Prevalence of Indicators of Low Energy Availability in Elite Female Sprinters.
Low energy availability (LEA), and subsequent relative energy deficiency in sport, has been observed in endurance, aesthetic, and team sport athletes, with limited data on prevalence in athletes in short-burst activities such as sprinting. We examined prevalence of signs and symptoms of LEA in elite female sprinters at the start of the training season (PRE), and at the end of a 5-month indoor training period (POST). Four of 13 female sprinters (31%) presented at PRE testing with at least one primary (amenorrhea, low bone mineral density, low follicle-stimulating hormone, luteinizing hormone, or estradiol, resting metabolic rate ≤29 kcal/kg fat-free mass, Low Energy Availability in Females Questionnaire score ≥8) and one secondary indicator of LEA (fasting blood glucose <4 mmol/L, free triiodothyronine <3.5 pmol/L, ferritin <25 μg/L, low-density lipoprotein cholesterol >3.0 mmol/L, fasting insulin <20 pmol/L, low insulin-like growth factor-1, systolic blood pressure <90 mmHg, and/or diastolic blood pressure <60 mmHg). At POST, seven out of 13 athletes (54%) presented with at least one primary and one secondary indicator of LEA, three of whom had also presented with indicators of LEA at PRE. Five out of 13 (39%) athletes had previous stress fracture history, though this was not associated with current indicators of LEA (PRE: r = .52, p = .07; POST: r = -.07, p = .82). In conclusion, elite female sprinters may present with signs and symptoms of LEA, even after off-season rest. Medical and coaching staff should be aware of the signs and symptoms of LEA and relative energy deficiency in sport and should include appropriate screening and intervention strategies when working with sprinters.


Geographical location specific composition of cultured microbiota and Lactobacillus occurrence in human breast milk in China.
Breast milk bacteria play an important role in the early development of the gut microbiota and the immune system. Dominant living bacteria of 89 healthy Chinese women from 11 cities in five regions were analysed by broad-range yeast extract, casitone, and fatty acid and de Man, Rogosa, and Sharpe-based culturing coupled with 16S rRNA sequence and quantitative polymerase chain reaction. Principal coordinate analysis showed that human breast milk samples were classified into three groups, driven by Enterococcus (abundance in group 1, 63.13%), Streptococcus (abundance in group 2, 68.16%) and Staphylococcus (abundance in group 3, 55.17%). The microbiota profile was highly region-specific. Samples from the Northwest and North of China showed higher alpha diversity compared to other regions (p < 0.05). Staphylococcus, Streptococcus, and Enterococcus were the dominant genera in all samples. Lactobacillus had a high occurrence in samples from the Northwest and North, dominated by Lactobacillus reuteri and Lactobacillus gasseri. Samples of mothers with a high postpartum body mass index showed more Staphylococcus and less Lactobacillus and Streptococcus. Staphylococcus was negatively correlated with Lactobacillus and Streptococcus. The mode of delivery also affected the composition of microbiota, even after culture. These findings indicate differences between the North and South, provide effective information for collection of samples in which Lactobacillus is the predominant genus, and lower the detection limit for small amounts of bacteria.


Do older adults change their eyewitness reports when re-questioned?
This study examined how older adults responded to different types of pressure to change their responses when questioned a second time about their memory for a crime. After watching a video of a crime and answering questions about remembered details, younger (18-22 years) and older adults (64-91 years) were either given negative feedback about their memory performance, were told that most people their age did poorly on the memory test (stereotype threat), or were simply asked to answer the questions again. This was done regardless of their actual accuracy, and the questions were then repeated. Results showed that both younger and older adults changed significantly more responses following negative feedback and changed more responses on misleading than on nonleading questions. Among older adults, as age increased, accuracy decreased and rate of response change increased. People were moderately confident overall about both their correct and incorrect responses. These results highlight the dangers of repeatedly questioning older witnesses with misleading questions and suggest that the responses that are changed may come to be remembered confidently-regardless of whether they are correct or incorrect.


A Blueprint to Advance Colorectal Cancer Immunotherapies.
Immunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in colorectal cancers with defective mismatch repair (microsatellite instability-high tumors) have reignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in colorectal cancer and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy. We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear. Whether biomarkers with prognostic value, such as the immunoscores and IFN signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with colorectal cancer will need to be incorporated into clinical guidelines. We have proposed a framework for research to identify immunologic factors that may be modulated to improve immunotherapy for colorectal cancer patients, with the goal that the biomarkers and treatment strategies identified will become part of the routine management of colorectal cancer. Cancer Immunol Res; 5(11); 942-9. ©2017 AACR.


