding by disease severity. This study provides evidence that the effectiveness of atypical and typical antipsychotics measured in terms of hospital readmissions appears to be similar in routine care. From a clinical perspective, this study provides evidence that the effectiveness of atypical and typical antipsychotics measured in terms of hospital readmissions appears to be similar in routine care. Routine data studies can yield valuable information for policy decision-makers on the costs and the effectiveness of pharmaceuticals in routine care, complementing efficacy data from randomised clinical trials currently used for licensing and reimbursement decisions. The non-significant differences in the effectiveness of atypical compared to typical antipsychotics according to severity of disease should be investigated in a prospective observational study or in a randomised clinical trial.


Are neonicotinoid insecticides driving declines of widespread butterflies?
There has been widespread concern that neonicotinoid pesticides may be adversely impacting wild and managed bees for some years, but recently attention has shifted to examining broader effects they may be having on biodiversity. For example in the Netherlands, declines in insectivorous birds are positively associated with levels of neonicotinoid pollution in surface water. In England, the total abundance of widespread butterfly species declined by 58% on farmed land between 2000 and 2009 despite both a doubling in conservation spending in the UK, and predictions that climate change should benefit most species. Here we build models of the UK population indices from 1985 to 2012 for 17 widespread butterfly species that commonly occur at farmland sites. Of the factors we tested, three correlated significantly with butterfly populations. Summer temperature and the index for a species the previous year are both positively associated with butterfly indices. By contrast, the number of hectares of farmland where neonicotinoid pesticides are used is negatively associated with butterfly indices. Indices for 15 of the 17 species show negative associations with neonicotinoid usage. The declines in butterflies have largely occurred in England, where neonicotinoid usage is at its highest. In Scotland, where neonicotinoid usage is comparatively low, butterfly numbers are stable. Further research is needed urgently to show whether there is a causal link between neonicotinoid usage and the decline of widespread butterflies or whether it simply represents a proxy for other environmental factors associated with intensive agriculture.


The Xenopus laevis isoform of G protein-coupled receptor 3 (GPR3) is a constitutively active cell surface receptor that participates in maintaining meiotic arrest in X. laevis oocytes.
Oocytes are held in meiotic arrest in prophase I until ovulation, when gonadotropins trigger a subpopulation of oocytes to resume meiosis in a process termed "maturation." Meiotic arrest is maintained through a mechanism whereby constitutive cAMP production exceeds phosphodiesterase-mediated degradation, leading to elevated intracellular cAMP. Studies have implicated a constitutively activated Galpha(s)-coupled receptor, G protein-coupled receptor 3 (GPR3), as one of the molecules responsible for maintaining meiotic arrest in mouse oocytes. Here we characterized the signaling and functional properties of GPR3 using the more amenable model system of Xenopus laevis oocytes. We cloned the X. laevis isoform of GPR3 (XGPR3) from oocytes and showed that overexpressed XGPR3 elevated intraoocyte cAMP, in large part via Gbetagamma signaling. Overexpressed XGPR3 suppressed steroid-triggered kinase activation and maturation of isolated oocytes, as well as gonadotropin-induced maturation of follicle-enclosed oocytes. In contrast, depletion of XGPR3 using antisense oligodeoxynucleotides reduced intracellular cAMP levels and enhanced steroid- and gonadotropin-mediated oocyte maturation. Interestingly, collagenase treatment of Xenopus oocytes cleaved and inactivated cell surface XGPR3, which enhanced steroid-triggered oocyte maturation and activation of MAPK. In addition, human chorionic gonadotropin-treatment of follicle-enclosed oocytes triggered metalloproteinase-mediated cleavage of XGPR3 at the oocyte cell surface. Together, these results suggest that GPR3 moderates the oocyte response to maturation-promoting signals, and that gonadotropin-mediated activation of metalloproteinases may play a partial role in sensitizing oocytes for maturation by inactivating constitutive GPR3 signaling.


Follow-up of patients with localized breast cancer and first indicators of advanced breast cancer recurrence: A retrospective study.
We conducted a retrospective study to assess the follow-up of patients with localized breast cancer and the first indicators of advanced breast cancer recurrence. All patients with advanced breast cancer recurrence treated between January 2010 and June 2016 in our institution were registered. Among these patients, 303 patients initially treated for early breast cancer with curative intent were identified. After initial curative treatment, follow-up involved the oncologist, the general practitioner and the gynecologist in 68.0%, 48.9% and 19.1% of cases, respectively. The median DFI was 4 years for luminal A, 3.8 years for luminal B, 3.7 years for HER2-positive and 1.5 years for TNBC (p = 0.07). Breast cancer tumor marker was prescribed for 164 patients (54.1%). No difference in terms of follow-up was observed according to the molecular subtype. Symptoms were the primary indicator of relapse for 143 patients (47.2%). Breast cancer recurrence was discovered by CA 15.3 elevation in 57 patients (18.8%) and by CAE elevation in 3 patients (1%). The rate of relapse diagnosed by elevation of CA 15.3 or CAE was not statistically associated with the molecular subtype (p = 0.65). Luminal A cases showed a significantly higher rate of bone metastases (p = 0.0003). TNBC cases showed a significantly higher rate of local recurrence (p = 0.002) and a borderline statistical significant higher rate of lung/pleural metastases (p = 0.07). Follow-up recommendations could be adapted in clinical practice according to the molecular subtype. General practitioners should be more involved by the specialists in breast cancer follow-up.


[Prevalence of risk factors for cardiovascular diseases in the east region of Goiânia, Goiás State].
Aiming to investigate the prevalence of cardiovascular risk factors in the population of the Eastern Region of Goiania, Goiás, a transversal study was done involving 3.275 individuals, men and women, aging 15 years and up. Data was collected through home visits for identification and information on living habits, measures blood pressure, anthropometry, and blood collection for identifying dyslipidemias. The variables investigated were: weight, height, blood pressure, physical activity, use of tobacco, cholesterol, triglycerides and glucose. Estimated prevalence at intervals of 95% confidence, differences in proportions assessed using chi-square test and values (p <0,05) considered statistically significant. The study showed that 33,4% of subjects had hypertension, 44.1% overweight/obesity, 16.2% used tobacco regular/occasionally; 72.5% in sedentary leisure and 70% at work, 48.4% with the waist circumference increased; 8.2% hyperglycemia plus impaired glucose tolerance; 44.4% hypercholesterolemia, 13.3% and high triglycerides. High prevalence of cardiovascular risk factors were observed in the study population suggesting greater attention of the authorities in the actions of promotion and prevention of these diseases.


Significant associations between CCL5 gene polymorphisms and post-transplantational diabetes mellitus in Korean renal allograft recipients.
Post-transplantational diabetes mellitus (PTDM) is a serious metabolic complication that may follow renal transplantation. The expression of chemokine (C-C motif) ligand 5 (CCL5) is inversely related to pancreatic β-cell function; thus, specific CCL5 gene polymorphisms are considered to be risk factors for diabetes. In this study, we investigated the association between CCL5 gene polymorphisms and the occurrence of PTDM in Korean patients who had undergone renal transplants. A total of 311 patients who had received kidney transplants without a prior history of diabetes were included. Three single nucleotide polymorphisms (SNPs) of the CCL5 gene were genotyped from genomic DNA with direct sequencing. PTDM developed in 56 patients (18.0%). The results showed that the allele frequencies of CCL5 gene polymorphisms, rs2107538*T, rs2280789*C and rs3817655*A were significantly higher in the patients with PTDM than in those without PTDM. In multiple logistic regression analysis, 3 SNPs (rs2107538, rs2280789 and rs3817655) of the CCL5 gene were significantly associated with the development of PTDM in the codominant 2 and recessive models. Among haplotypes of the 3 polymorphisms, the frequency of the TCA haplotype was significantly higher in patients with PTDM than in those without PTDM. Our results indicated that genetic polymorphisms of the CCL5 gene were associated with PTDM, suggesting that the CCL5 gene might confer susceptibility to PTDM in patients who receive renal transplants.


Family Stress, Well-Being and Hope for the Future When Supporting a Relative with AOD Misuse: A Cross-Sectional Survey.
While families have a central role supporting relatives with alcohol and other drug (AOD) misuse, this can undermine their own well-being and hopefulness. The aims of this study were to assess the effect of supporting a relative with AOD misuse on affected family members' (AFMs) psychological and physical well-being and hope for the future about their relative, and to identify factors associated with AFMs' well-being and hope. A cross-sectional survey design with 90 AFMs. Over three-quarters of AFMs had not received any assistance from AOD services recently, nearly 80% experienced adverse effects on their physical health and ability to socialise with relatives and friends, and just over 50% reported detrimental effects on their paid employment. AFMs living with their relative with AOD misuse experienced more harmful stress than those who were not residing with their relative. Intimate partner AFMs experienced more mild-to-moderate physical and psychological ill health than non-partner AFMs. No socio-demographic factors were significantly associated with AFMs' levels of hopefulness-hopelessness. Measures are needed to increase AFMs' access to mental health nurses and other AOD clinicians for their own needs. Services and AOD clinicians should target, but not be restricted to, reducing stress and strengthening their physical and mental well-being and hopefulness.


Independent regulation of cutaneous lymphocyte-associated antigen expression and cytokine synthesis phenotype during human CD4+ memory T cell differentiation.
Although considerable attention has been paid to the development of cytokine synthesis heterogeneity during memory T cell differentiation, little information is available on how this function is coregulated with homing receptor expression. The development of skin-homing, CD4+ memory T cells in the human provides an excellent model for such investigation, since 1) the skin supports both Th1- and Th2-predominant responses in different settings, and 2) the skin-homing capability of human memory T cells correlates with and appears to depend on expression of the skin-selective homing receptor cutaneous lymphocyte-associated Ag (CLA). In this study, we used multiparameter FACS analysis to examine expression of CLA vs IFN-gamma, IL-4, and IL-2 synthesis capabilities among fresh peripheral blood CD4+ memory T cells, and Th1 vs Th2 memory T cells generated in vitro from purified CD4+ naive precursors by cyclic activation in polarizing culture conditions. Among normal peripheral blood T cells, CLA expression was essentially identical among the IFN-gamma- vs IL-4-producing CD4+ memory subsets, clearly indicating the existence of in vivo mechanisms capable of producing both Th1 vs Th2 skin-homing T cells. In vitro differentiation of naive CD4+ T cells confirmed the independent regulation of CLA and all three cytokines examined, regulation that allowed differential production of IFN-gamma-, IL-4-, and IL-2-producing, CLA+ memory subsets. These studies also 1) demonstrated differences in regulatory factor activity depending on the differentiation status of the responding cell, and 2) revealed CLA expression to be much more rapidly reversible on established memory cells than cytokine synthesis capabilities.


Diabetic ketoasidosis is associated with prothrombotic tendency in children.
Children and adolescents with type I diabetes mellitus (DM) may present with diabetic ketoacidosis (DKA), which is associated with significant morbidity and mortality. This study aimed to evaluate the hematological parameters at diagnosis (0th hour) and 96th hour after the initiation of treatment in children with DKA. Twenty-six children with DKA treated in Dicle University Faculty of Medicine between September 2002 and August 2003 were included in this study. General characteristics of the patients and hematological parameters (platelet count, white blood cell count, prothrombin time, partial thromboplastin time (PTT), bleeding time, coagulation time, protein C, protein S, antithrombin III, fibrinogen, D-dimer, factor VIII, factor IX, and factor X levels) at diagnosis (0th hour) and 96th hour after the initiation of treatment were determined. The mean age of the children (10 girls and 16 boys) was 9.15 ± 3.85 years (range: 4-15 years). DKA developed for the first time in 58.3% of these children and they had recently been diagnosed as DM. After hematological parameters at 0th hour were evaluated, increased platelet count, decreased PTT, low protein C, and high factor VIII levels were determined at diagnosis, indicating prothrombotic tendency. If the hematological parameters at 0th hour were compared with those at 96th hour; platelet count decreased, PTT increased, protein C and factor VIII levels turned to be normal at 96th hour. When all the results are considered together, children with DKA appeared to have a prothrombotic tendency. Although this tendency was not reflected in clinical findings in this study, it should be kept in mind that children with DKA are prone to the development of thrombosis and they need to be investigated for the possibility of thrombosis.


Natural experiment concept to accelerate the Re-purposing of existing therapeutics for Covid-19.
One of the many questions with respect to controlling the novel coronavirus pandemic is whether existing drugs can be re-purposed (re-positioned) for the prevention or treatment of Covid-19 - or for any future epidemic. The usefulness of existing approaches for re-purposing range from computational modeling to clinical trials. These are often time-consuming, resource intensive, and prone to failure. Proposed here is a new but simple concept that would capitalize on the opportunity presented by the on-going natural experiment involving the collection of data from epidemiological surveillance screening and diagnostic testing for clinical treatment. The objective would be to also collect for each Covid-19 case the patient's prior usage of existing therapeutic drugs. These drug usage data would be collected for several major test groups - those who test positive for active SARS-CoV-2 infection (using molecular methods) and those who test negative for current infection but also test positive for past infection (using serologic antibody tests). Patients from each of these groups would also be categorized with respect to where they resided on the spectrum of morbidities (from no or mild symptomology to severe). By comparing the distribution of normalized usage data for each drug within each group, drugs that are more associated with particular test groups could be revealed as having potential prophylactic, therapeutic, or contraindicated effects with respect to disease progression. These drugs could then be selected as candidates for further evaluation in fighting Covid-19. Also summarized are some of the numerous attributes, advantages, and limitations of the proposed concept, all pointing to the need for further discussion and evaluation.


Can family physicians help patients initiate basal insulin therapy successfully?: randomized trial of patient-titrated insulin glargine compared with standard oral therapy: lessons for family practice from the Canadian INSIGHT trial.
To determine whether FPs could help patients implement bedtime basal insulin therapy as successfully as diabetes experts could. National, multicentre, randomized, open-label trial designed to assess use of bedtime basal insulin therapy compared with use of standard oral-agent therapy for patients with type 2 diabetes being treated by diabetes experts or FPs. Nineteen endocrinologist or expert sites and 34 family practices. A total of 405 adult patients with hemoglobin A1c (HbA1c) values of 7.5% to 11.0% who were taking 0 to 2 oral agents. Participants were randomized to receive either basal insulin therapy using glargine self-titrated according to a patient algorithm or conventional therapy with physician-adjusted doses of oral agents for a period of 24 weeks. The primary outcome was time to achieve 2 consecutive HbA1c values < or = 6.5%. Secondary outcomes were the proportion of subjects who achieved these HbA1c values, a fasting plasma glucose level < or = 5.5 mmol/L, and 2 consecutive HbA1c values < or = 7.0%; incidence, rate, and severity of hypoglycemia; daily variations in blood-glucose levels; and participants' lipid profiles. Post-hoc analysis sought to determine whether patients' outcomes differed in terms of the above measures depending on whether they had been treated by diabetes experts or FPs. A total of 206 patients were randomized to the glargine group, and 199 to the oral agents group. In total, 145 patients were followed by experts and 260 by FPs. Mean reductions in HbA1c and fasting plasma glucose levels and rates of hypoglycemia were comparable in the 2 groups. Patients of both types of physicians achieved significantly greater reductions in fasting plasma glucose with glargine than with oral agents (FPs: -4.14 vs -2.45 mmol/L, P = .0001; experts: -3.47 vs -2.19 mmol/L, P = .0013). Patients of FPs achieved significantly greater reductions in HbA1c levels with glargine than with oral agents (FPs: -1.64 vs -1.26%, P = .0058; experts: -1.41 vs-1.24%, P = .3331). Final mean insulin doses were higheramong FPs' patients than among experts' patients (41.74vs 31.66 units, P = .015). Family physicians were more aggressive in their use of insulin, while experts used more oral agents. There were no significant differences inefficacy of treatment. In most settings, FPs could easily implement the patient-driven bedtime basal insulin protocol used in this study.


Complete chloroplast and ribosomal sequences for 30 accessions elucidate evolution of Oryza AA genome species.
Cytoplasmic chloroplast (cp) genomes and nuclear ribosomal DNA (nR) are the primary sequences used to understand plant diversity and evolution. We introduce a high-throughput method to simultaneously obtain complete cp and nR sequences using Illumina platform whole-genome sequence. We applied the method to 30 rice specimens belonging to nine Oryza species. Concurrent phylogenomic analysis using cp and nR of several of specimens of the same Oryza AA genome species provides insight into the evolution and domestication of cultivated rice, clarifying three ambiguous but important issues in the evolution of wild Oryza species. First, cp-based trees clearly classify each lineage but can be biased by inter-subspecies cross-hybridization events during speciation. Second, O. glumaepatula, a South American wild rice, includes two cytoplasm types, one of which is derived from a recent interspecies hybridization with O. longistminata. Third, the Australian O. rufipogan-type rice is a perennial form of O. meridionalis.


Tumor-specific and HLA-A2-restricted cytolysis by tumor-associated lymphocytes in human metastatic breast cancer.
A tumor-specific cytotoxic T lymphocyte (CTL) immune response has been well documented in melanoma, renal cell carcinoma, and ovarian cancer. Conflicting evidence exists regarding the existence of tumor-specific CTL populations in breast cancer. Tumor cells and tumor-associated lymphocytes (TAL) were isolated from the pleural effusions of six consecutive patients with metastatic breast cancer. After solid-phase anti-CD3 stimulation, TAL cultures were expanded with weekly autologous tumor stimulation and low-dose IL-2 for 3 wk. T cell populations were characterized using flow cytometric analysis and ranged from 49 to 91% CD8+, > 98% CD3+, and < 3% CD16+. Functionally, tumor-stimulated TAL showed tumor-specific recognition of autologous tumor cells (241 +/- 142 LU20/10(7)) and no detectable lysis of autologous fibroblasts, Daudi or K562. Cytotoxicity of TAL against HLA-A2+ allogeneic targets was significantly higher when compared with HLA-A2- tumor cell lines (127 +/- 76 vs 6 +/- 18 LU, p = 0.0001). This cytotoxicity against autologous and allogeneic tumor cells was blocked by anti-HLA-A2 mAb and cold HLA-A2+ targets in cold-target inhibition assays. TAL from all HLA-A2+ patients recognized GP2, a known, HER2/neu-derived tumor-associated peptide Ag that is HLA-A2 restricted. We have shown that TAL obtained from metastatic effusions of breast cancer patients contain lymphocytes that can recognize and lyse autologous and allogeneic tumor cells in a tumor-specific, HLA-A2-restricted fashion. In addition, tumor-specific TAL derived from breast cancer patients can selectively lyse HLA-A2+ pancreatic and ovarian tumor cell targets, suggesting a common HLA-A2-restricted tumor-associated Ag between these distinct epithelial cancers. Further elucidation of the cell-mediated immune response to breast cancer and the identification of shared TAA could result in the development of broadly applicable vaccine therapies for many cancers.