Transseptal Access to the Left Atrium: Tips and Tricks to Keep it Safe Derived from Single Operator Experience and Review of the Literature.
Transseptal puncture (TSP) remains a demanding procedural step in accessing the left atrium with inherent risks and safety concerns, mostly related to cardiac tamponade. Based on our own experience with 249 TSP procedures and in-depth literature review, we present our results and offer several tips and tricks that may render TSP successful and safe. This prospective study comprised 249 consecutive patients (146 men), aged 41.6±17.4 years, undergoing TSP by a single operator for ablation of a variety of arrhythmias, mostly related to left accessory pathways (n=145) or left atrial tachycardias (n=33) and more recently, atrial fibrillation (n=70). TSP was guided by fluoroscopy alone in all patients without the use of echocardiography imaging. In addition, an extensive literature review of TSP-related topics was carried out in PubMed, Scopus and Google Scholar. Among 249 patients, 33 patients were children or young adolescents (aged 7-18 years); 14 patients were undergoing a repeat procedure. Patients with a manifest accessory pathway were the youngest (mean age 33.7±15.9) and patients with atrial fibrillation the oldest (mean age 56.0±10.8 years). A successful TSP was accomplished in 247 patients (99.2%). Two (0.8%) procedures were complicated by cardiac tamponade managed successfully with pericardiocentesis or surgical drainage. Review of the literature revealed no systematic reviews and meta-analyses of TSP studies; however, several patient series have documented that fluoroscopy-guided TSP, with various modifications in the technique employed in the present series, have been effective in 95-100% of the cases with a complication rate ranging from 0.0% to 6.7%, albeit with a mortality rate of 0.018%- 0.2%. Echo imaging techniques were employed in cases with difficult TSP. Employing a standardized protocol with use of fluoroscopy alone minimized serious complications to 0.8% (2 patients) among 249 consecutive patients undergoing TSP for ablation of a variety of cardiac arrhythmias. Based on this single-operator experience and review of the literature, a list of practical tips and tricks is provided for a successful and safe procedure, reserving the more expensive and patient inconveniencing echo-imaging techniques for difficult or failed cases.


In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma.
Glioblastoma multiforme (GBM), which account for more than 50% of all gliomas, is among the deadliest of all human cancers. Given the dismal prognosis of GBM, it would be advantageous to identify early biomarkers of a response to therapy to avoid continuing ineffective treatments and to initiate other therapeutic strategies. The present in vivo longitudinal study in an orthotopic mouse model demonstrates quantitative assessment of early treatment response during short-term chemotherapy with temozolomide (TMZ) by amide proton transfer (APT) imaging. In a GBM line, only one course of TMZ (3 d exposure and 4 d rest) at a dose of 80 mg/kg resulted in substantial reduction in APT signal compared with untreated control animals, in which the APT signal continued to increase. Although there were no detectable differences in tumor volume, cell density, or apoptosis rate between groups, levels of Ki67 (index of cell proliferation) were substantially reduced in treated tumors. In another TMZ-resistant GBM line, the APT signal and levels of Ki67 increased despite the same course of TMZ treatment. As metabolite changes are known to occur early in the time course of chemotherapy and precede morphologic changes, these results suggest that the APT signal in glioma may be a useful functional biomarker of treatment response or degree of tumor progression. Thus, APT imaging may serve as a sensitive biomarker of early treatment response and could potentially replace invasive biopsies to provide a definitive diagnosis. This would have a major impact on the clinical management of patients with glioma.


Beyond sequence variation: assessment of copy number variation in adult glioblastoma through targeted tumor somatic profiling.
Glioblastoma is the most common primary malignancy of the adult central nervous system. Gliomagenesis involves a complex range of alterations, including sequence changes, copy number variations (CNVs), and epigenetic modifications, that have clinical implications for disease classification and prognosis. Thus, multiple testing modalities are required to support a complete diagnostic workup. The goal of this study was to streamline the multipart workflow by predicting both sequence changes and CNVs (specifically EGFR amplifications) from a single next-generation sequencing (NGS) test. Eighty-six primary and secondary glioblastomas were submitted for clinical NGS to report sequence variants from a concise panel of cancer-relevant genes. Most specimens underwent concomitant testing by methylation-specific polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization. Using data generated during the course of clinical testing, we found that NGS-based variant predictions were concordant with immunohistochemistry and fluorescence in situ hybridization for IDH mutation and EGFR amplification status, respectively. We also noted that EGFR amplifications correlated with polysomy of chromosome 7, 19, and 20, and loss of PTEN and CDKN2A. EGFR-unamplified cases had lower rates of chromosome 7 polysomy, and PTEN and CDKN2A loss, but more CNVs overall. TP53, NF1, ATRX, and PDGFRA mutations were nearly exclusive to specimens without EGFR amplification. EGFR amplification was not associated with longer progression-free survival in this cohort, but amplifications were enriched in a group with slightly longer overall survival despite radiographic evidence of disease progression. Further study is needed to explore the mechanisms responsible for noted patterns of co-occurring variants and to correlate them with specific clinical outcomes.


Driving anger expression in Germany-Validation of the Driving Anger Expression Inventory for German drivers.
The main objective of this article is to examine whether the Driving Anger Expression Inventory (DAX) applies to German drivers because this scale has previously been given to drivers in many different countries. We applied German versions of the DAX, the Driving Anger Scale (DAS), and the State-Trait Anger Expression Inventory (STAXI) to a sample of 501 German drivers. We computed confirmatory factor analysis and principal axis factoring (PAF) analysis to examine the structure of driving anger expression in Germany. Finally, we related the drivers' anger exp ression scores to their driving anger experiences and their general anger propensities to assess the validity of the DAX for German drivers. Results indicated that the DAX's original factor structure does not apply to German drivers because the confirmatory factor analysis did not show a good model fit. An item analysis revealed that many DAX items had no meaningful variability. They were excluded from further analysis. The subsequent PAF analysis indicated that German drivers do not use personal physical aggression to express their driving anger. Instead, they reported unique preventive anger expression management behavior. In addition, their driving anger expressions were significantly related to their driving anger experiences and their general anger propensities indicated the validity of the refined DAX for German drivers. We conclude that German drivers do not use strong behaviors to express their driving anger. Many statements of Deffenbacher et al.'s (Behav Res Ther. 40:717-737, 2002) original American questionnaire were not applicable for our sample of German drivers. These findings are in line with several other studies showing discrepancies in driving anger expression in various countries. Future investigations should examine the reasons for discrepancies in driving anger expression.


Tick-borne viruses.
At least 38 viral species are transmitted by ticks. Virus-tick-vertebrate host relationships are highly specific and less than 10% of all tick species (Argasidae and Ixodidae) are known to play a role as vectors of arboviruses. However, a few tick species transmit several (e.g. Ixodes ricinus, Amblyomma variegatum) or many (I. uriae) tick-borne viruses. Tick-borne viruses are found in six different virus families (Asfarviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Flaviviridae) and at least 9 genera. Some as yet unassigned tick-borne viruses may belong to a seventh family, the Arenaviridae. With only one exception (African swine fever virus, family Asfarviridae) all tick-borne viruses (as well as all other arboviruses) are RNA viruses. Tick-borne viruses are found in all the RNA virus families in which insect-borne members are found, with the exception of the family Togaviridae. Some tick-borne viruses pose a significant threat to the health of humans (Tick-borne encephalitis virus, Crimean-Congo haemorrhagic fever virus) or livestock (African swine fever virus, Nairobi sheep disease virus). Key challenges are to determine the molecular adaptations that allow tick-borne viruses to infect and replicate in both tick and vertebrate cells, and to identify the principal ecological determinants of tick-borne virus survival.


Archaic Introgression Shaped Human Circadian Traits.
When the ancestors of modern Eurasians migrated out of Africa and interbred with Eurasian archaic hominins, namely Neanderthals and Denisovans, DNA of archaic ancestry integrated into the genomes of anatomically modern humans. This process potentially accelerated adaptation to Eurasian environmental factors, including reduced ultra-violet radiation and increased variation in seasonal dynamics. However, whether these groups differed substantially in circadian biology, and whether archaic introgression adaptively contributed to human chronotypes remains unknown. Here we traced the evolution of chronotype based on genomes from archaic hominins and present-day humans. First, we inferred differences in circadian gene sequences, splicing, and regulation between archaic hominins and modern humans. We identified 28 circadian genes containing variants with potential to alter splicing in archaics (e.g., CLOCK, PER2, RORB, RORC), and 16 circadian genes likely divergently regulated between present-day humans and archaic hominins, including RORA. These differences suggest the potential for introgression to modify circadian gene expression. Testing this hypothesis, we found that introgressed variants are enriched among eQTLs for circadian genes. Supporting the functional relevance of these regulatory effects, we found that many introgressed alleles have associations with chronotype. Strikingly, the strongest introgressed effects on chronotype increase morningness, consistent with adaptations to high latitude in other species. Finally, we identified several circadian loci with evidence of adaptive introgression or latitudinal clines in allele frequency. These findings identify differences in circadian gene regulation between modern humans and archaic hominins and support the contribution of introgression via coordinated effects on variation in human chronotype.


Genome sequence of Nitrosomonas sp. strain AL212, an ammonia-oxidizing bacterium sensitive to high levels of ammonia.
Nitrosomonas sp. strain AL212 is an obligate chemolithotrophic ammonia-oxidizing bacterium (AOB) that was originally isolated in 1997 by Yuichi Suwa and colleagues. This organism belongs to Nitrosomonas cluster 6A, which is characterized by sensitivity to high ammonia concentrations, higher substrate affinity (lower K(m)), and lower maximum growth rates than strains in Nitrosomonas cluster 7, which includes Nitrosomonas europaea and Nitrosomonas eutropha. Genome-informed studies of this ammonia-sensitive cohort of AOB are needed, as these bacteria are found in freshwater environments, drinking water supplies, wastewater treatment systems, and soils worldwide.


Heterogeneity in host HIV susceptibility as a potential contributor to recent HIV prevalence declines in Africa.
HIV prevalence has recently declined in several African countries, and prior to this the risk of HIV acquisition per unprotected sex contact also declined in Kenyan sex workers. We hypothesized that heterogeneity in HIV host susceptibility might underpin both of these observations. A compartmental mathematical model was used to explore the potential impact of heterogeneity in susceptibility to HIV infection on epidemic behavior, in the absence of other causative mechanisms. Studies indicated that a substantial heterogeneity in susceptibility to HIV infection may lead to an epidemic that peaks and then declines due to a depletion of the most susceptible individuals, even without changes in sexual behavior. This effect was most notable in high-risk groups such as female sex workers and was consistent with empirical data. Declines in HIV prevalence may have other causes in addition to behavior change, including heterogeneity in host HIV susceptibility. There is a need to further study this heterogeneity and its correlates, particularly as it confounds the ability to attribute HIV epidemic shifts to specific interventions, including behavior change.