Perinatal photoperiod and childhood cancer: pooled results from 182,856 individuals in the international childhood cancer cohort consortium (I4C).
Experimental evidence suggests that perinatal light imprinting of circadian clocks and systems may affect downstream physiology and cancer risk in later life. For humans, the predominant circadian stimulus is the daily light-dark cycle. Herein, we explore associations between perinatal photoperiod characteristics (photoperiod: duration of daylight as determined by time-of-year and location) and childhood cancer risk. We use pooled data on 182,856 mothers and babies from prospective birth cohorts in six countries (Australia, Denmark, Israel, Norway, UK, USA) within the International Childhood Cancer Cohort Consortium (I4C). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In line with predicted differential dose-responses, restricted cubic splines indicate a potential non-linear, non-monotonic relationship between perinatal mean daily photoperiod (0-24 h) and childhood cancer risk. In a restricted analysis of 154,121 individuals who experienced third trimester photoperiods exclusively within the 8-16-h range, the relative risk of developing childhood cancer decreased by 9% with every hour increase in third trimester mean daily photoperiod [HR: 0.91 (95%CIs: 0.84-0.99)]. In conclusion, in this first study of perinatal photoperiod and childhood cancer, we detected an inverse ["protective"] linear association between third trimester mean daily photoperiod and childhood cancer risk in the 8-16-h set of the total study population. Limited statistical power impeded the investigation of risks with individuals exposed to more extreme photoperiods. Future studies are needed to confirm differential photoperiod-associated risks and further investigations into the hypothesized circadian imprinting mechanism are warranted.


Vesicoureteral reflux in male and female neonates as detected by voiding ultrasonography.
Vesicoureteral reflux (VUR) is assumed to be congenital, and its early diagnosis is desired in order to prevent acquired renal damage. However, the incidence of VUR in neonates remains to be revealed. Two thousand newborn babies (1048 boys and 952 girls) underwent voiding ultrasonography (an ultrasound examination of urinary tract during provoked voiding). Those who showed transient renal pelvic dilation during voiding, who had small kidneys, or who subsequently developed urinary infection underwent voiding cystourethrography. Transient renal pelvic dilation was observed in 16 babies (0.8%), including one boy with small kidneys. Among the rest of the babies, one boy had a small kidney, and nine babies subsequently developed urinary infection. Voiding cystourethrography revealed VUR in 24 ureters of 16 children (11 boys and 5 girls). Dimercaptosuccinate renoscintigraphy confirmed small kidneys, with generally reduced tracer uptake in a total of three boys, all having VUR. Voiding ultrasonography detected transient renal pelvic dilation in 17 (71%) of the 24 kidneys with VUR and, strikingly, 16 of the 17 (94%) kidneys with high-grade VUR (grade III or more). This study effectively detected VUR in 0.8% of the neonates (mostly of high grades and predominantly in males) and voiding ultrasonography showed a decided usefulness for the detection of VUR. The male preponderance of VUR in neonates was considered to be due to the occurrence of congenitally small kidneys, with reflux found exclusively in males and easier ultrasound detection of VUR in male neonates because the majority of diagnoses are reported to be high grades of VUR.


Memantine for dementia in people with Down syndrome.
Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome (DS). There is an understanding that an increase in L-glutamate contributes to the pathogenesis of cerebral ischemias and AD. Memantine acts as an antagonist of N-methyl-D-aspartate (NMDA) type receptors, which is thought to reduce abnormal activation of glutamate neurotransmission. It binds with a low affinity to the NMDA receptor and so should not prevent learning and the formation of memory. Memantine can improve cognitive function and slow the decline of AD in the general population over time, and is the subject of this review. It is important to note that people with DS tend to present with AD at a much younger age than the normal population as well as having subtle differences in physiology (e.g. metabolism and heart rate) and may therefore have different requirements from the general population. To determine the effectiveness and safety of memantine for people with DS who develop AD. CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, BIOSIS, SCI, SSCI and the NRR were searched up to October 2008. We contacted the manufacturers of memantine, as well as experts in the field, to ask about reports of unpublished or ongoing trials. Randomised controlled trials of participants with DS and AD in which treatment with memantine was administered compared with a placebo group. No study was identified which met the inclusion criteria for this review. No study was identified which met inclusion criteria for this review, however there is an on-going randomised controlled study being conducted in the UK and data are expected in 2009. As there are no included trials, recommendations cannot be made about memantine for AD in DS. Well-designed, adequately powered studies are required.


Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis.
The extensive autophagic-lysosomal pathology in Alzheimer disease (AD) brain has revealed a major defect: in the proteolytic clearance of autophagy substrates. Autophagy failure contributes on several levels to AD pathogenesis and has become an important therapeutic target for AD and other neurodegenerative diseases. We recently observed broad therapeutic effects of stimulating autophagic-lysosomal proteolysis in the TgCRND8 mouse model of AD that exhibits defective proteolytic clearance of autophagic substrates, robust intralysosomal amyloid-β peptide (Aβ) accumulation, extracellular β-amyloid deposition and cognitive deficits. By genetically deleting the lysosomal cysteine protease inhibitor, cystatin B (CstB), to selectively restore depressed cathepsin activities, we substantially cleared Aβ, ubiquitinated proteins and other autophagic substrates from autolysosomes/lysosomes and rescued autophagic-lysosomal pathology, as well as reduced total Aβ40/42 levels and extracellular amyloid deposition, highlighting the underappreciated importance of the lysosomal system for Aβ clearance. Most importantly, lysosomal remediation prevented the marked learning and memory deficits in TgCRND8 mice. Our findings underscore the pathogenic significance of autophagic-lysosomal dysfunction in AD and demonstrate the value of reversing this dysfunction as an innovative therapeautic strategy for AD.


Hair evaluation methods: merits and demerits.
Various methods are available for evaluation (for diagnosis and/or quantification) of a patient presenting with hair loss. Hair evaluation methods are grouped into three main categories: Non-invasive methods (e.g., questionnaire, daily hair counts, standardized wash test, 60-s hair count, global photographs, dermoscopy, hair weight, contrasting felt examination, phototrichogram, TrichoScan and polarizing and surface electron microscopy), semi-invasive methods (e.g., trichogram and unit area trichogram) and invasive methods (e.g., scalp biopsy). Any single method is neither 'ideal' nor feasible. However, when interpreted with caution, these are valuable tools for patient diagnosis and monitoring. Daily hair counts, wash test, etc. are good methods for primary evaluation of the patient and to get an approximate assessment of the amount of shedding. Some methods like global photography form an important part of any hair clinic. Analytical methods like phototrichogram are usually possible only in the setting of a clinical trial. Many of these methods (like the scalp biopsy) require expertise for both processing and interpreting. We reviewed the available literature in detail in light of merits and demerits of each method. A plethora of newer methods is being introduced, which are relevant to the cosmetic industry/research. Such methods as well as metabolic/hormonal evaluation are not included in this review.


Favorable outcome in infants with AML after intensive first- and second-line treatment: an AML-BFM study group report.
Infants <1 year of age have a high prevalence of prognostically unfavorable leukemias and a presumed susceptibility to treatment-related toxicities. A total of 125 infants with acute myeloid leukemia (AML) were treated in studies AML-BFM-98 (n = 59) and -2004 (n = 66). Treatment regimens of both studies were comparable, consisting of intensive induction followed by four courses (mainly high-dose cytarabine and anthracyclines). Allogeneic-hematopoietic stem-cell-transplantation (allo-HSCT) in 1st remission was optional for high-risk (HR) patients. Most infants (120/125=96%) were HR patients according to morphological, cytogenetic/molecular genetic and response criteria. Five-year overall survival was 66 ± 4%, and improved from 61 ± 6% in study-98 to 75 ± 6% in study-2004 (P(logrank) 0.14) and event-free survival rates were 44 ± 6% and 51 ± 6% (P(logrank) 0.66), respectively. Results in HR infants were similar to those of older HR children (1-<2- or 2-<10-year olds, P(logrank) 0.90 for survival). Survival rates of HSCT in 1st remission, initial partial response and after relapse were high (13/14, 2/8 and 20/30 patients, respectively). The latter contributes to excellent 5-year survival after relapse (50±8%). Despite more severe infections and pulmonary toxicities in infants, treatment-related death rate was identical to that of older children (3%). Our data indicate that intensive frontline and relapse AML treatment is feasible in infants, toxicities are manageable, and outcome is favorable.


Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids in both humans and baboons.
Genetic studies in non-human primates serve as a potential strategy for identifying genomic intervals where polymorphisms impact upon human disease-related phenotypes. It remains unclear, however, whether independently arising polymorphisms in orthologous regions of non-human primates leads to similar variation in a quantitative trait found in both species. To explore this paradigm, we studied a baboon apolipoprotein gene cluster (APOA1/C3/A4/A5) for which the human gene orthologs have well-established roles in influencing plasma HDL-cholesterol and triglyceride concentrations. Our extensive polymorphism analysis of this 68 kb gene cluster in 96 pedigreed baboons identified several haplotype blocks each with limited diversity, consistent with haplotype findings in humans. To determine whether baboons, like humans, also have particular haplotypes associated with lipid phenotypes, we genotyped 634 well-characterized baboons using 16 haplotype tagging SNPs. Genetic analysis of single SNPs, as well as haplotypes, revealed an association of APOA5 and APOC3 variants with HDL-cholesterol and triglyceride concentrations, respectively. Thus, independent variation in orthologous genomic intervals does associate with similar quantitative lipid traits in both species, supporting the possibility of uncovering human quantitative trait loci genes in a highly controlled non-human primate model.