Aged garlic extract and S-allyl cysteine prevent formation of advanced glycation endproducts.
Hyperglycaemia causes increased protein glycation and the formation of advanced glycation endproducts which underlie the complications of diabetes and ageing. Glycation is accompanied by metal-catalysed oxidation of glucose and Amadori products to form free radicals capable of protein fragmentation. Aged garlic extract is a potent antioxidant with established lipid-lowering effects attributed largely to a key ingredient called S-allyl cysteine. This study investigated the ability of aged garlic extract and S-allyl cysteine to inhibit advanced glycation in vitro. Bovine serum albumin (BSA) was glycated in the presence of Cu(2+) ions and different concentrations of aged garlic extract and protein fragmentation was examined by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Lysozyme was glycated by glucose or methylglyoxal in the presence of different concentrations of aged garlic extract or S-allyl cysteine with subsequent analysis of glycation-derived crosslinking using SDS-PAGE. Amadori-rich protein was prepared by dialysing lysozyme that had been glycated by ribose for 24 h. This ribated lysozyme was reincubated and the effects of aged garlic extract, S-allyl cysteine and pyridoxamine on glycation-induced crosslinking was monitored. Aged garlic extract inhibited metal-catalysed protein fragmentation. Both aged garlic extract and S-allyl cysteine inhibited formation of glucose and methylglyoxal derived advanced glycation endproducts and showed potent Amadorin activity when compared to pyridoxamine. S-allyl cysteine inhibited formation of carboxymethyllysine (CML), a non-crosslinked advanced glycation endproduct derived from oxidative processes. Further studies are required to assess whether aged garlic extract and S-allyl cysteine can protect against the harmful effects of glycation and free radicals in diabetes and ageing.


Molecular characterization of hNRP, a cDNA encoding a human nucleosome-assembly-protein-I-related gene product involved in the induction of cell proliferation.
We have isolated from a human thymus cDNA library a cDNA clone encoding a potential protein with 54% amino acid similarity to that encoded by a previously identified cDNA for yeast nucleosome assembly protein I (NAP-I). The deduced amino acid sequence for this newly identified cDNA, designated hNRP (human NAP-related protein), contains a potential seven-residue nuclear localization motif, three clusters of highly acidic residues and other structural features found in various proteins implicated in chromatin formation. When expressed as a fusion protein in Escherichia coli, hNRP reacted specifically with a monoclonal antibody raised against human NAP-I. The hNRP transcript was detected in all tissues and cell lines studied, but levels were somewhat increased in rapidly proliferating cells. Moreover, levels of both hNRP mRNA and protein increased rapidly in cultured T-lymphocytes induced to proliferate by incubation with phorbol ester and ionomycin. Phorbol 12-myristate 13-acetate/ionomycin-induced increases in both hNRP mRNA and mitogenesis, as measured by thymidine incorporation, were markedly inhibited, however, in cells treated with an hNRP antisense oligonucleotide. These results demonstrate a correlation between induction of hNRP expression and mitogenesis and taken together with the structural similarities between hNRP and yeast NAP-I suggest that the hNRP gene product participates in DNA replication and thereby plays an important role in the process of cell proliferation.


Electromagnetic therapy for treating venous leg ulcers.
Leg ulceration is a common, chronic, recurring condition. The estimated prevalence of leg ulcers in the UK population is 1.5 to 3 per 1000. Venous ulcers (also called stasis or varicose ulcers) comprise 80% to 85% of all leg ulcers. Electromagnetic therapy (EMT) is sometimes used as a treatment to assist the healing of chronic wounds such as venous leg ulcers. To assess the effects of EMT on the healing of venous leg ulcers. For this third update, we searched The Cochrane Wounds Group Specialised Register (searched 12 November 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10); Ovid MEDLINE (2011 to November Week 1 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, November 12, 2012); Ovid EMBASE (2011 to 2012 Week 45); and EBSCO CINAHL (2011 to 9 November 2012). Randomised controlled trials comparing EMT with sham-EMT or other treatments. At least two review authors independently scrutinised search results and obtained full reports of potentially eligible studies for further assessment. We extracted and summarised details of eligible studies using a data extraction sheet, and made attempts to obtain missing data by contacting study authors. A second review author checked data extraction, and we resolved disagreements after discussion between review authors. Three randomised controlled trials (RCTs) of variable quality involving 94 people were included in the original review; subsequent updates have identified no new trials. All the trials compared the use of EMT with sham-EMT. In the two trials that reported healing rates; one small trial (44 participants) reported that significantly more ulcers healed in the EMT group than the sham-EMT group however this result was not robust to different assumptions about the outcomes of participants who were lost to follow up. The second trial that reported numbers of ulcers healed found no significant difference in healing. The third trial was also small (31 participants) and reported significantly greater reductions in ulcer size in the EMT group however this result may have been influenced by differences in the prognostic profiles of the treatment groups. There is no high quality evidence that electromagnetic therapy increases the rate of healing of venous leg ulcers, and further research is needed.