Arthroscopic airbrush assisted cell implantation for cartilage repair in the knee: a controlled laboratory and human cadaveric study.
The objective of this study was to investigate the feasibility of arthroscopic airbrush assisted cartilage repair. An airbrush device (Baxter) was used to spray both human expanded osteoarthritic chondrocytes and choncrocytes with their pericellular matrix (chondrons) at 1 × 10(6) cells/ml fibrin glue (Tissucol, Baxter) in vitro. Depth-dependent cell viability was assessed for both methods with confocal microscopy. Constructs were cultured for 21 days to assess matrix production. A controlled human cadaveric study (n = 8) was performed to test the feasibility of the procedure in which defects were filled with either arthroscopic airbrushing or needle extrusion. All knees were subjected to 60 min of continuous passive motion and scored on outline attachment and defect filling. Spraying both chondrocytes and chondrons in fibrin glue resulted in a homogenous cell distribution throughout the scaffold. No difference in viability or matrix production between application methods was found nor between chondrons and chondrocytes. The cadaveric study revealed that airbrushing was highly feasible, and that defect filling through needle extrusion was more difficult to perform based on fibrin glue adhesion and gravity-induced seepage. Defect outline and coverage scores were consistently higher for extrusion, albeit not statistically significant. Both chondrons and chondrocytes can be evenly distributed in a sprayed fibrin glue scaffold without affecting viability while supporting matrix production. The airbrush technology is feasible, easier to perform than needle extrusion and allows for reproducible arthroscopic filling of cartilage defects.


Structure of a longitudinal actin dimer assembled by tandem w domains: implications for actin filament nucleation.
Actin filament nucleators initiate polymerization in cells in a regulated manner. A common architecture among these molecules consists of tandem WASP homology 2 domains (W domains) that recruit three to four actin subunits to form a polymerization nucleus. We describe a low-resolution crystal structure of an actin dimer assembled by tandem W domains, where the first W domain is cross-linked to Cys374 of the actin subunit bound to it, whereas the last W domain is followed by the C-terminal pointed end-capping helix of thymosin β4. While the arrangement of actin subunits in the dimer resembles that of a long-pitch helix of the actin filament, important differences are observed. These differences result from steric hindrance of the W domain with intersubunit contacts in the actin filament. We also determined the structure of the first W domain of Vibrio parahaemolyticus VopL cross-linked to actin Cys374 and show it to be nearly identical with non-cross-linked W-Actin structures. This result validates the use of cross-linking as a tool for the study of actin nucleation complexes, whose natural tendency to polymerize interferes with most structural methods. Combined with a biochemical analysis of nucleation, the structures may explain why nucleators based on tandem W domains with short inter-W linkers have relatively weak activity, cannot stay bound to filaments after nucleation, and are unlikely to influence filament elongation. The findings may also explain why nucleation-promoting factors of the Arp2/3 complex, which are related to tandem-W-domain nucleators, are ejected from branch junctions after nucleation. We finally show that the simple addition of the C-terminal pointed end-capping helix of thymosin β4 to tandem W domains can change their activity from actin filament nucleation to monomer sequestration.


Palmitoylation targets AKAP79 protein to lipid rafts and promotes its regulation of calcium-sensitive adenylyl cyclase type 8.
PKA anchoring proteins (AKAPs) optimize the efficiency of cAMP signaling by clustering interacting partners. Recently, AKAP79 has been reported to directly bind to adenylyl cyclase type 8 (AC8) and to regulate its responsiveness to store-operated Ca(2+) entry (SOCE). Although AKAP79 is well targeted to the plasma membrane via phospholipid associations with three N-terminal polybasic regions, recent studies suggest that AKAP79 also has the potential to be palmitoylated, which may specifically allow it to target the lipid rafts where AC8 resides and is regulated by SOCE. In this study, we have addressed the role of palmitoylation of AKAP79 using a combination of pharmacological, mutagenesis, and cell biological approaches. We reveal that AKAP79 is palmitoylated via two cysteines in its N-terminal region. This palmitoylation plays a key role in targeting the AKAP to lipid rafts in HEK-293 cells. Mutation of the two critical cysteines results in exclusion of AKAP79 from lipid rafts and alterations in its membrane diffusion behavior. This is accompanied by a loss of the ability of AKAP79 to regulate SOCE-dependent AC8 activity in intact cells and decreased PKA-dependent phosphorylation of raft proteins, including AC8. We conclude that palmitoylation plays a key role in the targeting and action of AKAP79. This novel property of AKAP79 adds an unexpected regulatory and targeting option for AKAPs, which may be exploited in the cellular context.


Inhibition of hepatitis B virus replication in vivo using lipoplexes containing altritol-modified antiviral siRNAs.
Chronic infection with the hepatitis B virus (HBV) occurs in approximately 6% of the world's population and carriers of the virus are at risk for complicating hepatocellular carcinoma. Current treatment options have limited efficacy and chronic HBV infection is likely to remain a significant global medical problem for many years to come. Silencing HBV gene expression by harnessing RNA interference (RNAi) presents an attractive option for development of novel and effective anti HBV agents. However, despite significant and rapid progress, further refinement of existing technologies is necessary before clinical application of RNAi-based HBV therapies is realized. Limiting off target effects, improvement of delivery efficiency, dose regulation and preventing reactivation of viral replication are some of the hurdles that need to be overcome. To address this, we assessed the usefulness of the recently described class of altritol-containing synthetic siRNAs (ANA siRNAs), which were administered as lipoplexes and tested in vivo in a stringent HBV transgenic mouse model. Our observations show that ANA siRNAs are capable of silencing of HBV replication in vivo. Importantly, non specific immunostimulation was observed with unmodified siRNAs and this undesirable effect was significantly attenuated by ANA modification. Inhibition of HBV replication of approximately 50% was achieved without evidence for induction of toxicity. These results augur well for future application of ANA siRNA therapeutic lipoplexes.


Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease.
The objective of this study was to evaluate the efficacy and safety of three daily dosages of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) compared to placebo as monotherapy in early Parkinson's disease (PD). In MPTP (1-methyl 4-phenyl-tetrahydropyridine 1,2,3,6)-lesioned marmosets, dopamine reuptake inhibitors have been demonstrated to reverse parkinsonian signs without evoking established dyskinesia. NS 2330 inhibits reuptake of dopamine, serotonin, and norepinephrine. We performed a proof-of-concept, randomized, double-blind trial of NS 2330. Two hundred sixty-one subjects with PD < 5 years and not receiving dopaminergic treatment were randomly assigned to daily treatment with NS 2330 at 0.25 mg, 0.5 mg, 1.0 mg, or placebo. Adjusted mean difference in total Unified Parkinson's Disease Rating Scale (UPDRS) scores from baseline to week 14 was -0.7 (P = 0.64) in the 0.25-mg group, -1.3 (P = 0.41) in the 0.5-mg group, and -1.7 (P = 0.27) in the 1.0-mg group. The adjusted mean difference in total UPDRS score for the highest dose group (1.0 mg/day) was superior to placebo at week 6 (-3.1; P = 0.02), but this effect was not sustained. NS 2330 was generally well tolerated and the most commonly reported adverse events were constipation, insomnia, and dry mouth. Decreased body weight and elevated heart rate were common in the 1.0-mg dosage group. At the dosages tested, NS 2330 did not provide significantly greater benefit than placebo. It is possible that inhibition of dopamine reuptake alone does not provide clinical benefit in early PD, adequate inhibition of dopamine reuptake was not achieved in this study, or countervailing physiologic mechanisms offset the potential benefit.


Identification of in vivo-induced bacterial protein antigens during human infection with Salmonella enterica serovar Typhi.
We applied an immunoscreening technique, in vivo-induced antigen technology (IVIAT), to identify immunogenic bacterial proteins expressed during human infection with Salmonella enterica serovar Typhi, the cause of typhoid fever. We were able to assign a functional classification to 25 of 35 proteins identified by IVIAT. Of these 25, the majority represent proteins with known or potential roles in the pathogenesis of S. enterica. These include proteins implicated in fimbrial structure and biogenesis, antimicrobial resistance, heavy metal transport, bacterial adhesion, and extracytoplasmic substrate trafficking as well as secreted hydrolases. The 10 remaining antigens represent proteins with unknown functions. Of the 35 identified antigens, four had no immunoreactivity when probed with control sera from individuals never exposed to serovar Typhi organisms; these four included PagC, TcfB, and two antigens of unknown function encoded by STY0860 and STY3683. PagC is a virulence factor known to be upregulated in vivo in S. enterica serovar Typhimurium infection of mice. TcfB is the major structural subunit of a fimbrial operon found in serovar Typhi with no homolog in serovar Typhimurium organisms. By examining differential immunoreactivities in acute- versus convalescent-phase human serum samples, we found specific anti-PagC and anti-TcfB immunoglobulin G responses in patients with serovar Typhi bacteremia. Serovar Typhi antigens identified by IVIAT warrant further evaluation for their contributions to pathogenesis, and they may have diagnostic, therapeutic, or preventive uses.


Determination of the action spectrum of the blue-light hazard for different intraocular lenses.
The spectral transmittance of various models of intraocular lenses (IOLs) has been studied. Significant differences among them were found, primarily regarding the cutoff wavelength. Based on these findings, modifications of the action spectrum for the blue-light hazard photobiological effect are proposed for each type of IOL. Moreover, the potential hazard of a representative range of radiation sources to subjects implanted with those IOLs has been calculated based on the corrected action spectra.