The Polycomb group protein CRAMPED is involved with TRF2 in the activation of the histone H1 gene.
CRAMPED (CRM), conserved from plants to animals, was previously characterized genetically as a repressive factor involved in the formation of facultative and constitutive heterochromatin (Polycomb silencing, position effect variegation). We show that crm is dynamically regulated during replication and identify the Histone gene cluster (His-C) as a major CRM target. Surprisingly, CRM is specifically required for the expression of the Histone H1 gene, like the promoter-bound transcription factor TRF2. Consistently with this, CRM genetically interacts and co-immunoprecipitates with TRF2. However, the Polycomb phenotypes observed in crm mutants are not observed in TRF2 hypomorphic mutants, suggesting that they correspond to independent roles of CRM. CRM is thus a highly pleiotropic factor involved in both activation and repression.


A review of stroke rehabilitation and physiotherapy.
Most of the members of the therapeutic team in stroke rehabilitation take the effectiveness of physical treatments after stroke for granted. Yet, published data show that the evidence is not so straightforward or easy to evaluate. The majority of the hard evidence, however, does imply that stroke patients benefit from rehabilitation with physiotherapy. This benefit may be statistically small, but for a given individual, it could mean the difference between living at home or in an institution. Few studies address the question of the optimal physiotherapy in stroke rehabilitation. The evidence available today suggests that it does not matter which form of treatment is chosen and that any of the available approaches will improve the patient's functional status. In other words, if an optimal treatment exists, we have, so far, failed to identify it. Until further evidence emerges, we should therefore select therapies that are most cost-effective and that can be given to the largest number of patients. Well-planned clinical trials aimed at finding the best approach and discriminating potential responders from nonresponders are urgently needed.


Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion.
To evaluate the roles of counterregulatory hormones and insulin antibodies in the impairment of plasma glucose recovery from hypoglycemia in diabetes mellitus, and to assess the relationship between the glucagon response and duration of the disease, 21 insulin-dependent diabetic patients and 10 nondiabetic subjects were studied. The diabetics consisted of 5 patients with recent onset of diabetes (less than 1 mo); 11 with 2.6 +/- 0.3 (mean +/- SEM) yr duration of diabetes, 5 of whom had insulin antibodies; and 5 patients with long-term diabetes (21 +/- 3 yr), insulin antibodies, and autonomic neuropathy. During insulin-induced hypoglycemia (28 mU/m2 X min for 60 min) in patients with recent-onset diabetes, plasma free insulin, glucose, and counterregulatory hormone concentrations did not differ from those of nondiabetic subjects. In patients with insulin antibodies, the disappearance of insulin after insulin infusion was delayed, and both restitution of normoglycemia and plasma glucagon response were blunted compared with patients without antibodies. When glucagon was infused (80-130 ng/m2 X min) during hypoglycemia in diabetics with impaired glucagon responses in order to simulate normal glucagon responses, plasma glucose recovery was normalized in patients without antibodies but not in those with antibodies. In patients with long-standing diabetes, restitution of normoglycemia was further impaired and this was associated with an absent plasma glucagon response and a diminished plasma epinephrine response. Plasma glucagon responses to hypoglycemia were inversely correlated to the duration of diabetes (r = -0.943; P less than 0.0005). It is concluded that impaired A-cell secretion is the predominant mechanism for the delayed glucose recovery after hypoglycemia in diabetic patients without insulin antibodies and normal epinephrine responses. Slowed disappearance of insulin due to the presence of insulin antibodies further delays the restoration of normoglycemia. Patients with long-standing diabetes and autonomic neuropathy exhibit decreased epinephrine secretion, which leads to an additional retardation of glucose recovery. Since plasma glucagon and epinephrine responses to hypoglycemia were normal at the onset of diabetes but diminished in long-term diabetes, it appears that the impaired glucagon and epinephrine responses to hypoglycemia are acquired defects that develop subsequent to B-cell failure.


Membrane association of the RNA-dependent RNA polymerase is essential for hepatitis C virus RNA replication.
The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp), represented by nonstructural protein 5B (NS5B), belongs to a class of integral membrane proteins termed tail-anchored proteins. Its membrane association is mediated by the C-terminal 21 amino acid residues, which are dispensable for RdRp activity in vitro. For this study, we investigated the role of this domain, termed the insertion sequence, in HCV RNA replication in cells. Based on a structural model and the amino acid conservation among different HCV isolates, we designed a panel of insertion sequence mutants and analyzed their membrane association and RNA replication. Subgenomic replicons with a duplication of an essential cis-acting replication element overlapping the sequence that encodes the C-terminal domain of NS5B were used to unequivocally distinguish RNA versus protein effects of these mutations. Our results demonstrate that the membrane association of the RdRp is essential for HCV RNA replication. Interestingly, certain amino acid substitutions within the insertion sequence abolished RNA replication without affecting membrane association, indicating that the C-terminal domain of NS5B has functions beyond serving as a membrane anchor and that it may be involved in critical intramembrane protein-protein interactions. These results have implications for the functional architecture of the HCV replication complex and provide new insights into the expanding spectrum of tail-anchored proteins.