How Therapeutic Tapping Can Alter Neural Correlates of Emotional Prosody Processing in Anxiety.
Anxiety disorders are the most common psychological disorders worldwide resulting in a great demand of adequate and cost-effective treatment. New short-term interventions can be used as an effective adjunct or alternative to pharmaco- and psychotherapy. One of these approaches is therapeutic tapping. It combines somatic stimulation of acupressure points with elements from Cognitive Behavioral Therapy (CBT). Tapping reduces anxiety symptoms after only one session. Anxiety is associated with a deficient emotion regulation for threatening stimuli. These deficits are compensated e.g., by CBT. Whether Tapping can also elicit similar modulations and which dynamic neural correlates are affected was subject to this study. Anxiety patients were assessed listening to pseudowords with a different emotional prosody (happy, angry, fearful, and neutral) prior and after one Tapping session. The emotion-related component Late Positive Potential (LPP) was investigated via electroencephalography. Progressive Muscle Relaxation (PMR) served as control intervention. Results showed LPP reductions for negative stimuli after the interventions. Interestingly, PMR influenced fearful and Tapping altered angry prosody. While PMR generally reduced arousal for fearful prosody, Tapping specifically affected fear-eliciting, angry stimuli, and might thus be able to reduce anxiety symptoms. Findings highlight the efficacy of Tapping and its impact on neural correlates of emotion regulation.


β Cell tone is defined by proglucagon peptides through cAMP signaling.
Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α to β cell communication and control of insulin secretion. Signaling through this system occurs through both the glucagon-like peptide receptor (Glp1r) and glucagon receptor (Gcgr). Loss of PGDPs, or blockade of their receptors, decreases insulin secretion in response to both metabolic and nonmetabolic stimulation of mouse and human islets. This effect is due to reduced β cell cAMP and affects the quantity but not dynamics of insulin release, indicating that PGDPs dictate the magnitude of insulin output in an isolated islet. In healthy mice, additional factors that stimulate cAMP can compensate for loss of PGDP signaling; however, input from α cells is essential to maintain glucose tolerance during the metabolic stress induced by high-fat feeding. These findings demonstrate an essential role for α cell regulation of β cells, raising the possibility that abnormal paracrine signaling contributes to impaired insulin secretion in diabetes. Moreover, these findings support reconsideration of the role for α cells in postprandial glucose control.


High pulse repetition frequency, multiple wavelength, pulsed CO(2) lidar system for atmospheric transmission and target reflectance measurements.
A multiple wavelength, pulsed CO(2) lidar system operating at a pulse repetition frequency of 200 Hz and permitting the random selection of CO(2) laser wavelengths for each laser pulse is presented. This system was employed to measure target reflectance and atmospheric transmission by using laser pulse bursts consisting of groups with as many as 16 different wavelengths at a repetition rate of 12 Hz. The wavelength tuning mechanism of the transversely excited atmospheric laser consists of a stationary grating and a flat mirror controlled by a galvanometer. Multiple wavelength, differential absorption lidar (DIAL) measurements reduce the effects of differential target reflectance and molecular absorption interference. Examples of multiwavelength DIAL detection for ammonia and water vapor show the dynamic interaction between these two trace gases. Target reflectance measurements for maple trees in winter and autumn are presented.


Cariogenicity tests.
An American Dental Association Scientific Consensus Conference on Methods for the Assessment of the Cariogenic Potential (CP) of Foods was held in San Antonio, Texas, in 1985. The aim was to establish a scientific consensus regarding methods to assess the CP of foods. As a result, a sequential food-testing program was proposed involving Animal Caries, Human Plaque Acidity, and Demineralization/Remineralization Models. Two categories of CP--namely, no CP and low CP--were included. The test protocol has hardly been followed since, primarily because the category of low CP was not considered useful in dietary counseling. It is advocated that research into possible caries-preventive factors of food will be more beneficial for improvements of the oral health of the general population than assessments of low CP.


Bringing together scientific disciplines for collaborative undertakings: a vision for advancing the adverse outcome pathway framework.
Decades of research to understand the impacts of various types of environmental occupational and medical stressors on human health have produced a vast amount of data across many scientific disciplines. Organizing these data in a meaningful way to support risk assessment has been a significant challenge. To address this and other challenges in modernizing chemical health risk assessment, the Organisation for Economic Cooperation and Development (OECD) formalized the adverse outcome pathway (AOP) framework, an approach to consolidate knowledge into measurable key events (KEs) at various levels of biological organisation causally linked to disease based on the weight of scientific evidence (http://oe.cd/aops). Currently, AOPs have been considered predominantly in chemical safety but are relevant to radiation. In this context, the Nuclear Energy Agency's (NEA's) High-Level Group on Low Dose Research (HLG-LDR) is working to improve research co-ordination, including radiological research with chemical research, identify synergies between the fields and to avoid duplication of efforts and resource investments. To this end, a virtual workshop was held on 7 and 8 October 2020 with experts from the OECD AOP Programme together with the radiation and chemical research/regulation communities. The workshop was a coordinated effort of Health Canada, the Electric Power Research Institute (EPRI), and the Nuclear Energy Agency (NEA). The AOP approach was discussed including key issues to fully embrace its value and catalyze implementation in areas of radiation risk assessment. A joint chemical and radiological expert group was proposed as a means to encourage cooperation between risk assessors and an initial vision was discussed on a path forward. A global survey was suggested as a way to identify priority health outcomes of regulatory interest for AOP development. Multidisciplinary teams are needed to address the challenge of producing the appropriate data for risk assessments. Data management and machine learning tools were highlighted as a way to progress from weight of evidence to computational causal inference.


Differences in Hancock and Carpentier-Edwards porcine xenograft aortic valve hemodynamics. Effect of valve size.
We prospectively compared the hemodynamic performance of Hancock and Carpentier-Edwards bioprosthetic aortic valves in a randomized study of 100 patients. A total of 47 patients received the Hancock valve, and 53 received the Carpentier-Edwards valve. Mean pressure gradients were measured using micromanometer catheters and cardiac outputs by thermodilution. Multiple measurements were made in each patient with atrial pacing, volume infusion, and inotropic drugs for a total of 319 observations. The pressure gradients and Gorlin valve areas showed significant scatter caused by both flow-dependent and patient-dependent variability. Mean transvalvular pressure gradients were therefore compared after adjustment for flow rate and for random interpatient differences using analysis of variance and covariance. Pressure gradients were lower and Gorlin valve areas larger for the Hancock valve than for the Carpentier-Edwards valve, but the differences were significant only for the smaller valve sizes. Compared with the Carpentier-Edwards valve, the mean pressure gradients were significantly lower for the Hancock 19-mm modified orifice (MO) valves (16.9 versus 31.7 mm Hg, p = 0.04), for the 21-mm valves (15.2 versus 22.4 mm Hg, p = 0.003), and for the 23-mm MO valve (9.2 versus 13.8 mm Hg, p = 0.04). The Gorlin areas were also significantly larger for the Hancock 19-mm MO valve (0.85 versus 0.77 cm2, p = 0.004) and the 21-mm MO valve (1.11 versus 0.89 cm2, p = 0.0009) but not for the 23-mm MO valve (1.59 versus 1.14, p = 0.08). Mean gradients and valve areas were not different for any of the larger valve sizes.(ABSTRACT TRUNCATED AT 250 WORDS)


Melatonin Effects on Glucose Metabolism: Time To Unlock the Controversy.
The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B - the melatonin receptor gene - is a risk factor for impaired fasting glucose and type 2 diabetes (T2D). Despite intensive investigation, there is considerable confusion and seemingly conflicting data on the metabolic effects of melatonin and MTNR1B variation, and disagreement on whether melatonin is metabolically beneficial or deleterious, a crucial issue for melatonin agonist/antagonist drug development and dosing time. We provide a conceptual framework - anchored in the dimension of 'time' - to reconcile paradoxical findings in the literature. We propose that the relative timing between elevated melatonin concentrations and glycemic challenge should be considered to better understand the mechanisms and therapeutic opportunities of melatonin signaling in glycemic health and disease.


Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.
Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.


The effect of heavy metals and other environmental conditions on the anaerobic phosphate metabolism of Acinetobacter johnsonii.
A strain of Acinetobacter with potential for bioremediation of heavy metal-contaminated waters was isolated from a wastewater-treatment plant operating an enhanced biological phosphate removal process. NMR and extractive methods showed that polyphosphate accumulated aerobically was degraded under anaerobic conditions both in the presence and absence of cadmium or uranium (0.2-0.5 mM). NMR showed that free phosphate was formed at the expense of polyphosphate, and an extractive technique indicated that this reaction could be stimulated by the presence of UO(2)2+ under these conditions. Energy-dispersive X-ray microanalysis demonstrated that only cadmium could enter the cells, and co-localized with intra-cellular granules containing phosphate and other divalent metals. The effects of other environmental parameters on the anaerobic phosphate metabolism were also investigated. Between pH 5.5 and 8.0, phosphate release increased with increasing pH. Between 4 degrees C and 37 degrees C, phosphate release increased with increasing temperature. The presence of nitrate at concentrations of 10 mM and above inhibited anoxic phosphate release, but supplying tungstate in the growth medium prior to anoxic incubation reduced the production of active nitrate reductase and alleviated this effect.


[Adverse events of immune checkpoint inhibitors].
After immune checkpoint inhibitor therapy was approved for renal cell carcinoma last year, this new immune therapy has spread to urology. Further approvals (atezolizumab, nivolumab, pembrolizumab) are expected in 2017 for metastatic urothelial carcinoma that has progressed following treatment with platinum-based chemotherapy. With expanding use of immune checkpoint inhibitors, experience in diagnosing and managing immune-mediated adverse events increases. Although of low incidence, grade 3/4 toxicities play a central role. Organs most common for immune-mediated adverse events are skin, liver (hepatitis), kidneys (nephritis), gastrointestinal tract (diarrhea and colitis), lungs (pneumonitis), and endocrine organs (hyper-, hypothyroidism and hypophysitis). Diagnostic workup includes routine laboratory tests (including liver function tests) and may be supplemented with hormone values. In cases of pneumonitis or hypophysitis, imaging (high-resolution CT, MRI) can confirm diagnoses. Immune-mediated toxicities are treated with therapy interruption and administration of corticosteroids (and in individual cases additional immunosuppression). Dose modification is not intended!


Applicability and potential clinical effects of 2013 cholesterol guidelines on major cardiovascular events.
The applicability to different race/ethnic groups and effects on cardiovascular disease (CVD) outcomes of the 2013 American College of Cardiology and American Heart Association (ACC/AHA) guidelines for cholesterol management remain to be determined. We estimated the proportion of Korean adults who would be affected by the 2013 cholesterol guidelines and to determine the related effects on cardiovascular events. Using data from the Korean National Health and Nutrition Examination Survey of 2008 to 2012 (n = 18,573), we compared the estimated number of statin candidates under the 2013 ACC/AHA and the Third Adult Treatment Panel (ATP-III) guidelines and extrapolated the results to 19.0 million Koreans between the ages of 40 and 75 years. Using an external cohort (n = 63,329) from the 2003 National Health Examination with 7 years of prospective follow-up, we determined the potential effects of recent recommendations changes on atherosclerotic CVD events (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Compared with the ATP-III guidelines, the ACC/AHA guidelines would increase the number of statin candidates from 3.5 million (18.6%) to 6.7 million (35.1%). The increase of statin candidates would be larger among older adults (60-75 years; from 29.8% to 74.9%) as compared with younger adults (40-59 years; from 15.6% to 19.8%) and among men (from 25.7% to 45.4%) compared with women (from 14.6% to 26.8%). In the external cohort, compared with adults who were recommended by neither of the 2 guidelines, those who were recommended by both and those who were recommended by ACC/AHA but not ATP-III guidelines had significantly higher risks of atherosclerotic CVD events (hazard ratios [HRs] 3.65 [95% CI, 3.33-4.02] and 3.98 [95% CI 3.64-4.35], respectively). However, adults who were recommended by ATP-III but not ACC/AHA guidelines did not have an increased risk (HR 0.90, 95% CI 0.64-1.28). In the Korean population, the 2013 ACC/AHA cholesterol guidelines would substantially increase the number of adults who are potentially eligible for statin therapy and would recommend statin therapy for more adults at higher cardiovascular risk. However, the clinician-patient discussion of the potential benefits, possible harms, and other factors before the initiation of statin therapy must be considered.


National trends in psychotropic medication polypharmacy in office-based psychiatry.
Psychotropic medication polypharmacy is common in psychiatric outpatient settings and, in some patient groups, may have increased in recent years. To examine patterns and recent trends in psychotropic polypharmacy among visits to office-based psychiatrists. Annual data from the 1996-2006 cross-sectional National Ambulatory Medical Care Surveys were analyzed to examine patterns and trends in psychotropic polypharmacy within nationally representative samples of 13 079 visits to office-based psychiatrists. Office-based psychiatry practices in the United States. Outpatients with mental disorder diagnoses visiting office-based psychiatrists. Number of medications prescribed in each visit and specific medication combinations. There was an increase in the number of psychotropic medications prescribed across years; visits with 2 or more medications increased from 42.6% in 1996-1997 to 59.8% in 2005-2006; visits with 3 or more medications increased from 16.9% to 33.2% (both P < .001). The median number of medications prescribed in each visit increased from 1 in 1996-1997 to 2 in 2005-2006 (mean increase: 40.1%). The increasing trend of psychotropic polypharmacy was mostly similar across visits by different patient groups and persisted after controlling for background characteristics. Prescription for 2 or more antidepressants, antipsychotics, sedative-hypnotics, and antidepressant-antipsychotic combinations, but not other combinations, significantly increased across survey years. There was no increase in prescription of mood stabilizer combinations. In multivariate analyses, the odds of receiving 2 or more antidepressants were significantly associated with a diagnosis of major depression (odds ratio [OR], 3.44; 99% confidence interval [CI], 2.58-4.58); 2 or more antipsychotics, with schizophrenia (OR, 6.75; 99% CI, 3.52-12.92); 2 or more mood stabilizers, with bipolar disorder (OR, 15.46; 99% CI, 6.77-35.31); and 2 or more sedative-hypnotics, with anxiety disorders (OR, 2.13; 99% CI, 1.41-3.22). There has been a recent significant increase in polypharmacy involving antidepressant and antipsychotic medications. While some of these combinations are supported by clinical trials, many are of unproven efficacy. These trends put patients at increased risk of drug-drug interactions with uncertain gains for quality of care and clinical outcomes.


Prevalence of inappropriate sinus tachycardia and the comparison of the heart rate variability characteristics with propensity score-matched controls.
Inappropriate sinus tachycardia (IST) is a syndrome characterized by an elevated resting heart rate with distressing symptoms and no secondary cause of sinus tachycardia. This study was conducted to evaluate both the prevalence of IST among symptomatic patients and heart rate variability (HRV) characteristics. The records of all consecutive symptomatic patients who had undergone 24-hour Holter monitoring between September 2015 and November 2016 at a single center were retrospectively evaluated. IST was defined as a 24-hour mean heart rate (HR) of ≥90 beats/minute and a resting HR of ≥100 beats/minute in the absence of any secondary cause of sinus tachycardia. All of the study data related to clinical characteristics, symptoms, concomitant diseases, and Holter electrocardiogram parameters were obtained from the electronic hospital records. A propensity age- and sex-matched control group was selected from a non-IST patient cohort. A total of 1865 consecutive patients were evaluated and 32% were excluded due to an inadequate Holter recording period or insufficient quality, atrial fibrillation episodes, atrioventricular block, or >1% atrial or ventricular extrasystoles. Among 1265 patients with sinus rhythm, 4.98% (n=63) had IST. The IST patients were younger (39.6±17.4 vs. 50.2±17.2 years; <0.001), and female gender was more prominent (60.3% vs. 43.8%; p=0.009). All of the time and frequency domain parameters of HRV except the low frequency/high frequency ratio were significantly reduced in the IST group compared with the propensity-matched controls. The IST prevalence among symptomatic patients in sinus rhythm was 4.98%. IST was primarily seen in younger women, and they had diminished time and frequency domain HRV parameters.


Systematic exploration of synergistic drug pairs.
Drug synergy allows a therapeutic effect to be achieved with lower doses of component drugs. Drug synergy can result when drugs target the products of genes that act in parallel pathways ('specific synergy'). Such cases of drug synergy should tend to correspond to synergistic genetic interaction between the corresponding target genes. Alternatively, 'promiscuous synergy' can arise when one drug non-specifically increases the effects of many other drugs, for example, by increased bioavailability. To assess the relative abundance of these drug synergy types, we examined 200 pairs of antifungal drugs in S. cerevisiae. We found 38 antifungal synergies, 37 of which were novel. While 14 cases of drug synergy corresponded to genetic interaction, 92% of the synergies we discovered involved only six frequently synergistic drugs. Although promiscuity of four drugs can be explained under the bioavailability model, the promiscuity of Tacrolimus and Pentamidine was completely unexpected. While many drug synergies correspond to genetic interactions, the majority of drug synergies appear to result from non-specific promiscuous synergy.


Liquid biopsy and PCR-free ultrasensitive detection systems in oncology (Review).
In oncology, liquid biopsy is used in the detection of next-generation analytes, such as tumor cells, cell-free nucleic acids and exosomes in peripheral blood and other body fluids from cancer patients. It is considered one of the most advanced non-invasive diagnostic systems to enable clinically relevant actions and implement precision medicine. Medical actions include, but are not limited to, early diagnosis, staging, prognosis, anticipation (lead time) and the prediction of therapy responses, as well as follow-up. Historically, the applications of liquid biopsy in cancer have focused on circulating tumor cells (CTCs). More recently, this analysis has been extended to circulating free DNA (cfDNA) and microRNAs (miRNAs or miRs) associated with cancer, with potential applications for development into multi-marker diagnostic, prognostic and therapeutic signatures. Liquid biopsies avoid some key limitations of conventional tumor tissue biopsies, including invasive tumor sampling, under-representation of tumor heterogeneity and poor description of clonal evolution during metastatic dissemination, strongly reducing the need for multiple sampling. On the other hand, this approach suffers from important drawbacks, i.e., the fragmentation of cfDNA, the instability of RNA, the low concentrations of certain analytes in body fluids and the confounding presence of normal, as well as aberrant DNAs and RNAs. For these reasons, the analysis of cfDNA has been mostly focused on mutations arising in, and pathognomonicity of, tumor DNA, while the analysis of cfRNA has been mostly focused on miRNA patterns strongly associated with neoplastic transformation/progression. This review lists some major applicative areas, briefly addresses how technology is bypassing liquid biopsy limitations, and places a particular emphasis on novel, PCR-free platforms. The ongoing collaborative efforts of major international consortia are reviewed. In addition to basic and applied research, we will consider technological transfer, including patents, patent applications and available information on clinical trials aimed at verifying the potential of liquid biopsy in cancer.


Synthesis of l-indospicine, [5,5,6-(2)H3]-l-indospicine and l-norindospicine.
Indospicine is a non-proteogenic amino acid that accumulates as the free amino acid in livestock grazing Indigofera plant species and causes both reproductive losses and hepatotoxic effects. An efficient synthetic route to l-indospicine from l-homoserine lactone is described. The methodology is applicable for the synthesis of both deuterium labelled isotopomers and structural analogues for utilisation in biological studies. The key steps are a zinc mediated Barbier reaction with acrylonitrile and a Pinner reaction that together introduce the target amidine moiety.