CD40-CD40 ligand interactions are critical in T-B cooperation but not for other anti-viral CD4+ T cell functions.
CD40-CD40 ligand (CD40L) interaction is required for the generation of antibody responses to T-dependent antigens as well as for the development of germinal centers and memory B cells. The role of the CD40-CD40L interaction in the induction of antigen-specific. Th cells and in mediating Th cell effector functions other than cognate help for B cells is less well understood. Using CD40- and CD40L-deficient mice together with lymphocytic choriomeningitis virus and vesicular stomatitis virus as viral model antigens, this study corroborates earlier findings that no lg isotype switching of virus-specific antibodies was measurable upon infection of CD40- or CD40L-deficient mice. In contrast, in vivo induction of virus-specific CD4+ T cells measured by proliferation and cytokine secretion of primed virus-specific Th cells in vitro was not crucially dependent on the CD40-CD40L interaction. In addition, virus-specific Th cells primed in a CD40-deficient environment, adoptively transferred into CD40-competent recipients, were able to mediate lg isotype switch. Th-mediated effector functions distinct from and in addition to T-B collaboration were analyzed in CD40- and CD40L-deficient and normal mice: (a) local inflammatory reactions upon LCMV infection mediated by LCMV-specific Th cells were not dependent on a functional CD40-CD40L interaction, (b) cytokine-mediated protection by CD4+ T cells primed by vesicular stomatitis virus against a challenge infection with recombinant vaccinia virus expressing the glycoprotein of vesicular stomatitis virus was found to be equivalent in CD40L-deficient and normal mice. Thus, CD40-CD40L interaction plays a crucial role in T-B interactions for Th-dependent activation of B cells but not, or to a much lesser extent, in T cell activation, antigen-specific Th cell responses in vitro, and for interleukin-mediated Th cell effector functions in vivo.


Reciprocal relationships and potential feedbacks between biodiversity and disturbance.
Two major foci of ecological research involve reciprocal views of the relationship between biodiversity and disturbance: disturbance determines community diversity or diversity determines realized disturbance severity. Here, we present an initial attempt to synthesize these two approaches in order to understand whether feedbacks occur, and what their effects on patterns of diversity might be. Our review of published experiments shows that (i) disturbance severity can be both a cause and a consequence of local diversity in a wide range of ecosystems and (ii) shapes of the unidirectional relationships between diversity and disturbance can be quite variable. To explore how feedbacks between diversity and disturbance might operate to alter expected patterns of diversity in nature, we develop and then evaluate a conceptual model that decomposes the relationships into component parts, considering sequentially the effect of diversity on disturbance severity, and the effect of realized disturbance on diversity loss, subsequent recruitment, and competitive exclusion. Our model suggests that feedbacks can increase mean values of richness, decrease variability, and alter the patterns of correlation between diversity and disturbance in nature. We close by offering ideas for future research to help fill gaps in our understanding of reciprocal relationships among ecological variables like diversity and disturbance.


A glimpse at the aging eye.
Extensive investigations have demonstrated that organismal aging is associated with tissue dysfunction in many organs. The eye is no exception to this rule. Under healthy conditions, the eye is designed like an advanced camera with the central role of translating light from the external world into a coherent neural signal that can be transmitted to the brain for processing into a precise visual image. This complex process requires precisely maintained machinery. At the front of the eye, the transparency of both the cornea and the lens are crucial to allow passage of photons to the light-sensitive portion of the eye. Similarly, the highly organized structure of the retina located at the back of the eye is indispensable to allow for effective signal transduction and efficient signal transmission. Aging affects ocular structures in various ways, and these sequelae have been well defined as distinct clinical entities. In many instances, aging leads to ocular tissue dysfunction and disease. Nonetheless, despite clear evidence that age-associated visual impairment has significant psychosocial consequences, current treatment paradigms for many of these conditions are inadequate. In addition, strategies to decelerate or reverse age-associated deterioration in ocular function are still in their infancy. This review focuses on the cellular and molecular pathophysiology of the aging eye. Ultimately, we hope that a refined understanding of the aging eye can guide targeted therapies against cellular aging and disease.


AMnO3 (A = Sr, La, Ca, Y) Perovskite Oxides as Oxygen Reduction Electrocatalysts.
A series of perovskite-type manganites AMnO3 (A = Sr, La, Ca and Y) particles were investigated as electrocatalysts for the oxygen reduction reaction. AMnO3 materials were synthesized by means of an ionic-liquid method, yielding phase pure particles at different temperatures. Depending on the calcination temperature, particles with mean diameter between 20 and 150 nm were obtained. Bulk versus surface composition and structure are probed by X-ray photoelectron spectroscopy and extended X-ray absorption fine structure. Electrochemical studies were performed on composite carbon-oxide electrodes in alkaline environment. The electrocatalytic activity is discussed in terms of the effective Mn oxidation state, A:Mn particle surface ratio and the Mn-O distances.