Few-Shot Learning With Geometric Constraints.
In this article, we consider the problem of few-shot learning for classification. We assume a network trained for base categories with a large number of training examples, and we aim to add novel categories to it that have only a few, e.g., one or five, training examples. This is a challenging scenario because: 1) high performance is required in both the base and novel categories; and 2) training the network for the new categories with a few training examples can contaminate the feature space trained well for the base categories. To address these challenges, we propose two geometric constraints to fine-tune the network with a few training examples. The first constraint enables features of the novel categories to cluster near the category weights, and the second maintains the weights of the novel categories far from the weights of the base categories. By applying the proposed constraints, we extract discriminative features for the novel categories while preserving the feature space learned for the base categories. Using public data sets for few-shot learning that are subsets of ImageNet, we demonstrate that the proposed method outperforms prevalent methods by a large margin.


Acute disseminated encephalomyelitis and its place amongst other acute inflammatory demyelinating CNS disorders.
The diagnosis of acute inflammatory demyelinating CNS conditions is complex and this is reflected in variations in how cohorts are defined across studies. For some conditions the diagnosis relies on whether it is monophasic or relapsing, in others the anatomical site of inflammation is used as a means of categorisation. Clinical features such as precipitants, gender and age may affect the probability of certain diagnoses, but are not highly accurate. Exclusive features for the pathology are identifiable for some but not all conditions, and are seldom available during life. Specific markers such as antibodies are informative and new developments in this area are likely in the near future. This review outlines the features and classification of acute disseminated encephalomyelitis and contrasts it with other related conditions before attempting to define a pragmatic organisation of these conditions based upon present evidence.


Fish oil: what the prescriber needs to know.
There is a general belief among doctors, in part grounded in experience, that patients with arthritis need nonsteroidal anti-inflammatory drugs (NSAIDs). Implicit in this view is that these patients require the symptomatic relief provided by inhibiting synthesis of nociceptive prostaglandin E2, a downstream product of the enzyme cyclo-oxygenase (COX), which is inhibited by NSAIDs. However, the concept of 'safe' NSAIDs has collapsed following a multiplicity of observations establishing increased risk for cardiovascular events associated with NSAID use, especially but not uniquely with the new COX-2-selective NSAIDs. This mandates greater parsimony in the use of these agents. Fish oils contain a natural inhibitor of COX, reduce reliance on NSAIDs, and reduce cardiovascular risk through multiple mechanisms. Fish oil thus warrants consideration as a component of therapy for arthritis, especially rheumatoid arthritis, in which its symptomatic benefits are well established. A major barrier to the therapeutic use of fish oil in inflammatory diseases is ignorance of its mechanism, range of beneficial effects, safety profile, availability of suitable products, effective dose, latency of effects and instructions for administration. This review provides an evidence-based resource for doctors and patients who may choose to prescribe or take fish oil.


A retrospective analysis of a human cellular repair matrix for the treatment of chronic wounds.
Despite the introduction of advanced wound care modalities over the last 15 years, chronic wounds are an increasing problem. Few single options are available for clinicians to treat recalcitrant wounds such as diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs). A retrospective, single-center study was conducted at an outpatient wound care center to evaluate the clinical effect of a human cellular repair matrix (h-CRM) on chronic wounds that had failed to heal. Data from all patients who had received this treatment modality during a period of 2 years were abstracted. Standard care included weekly visits, regular debridement, offloading DFUs, compression for VLUs, and h-CRM for wounds >4 weeks duration. A total of 66 patients (30 male, 36 female, mean age 71.1 [± 8.8] years) received h-CRM treatment for 67 wounds (34 VLUs, 27 DFUs, and six other chronic wounds). The average wound size at baseline was 6.65 (± 9.68) cm2, and the average wound duration before h-CRM treatment was 38 (±70.8) weeks. Fifty (50) patients (74.6%) had failed to heal using other advanced therapies. After 12 weeks of care, 51 of the 67 wounds (76.1%) were healed: 23 of 34 (67.6%) VLUs and 23 of 27 (85.2%) DFUs. Average time to closure in these wounds was 5.8 (±2.5) weeks. No significant differences were found between proportions of VLUs and DFUs healed. No adverse events or recurrences occurred during an average follow-up time of 20.4 months (range 11 to 32 months). Overall, patients received an average of 3.8 applications of h-CRM, and 3.2 applications were used among patients that healed. The study results suggest h-CRM may benefit patients with chronic wounds. Prospective, randomized clinical studies are warranted.


Impact of repeated bouts of eccentric exercise on sarcolemma disruption in human skeletal muscle.
In animal models, unaccustomed eccentric exercise (EE) has been widely related to muscle fiber membrane (sarcolemma) damage. On the contrary, studies in humans reported that sarcolemma was not susceptible to damage following a single bout of EE. We hypothesized that the single bout of EE used by those studies was not sufficient to induce sarcolemma damage, in humans. In this study we examined muscle biopsies from untrained males who either performed six sets of 15 reps of maximum voluntary eccentric contractions (n=9), for six consecutive days, or served as control-group (n=6). Blood and biopsy samples were obtained one week prior to exercise, immediately after bout 3, and 24h after the last training session. In addition to standard haematoxylin-eosin staining, all biopsies were stained immunohistochemically using antibodies specific for fibronectin and desmin antigens. In the exercise-group, no biopsies taken at pre-exercise or post-exercise level showed evidence of sarcolemma damage as stained by anti-fibronectin antibody in eight of nine subjects. Serum creatine kinase (CK) and lactate dehydrogenase (LDH) activities increased significantly throughout the study despite the lack of sarcolemma damage.We suggest that in humans, repeated bouts of EE do not cause gross sarcolemma damage in the mid-belly of Vastus Lateralis.


Adaptive free energy sampling in multidimensional collective variable space using boxed molecular dynamics.
The past decade has seen the development of a new class of rare event methods in which molecular configuration space is divided into a set of boundaries/interfaces, and then short trajectories are run between boundaries. For all these methods, an important concern is how to generate boundaries. In this paper, we outline an algorithm for adaptively generating boundaries along a free energy surface in multi-dimensional collective variable (CV) space, building on the boxed molecular dynamics (BXD) rare event algorithm. BXD is a simple technique for accelerating the simulation of rare events and free energy sampling which has proven useful for calculating kinetics and free energy profiles in reactive and non-reactive molecular dynamics (MD) simulations across a range of systems, in both NVT and NVE ensembles. Two key developments outlined in this paper make it possible to automate BXD, and to adaptively map free energy and kinetics in complex systems. First, we have generalized BXD to multidimensional CV space. Using strategies from rigid-body dynamics, we have derived a simple and general velocity-reflection procedure that conserves energy for arbitrary collective variable definitions in multiple dimensions, and show that it is straightforward to apply BXD to sampling in multidimensional CV space so long as the Cartesian gradients ∇CV are available. Second, we have modified BXD to undertake on-the-fly statistical analysis during a trajectory, harnessing the information content latent in the dynamics to automatically determine boundary locations. Such automation not only makes BXD considerably easier to use; it also guarantees optimal boundaries, speeding up convergence. We have tested the multidimensional adaptive BXD procedure by calculating the potential of mean force for a chemical reaction recently investigated using both experimental and computational approaches - i.e., F + CD3CN → DF + D2CN in both the gas phase and a strongly coupled explicit CD3CN solvent. The results obtained using multidimensional adaptive BXD agree well with previously published experimental and computational results, providing good evidence for its reliability.


The Ocean 100: Transnational corporations in the ocean economy.
The ocean economy is growing as commercial use of the ocean accelerates, while progress toward achieving international goals for ocean conservation and sustainability is lagging. In this context, the private sector is increasingly recognized as having the capacity to hamper efforts to achieve aspirations of sustainable ocean-based development or alternatively to bend current trajectories of ocean use by taking on the mantle of corporate biosphere stewardship. Here, we identify levels of industry concentration to assess where this capacity rests. We show that the 10 largest companies in eight core ocean economy industries generate, on average, 45% of each industry's total revenues. Aggregating across all eight industries, the 100 largest corporations (the "Ocean 100") account for 60% of total revenues. This level of concentration in the ocean economy presents both risks and opportunities for ensuring sustainability and equity of global ocean use.


Characterization of nuclear factors for elicitor-mediated activation of the promoter of the pea phenylalanine ammonia-lyase gene 1.
The nuclear factors presumably associated with the activation of the gene encoding phenylalanine ammonia-lyase by a fungal elicitor were characterized in pea (Pisum sativum L.) epicotyls. The TATA-proximal region was dissected and putative cis-regulatory elements in the promoter of pea phenylalanine ammonia-lyase gene 1 were examined by gel-mobility shift and in vitro footprinting analyses. Specific binding of the nuclear factors to the promoter-proximal regions of pea phenylalanine ammonia-lyase gene 1 associated with elicitor-mediated activation was detected at a region containing consensus sequence motifs of boxes 2 and 4 and other AT-rich sequences. The analyses of DNA fragments containing the deleted promoter regions suggested that a residue from -183 to -173 (ATTAGTAAGTGAT) was essential for a maximal activity of forming low-mobility complex (LMC) in the gel-mobility shift assay, and synthetic oligonucleotides confirmed the presence of at least one nuclear component associated with the formation of an active LMC. Competition experiments and treatment with Hoechst 33258 provided direct evidence that the formation of LMC with the promoter fragments from genes encoding phenylalanine ammonia-lyase and chalcone synthase in pea contained one or more of the same proteins that recognize AT-rich sequence motifs for binding. It also suggests that common high-mobility group-like proteins might be involved in the regulation of elicitor-inducible genes in pea.


A Horizon Scan of Global Conservation Issues for 2016.
This paper presents the results of our seventh annual horizon scan, in which we aimed to identify issues that could have substantial effects on global biological diversity in the future, but are not currently widely well known or understood within the conservation community. Fifteen issues were identified by a team that included researchers, practitioners, professional horizon scanners, and journalists. The topics include use of managed bees as transporters of biological control agents, artificial superintelligence, electric pulse trawling, testosterone in the aquatic environment, building artificial oceanic islands, and the incorporation of ecological civilization principles into government policies in China.


Quantification of brain glucose metabolism by 18F-FDG PET with real-time arterial and image-derived input function in mice.
Kinetic modeling of PET data derived from mouse models remains hampered by the technical inaccessibility of an accurate input function (IF). In this work, we tested the feasibility of IF measurement with an arteriovenous shunt and a coincidence counter in mice and compared the method with an image-derived IF (IDIF) obtained by ensemble-learning independent component analysis of the heart region. (18)F-FDG brain kinetics were quantified in 2 mouse strains, CD1 and C57BL/6, using the standard 2-tissue-compartment model. Fits obtained with the 2 IFs were compared regarding their goodness of fit as assessed by the residuals, fit parameter SD, and Bland-Altman analysis. On average, cerebral glucose metabolic rate was 10% higher for IDIF-based quantification. The precision of model parameter fitting was significantly higher using the shunt-based IF, rendering the quantification of single process rate constants feasible. We demonstrated that the arterial IF can be measured in mice with a femoral arteriovenous shunt. This technique resulted in higher precision for kinetic modeling parameters than did use of the IDIF. However, for longitudinal or high-throughput studies, the use of a minimally invasive IDIF based on ensemble-learning independent component analysis represents a suitable alternative.


Social Networks and the Emergence of Health Inequalities Following a Medical Advance: Examining Prenatal H1N1 Vaccination Decisions.
Health inequalities persist, in part, because people in socioeconomically advantageous positions possess resources to avoid new health risks when medicine advances. Although these health decisions rarely occur in isolation, we know less about the specific role of networks. We examine whether social capital mediates the relationship between individual educational attainment and decisions about a medical advance: H1N1 vaccination during pregnancy. Building on prior work that defines social capital as the resources of network members, we examine two mechanisms through which social capital may affect health decisions, facilitating information flow and exerting influence. Using egocentric network data collected from 225 pregnant women during the 2009-10 H1N1 pandemic, we measure social capital as the proportion of networks that are college-educated H1N1 discussants (information flow) and the proportion of college-educated H1N1 supporters (influence). Findings reveal that college-educated women knew more college-educated H1N1 discussants and supporters. Further, both measures of social capital predicted higher probabilities of vaccination, with the latter mechanism emerging as a particularly strong predictor. Our findings provide evidence that health decisions are shaped by individual resources as well as social capital available through network ties, offering a unique perspective of the ways that social networks contribute to producing, and potentially reproducing, unequal health.


Systematic review to support the development of nutrient reference intake values: challenges and solutions.
Workshops sponsored by the Institute of Medicine (IOM) and the World Health Organization suggested that incorporating systematic (evidence) reviews into the process of updating nutrient reference values would provide a comprehensive and distilled evidence document to decision makers and enhance the transparency of the decision-making process the IOM used in recommending the Dietary Reference Intake values (DRIs) for US and Canadian populations. At the request of the US and Canadian government sponsors of the ongoing review of the 1997 vitamin D and calcium DRI values, the Tufts Evidence-based Practice Center performed a systematic review for the current DRI Committee to use early in its deliberations. We described the approach used to include systematic review into the IOM process for updating nutrient reference values and highlighted major challenges encountered along with the solutions used. The challenges stemmed from the need to review and synthesize a large number of primary studies covering a broad range of outcomes. We resolved these challenges by 1) working with a technical expert panel to prioritize and select outcomes of interest, 2) developing methods to use existing systematic reviews and documenting the limitations by doing so, 3) translating results from studies not designed to address issues of interest by using a transparent process, and 4) establishing tailored quality-assessment tools to assist in decision making. The experiences described in this article can serve as a basis for future improvements in systematic reviews of nutrients and to better integrate systematic review into development of future nutrient reference values.


Spinal cord MRI at 7T.
Magnetic resonance imaging (MRI) of the human spinal cord at 7T has been demonstrated by a handful of research sites worldwide, and the spinal cord remains one of the areas in which higher fields and resolution could have high impact. The small diameter of the cord (∼1 cm) necessitates high spatial resolution to minimize partial volume effects between gray and white matter, and so MRI of the cord can greatly benefit from increased signal-to-noise ratio and contrasts at ultra-high field (UHF). Herein we review the current state of UHF spinal cord imaging. Technical challenges to successful UHF spinal cord MRI include radiofrequency (B1) nonuniformities and a general lack of optimized radiofrequency coils, amplified physiological noise, and an absence of methods for robust B0 shimming along the cord to mitigate image distortions and signal losses. Numerous solutions to address these challenges have been and are continuing to be explored, and include novel approaches for signal excitation and acquisition, dynamic shimming and specialized shim coils, and acquisitions with increased coverage or optimal slice angulations.


Dimethyl fumarate for treating relapsing multiple sclerosis.
Outcomes of two large double-blind placebo-controlled studies of oral dimethyl fumarate (DMF) in multiple sclerosis (MS) provided the basis for its marketing approval as Tecfidera® by the US FDA in early 2013 and the European Medicines Agency in February 2014. The safety of DMF is complemented by experience in the use of an oral mixture of fumaric acid esters, including DMF for psoriasis (Fumaderm®; DMF and monoethyl fumarate [DMF-MEF]) licensed in Germany in 1994. This article reviews the pivotal trials leading to the approval of DMF for MS and the pharmacological literature related to the extensive use of oral fumaric acid esters for psoriasis over the last quarter century. Anecdotal reports of serious adverse reactions to DMF-MEF are also reviewed in this report. DMF is generally safe and well tolerated. Flushing and gastrointestinal side effects are relatively common for the approved DMF dose but are ordinarily mild and self-limited. No increase in malignancies has been reported despite theoretical concerns. Although progressive multifocal encephalopathy has been reported anecdotally in 5 of > 196,000 patient-years of experience with fumaric acid esters, none of the 65,000 DMF MS patients treated in the first year has been affected. Appendix to the abstract: Subsequent to the acceptance of this article for publication, the manufacturer has notified physicians of the death of one patient from PML complicating use of DMF in the DEFINE study extension (ENDORSE). This does not alter the expert opinion rendered regarding the safety of DMF. We await the outcomes and recommendations from the ongoing investigation into this case.


Screening for pre-eclampsia and fetal growth restriction in twin pregnancies at 23 weeks of gestation by transvaginal uterine artery Doppler.
To assess the value of transvaginal uterine artery Doppler at 23 weeks of gestation in predicting the development of adverse perinatal outcomes in twin pregnancies. Women with twin pregnancies attending for routine ultrasound examination at 23 weeks in any one of seven hospitals underwent Doppler assessment of the uterine arteries. The right and left uterine arteries were identified using color flow mapping and velocity waveforms were obtained using pulsed Doppler. The mean pulsatility index (PI) of the two arteries was determined and the presence of uterine artery notching noted. Results were compared between monochorionic and dichorionic twins, and with our previously reported data from singleton pregnancies. Screening characteristics in the prediction of pre-eclampsia, fetal growth restriction (FGR), placental abruption, fetal death and early preterm delivery were calculated. Uterine artery Doppler at 22-24 weeks of gestation was performed in 360 twin pregnancies, including 324 dichorionic and 36 monochorionic diamniotic twins. Complete outcome data were available in 351 (97.5%). The mean uterine artery PI did not change significantly with gestation and there was no significant difference in mean PI between the dichorionic and monochorionic groups. However, the mean PI was significantly lower in twin pregnancies than in singletons. The pregnancy was complicated by pre-eclampsia in 6.0% of cases, FGR below the 5th centile of both twins in 8.8%, abruption in 0.9%, intrauterine fetal death in 1.7% and early preterm delivery at less than 32 completed weeks of gestation in 5.7% of cases. The respective sensitivities of uterine artery mean PI above the 95th centile for these complications were 33.3%, 9.7%, 66.6%, 33.3% and 18.6%. In twin pregnancies PI in the uterine arteries is lower than that in singleton pregnancies, but there is no significant difference between dichorionic and monochorionic twins. Doppler assessment of the uterine arteries at 23 weeks identifies a large proportion of twin pregnancies destined to develop adverse outcomes related to uteroplacental insufficiency.


267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation.
Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalog of local variability motivated the whole-exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one-third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including ∼10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes, and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies to distinguish real disease associations from population-specific polymorphisms.


Hyponatremia after trans-sphenoidal surgery.
Fluid and electrolyte imbalances are the most frequent complications following pituitary surgery. Among the several patterns of occurrence, hyponatremia can occur in an isolated fashion or as part of a bi- or triphasic pattern. The frequency of hyponatremia after trans-sphenoidal surgery is between 2% and 25%, according to the literature. However, these numbers are probably underestimating the real prevalence, since mild hyponatremia does not lead to symptoms and measurement of sodium level. No association has been described between entity of the pituitary tumor or tumor size and hyponatremia. Therefore no predictors exist to determine patients with a higher risk for electrolyte imbalances after surgery. However, since delayed hyponatremia occurs mainly around the 8-10th day after surgery, routine measurement of sodium should be recommended on the day of hospital dismission. In case of a symptomatic hyponatremia, insufficiency of the corticotrophe pituitary function as the leading differential diagnosis needs to be ruled out. If the patient is euvoleme, pretest probability of syndrome of inadequate antidiuretic hormone production (SIADH) is very high and therapy may be started according to this. In case of SIADH, therapeutic options include fluid restriction or vaptane therapy. Only in severe cases infusion of hypertonic saline is appropriate. Usually SIADH following pituitary surgery is a self-limiting condition and will cease within 2-5 days.