Results of combined-modality therapy for primary and secondary malignant lymphoma of the central nervous system (CNS).
We consider that whatever the vital prognosis of secondary CNS lymphoma (SCNSL), its local control is as serious as that of primary CNS lymphoma (PCNSL). In this study, both the treatment outcomes and local control of patients with SCNSL and PCNSL were compared, with the aim of improving the treatment of SCNSL. This study included 11 patients with PCNSL and 14 with SCNSL treated from January 1984 to October 1997. PCNSL patients underwent partial tumor resection and received systemic chemotherapy. All SCNSL patients received systemic chemotherapy, and eight also received intrathecal anticancer drug infusion. Nine PCNSL patients and 11 SCNSL patients underwent whole-brain radiation therapy with 4-MV photons. Among the SCNSL patients, three patients underwent localized-brain irradiation and two patients also received whole-spine irradiation. Five-year survival rates were 34% for PCNSL and 33% for SCNSL. In SCNSL, survival times after CNS involvement were very short, irrespective of treatment. One-year local control rates after CNS irradiation were 38% for PCNSL and 14% for SCNSL. Recurrence was mainly found in the cranial region, in seven of 11 PCNSL patients and 10 of 14 SCNSL patients. Patients with SCNSL had a poor prognosis, and local control in them was more problematic than in patients with PCNSL. It is necessary to develop new combined modality therapy for patients with SCNSL,including the participation of a radiation oncologist, before the disease becomes progressive.


Effects of drinking water fluorosis on L-type calcium channel of hippocampal neurons in mice.
The study aimed to investigate the effects of drinking water fluorosis on L-type calcium channels (LTCCs) in mouse hippocampal neurons. A total of 60 newly weaned ICR male mice were randomly divided into control, low fluoride and high fluoride groups. After 3 and 6 months of exposure to fluoride, the patch clamp technique was used to detect the peak and relative values (I/Imax), steady-state activation curve ratio (G/Gmax), decay time constant, and tail current time constant of LTCCs currents in hippocampal CA1 region of mouse brain slices. Fluoride greatly reduced the serum and urinary calcium concentrations in mice, and the chronic fluorosis has a greater impact than subchronic fluorosis. The peak value of LTCCs current in pyramidal neurons of hippocampal CA1 area was significant and increased with the prolonged exposure time. The relative values of current and steady-state coefficients were changed greatly. The decay and tail current time increased significantly. High fluorine concentration indicates great peak value and open time of LTCCs opening. LTCCs are sensitive to fluoride exposure. The activation voltage of calcium channels induced by fluoride exposure is decreased, the opening time of calcium channels is prolonged, and the calcium influx per unit time increased, thereby overloading calcium concentration in neurons and this may be an explanation for intracellular calcium overload caused by fluoride. The imbalance of calcium metabolism caused by fluorosis may be a pathogenesis of brain injury induced by fluoride. Furthermore, the risk of brain damage from low-fluorine exposure cannot be ignored.


Glucose transporter levels in tissues of spontaneously diabetic Zucker fa/fa rat (ZDF/drt) and viable yellow mouse (Avy/a).
We used antibodies to the fat/muscle glucose transporter (GLUT4) and the liver glucose transporter (GLUT2) to measure levels of these proteins in various tissues of two rodent models of non-insulin-dependent (type II) diabetes mellitus: the obese spontaneously diabetic male Zucker fa/fa rat (ZDF/drt) and the male viable yellow Avy/a obese diabetic mouse. The ZDF/drt strain generally develops overt diabetes associated with decreased plasma insulin levels. Depending on the age of the animals, the ZDF/drt rats can be arbitrarily segregated into age-matched obese, mildly diabetic (blood glucose less than 11 mM) and obese, and severely diabetic (blood glucose greater than 20 mM) groups. Avy/a mice are comparably hyperglycemic but unlike the ZDF/drt rats are severely hyperinsulinemic. In both groups of diabetic animals, GLUT4 in adipose tissue, heart, and skeletal muscle was reduced 25-55%, and GLUT2 in liver was increased 30-40%, relative to lean, age-matched controls. However, when the mildly diabetic ZDF/drt rats were compared to the lean controls, the only significant difference was a 25% reduction of GLUT4 in heart. Within all of the ZDF/drt rats (excluding the lean controls), GLUT2 in liver and GLUT4 in adipose tissue, heart, and skeletal muscle correlated significantly with glycemia. These data suggest that, in these two models of type II diabetes, glucose transporter levels in muscle, adipose tissue, and liver are regulated in a tissue-selective manner in response to changes in insulin and glucose. Furthermore, at least in the ZDF/drt rat, alterations in GLUT2 and/or GLUT4 protein levels appear not to be associated with obesity per se but appear to be secondary to the severely diabetic state.(ABSTRACT TRUNCATED AT 250 WORDS)


Developing a Hypothetical Implementation Framework of Expectations for Monitoring Early Signs of Psychosis Relapse Using a Mobile App: Qualitative Study.
Relapse is a common experience for people diagnosed with psychosis, which is associated with increased service costs and profound personal and familial distress. EMPOWER (Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery) is a peer worker-supported digital intervention that aims to enable service users to self-monitor their mental health with the aim of encouraging self-management and the shared use of personal data to promote relapse prevention. Digital interventions have not been widely used in relapse prevention and, therefore, little is currently known about their likely implementation-both within trials and beyond. Seeking the perspectives of all relevant stakeholder groups is recommended in developing theories about implementation because this can reveal important group differences in understandings and assumptions about whether and for whom the intervention is expected to work. However, the majority of intervention implementation research has been retrospective. This study aimed to discover and theoretically frame implementation expectations in advance of testing and synthesize these data into a framework. To develop a hypothetical implementation framework, 149 mental health professionals, carers, and people diagnosed with psychosis participated in 25 focus groups in both Australia and the United Kingdom. An interview schedule informed by the normalization process theory was used to explore stakeholders' expectations about the implementation of the EMPOWER intervention. Data were analyzed using thematic analysis and then theoretically framed using the Medical Research Council guidelines for understanding the implementation of complex interventions. All groups expected that EMPOWER could be successfully implemented if the intervention generated data that were meaningful to mental health staff, carers, and service users within their unique roles. However, there were key differences between staff, carers, and service users about what facilitators and barriers that stakeholders believe exist for intervention implementation in both the cluster randomized controlled trial stage and beyond. For example, service user expectations mostly clustered around subjective user experiences, whereas staff and carers spoke more about the impact upon staff interactions with service users. A hypothetical implementation framework synthesized from stakeholder implementation expectations provides an opportunity to compare actual implementation data gathered during an ongoing clinical trial, giving valuable insights into the accuracy of these stakeholders' previous expectations. This is among the first studies to assess and record implementation expectations for a newly developed digital intervention for psychosis in advance of testing in a clinical trial. ISRCTN Registry ISRCTN99559262; http://www.isrctn.com/ISRCTN99559262.


Catabolic signaling pathways, atrogenes, and ubiquitinated proteins are regulated by the nutritional status in the muscle of the fine flounder.
A description of the intracellular mechanisms that modulate skeletal muscle atrophy in early vertebrates is still lacking. In this context, we used the fine flounder, a unique and intriguing fish model, which exhibits remarkably slow growth due to low production of muscle-derived IGF-I, a key growth factor that has been widely acknowledged to prevent and revert muscle atrophy. Key components of the atrophy system were examined in this species using a detailed time-course of sampling points, including two contrasting nutritional periods. Under basal conditions high amounts of the atrogenes MuRF-1 and Atrogin-1 were observed. During fasting, the activation of the P38/MAPK and Akt/FoxO signaling pathways decreased; whereas, the activation of the IκBα/NFκB pathway increased. These changes in signal transduction activation were concomitant with a strong increase in MuRF-1, Atrogin-1, and protein ubiquitination. During short-term refeeding, the P38/MAPK and Akt/FoxO signaling pathways were strongly activated, whereas the activation of the IκBα/NFκB pathway decreased significantly. The expression of both atrogenes, as well as the ubiquitination of proteins, dropped significantly during the first hour of refeeding, indicating a strong anti-atrophic condition during the onset of refeeding. During long-term refeeding, Akt remained activated at higher than basal levels until the end of refeeding, and Atrogin-1 expression remained significantly lower during this period. This study shows that the components of the atrophy system in skeletal muscle appeared early in the evolution of vertebrates and some mechanisms have been conserved, whereas others have not. These results represent an important achievement for the area of fish muscle physiology, showing an integrative view of the atrophy system in a non-mammalian species and contributing to novel insights on the molecular basis of muscle growth regulation in earlier vertebrates.


Safety of primaquine in infants with Plasmodium vivax malaria in Papua, Indonesia.
Primaquine (PQ) prevents relapses of vivax malaria but may induce severe haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients. Data on the safety of primaquine in infants are limited. A retrospective, hospital-based cohort study of infants aged 1-12 months with vivax malaria was carried out in Timika, Papua province, Indonesia. Risks of admission, death and severe haematological outcomes within 30 days of first presentation were compared between infants who did and did not receive primaquine. Infants were not tested routinely for G6PD deficiency as per local guidelines. Between 2004 and 2013, 4078 infants presented to the hospital for the first time with vivax malaria, of whom 3681 (90.3%) had data available for analysis. In total 1228 (33.4%) infants were aged between 1 and 6 months and 2453 (66.6%) between 6 and 12 months of age. Thirty-three (0.9%) patients received low-dose primaquine (LDP), 174 (4.7%) received high-dose primaquine (HDP), 3432 (93.2%) received no primaquine (NPQ) and 42 patients received either a single dose or an unknown dose of primaquine. The risk of the Hb concentration falling by > 25% to less than 5 g/dL was similar in the LDP or HDP groups (4.3%, 1/23) versus the NPQ group (3.5%, 16/461). Three infants (1.4%) died following receipt of PQ, all of whom had major comorbidities. Seventeen patients (0.5%) died in the NPQ group. None of the infants had documented massive haemolysis or renal impairment. Severe clinical outcomes amongst infants treated with primaquine in Papua were rare. The risks of using primaquine in infancy must be weighed against the risks of recurrent vivax malaria in early life.


Strategies of nodal staging of the TNM system for esophageal cancer.
The 8th edition of UICC/AJCC TNM staging for esophageal cancer will start in use since 2018. The nodal staging in this version of TNM system remains unchanged from the 7th edition that based on the number of lymph nodes (LN) involved, except the limited revision of the regional LN map. In this review, N staging revision was evaluated from its initially simple definition of negative (N0) and positive (N1) LN(s) to the current positive node number based proposal. Meanwhile the disadvantages of current N staging were discussed. The refined nodal staging system in view of the number of metastatic node stations was introduced; as well as the extent and station of metastatic node could better reflect the disease progression and prognosis. The controversy on N staging of esophagogastric junction cancer was also discussed. Other reported N staging associated elements including LN ratio and lymphatic vessel invasion were reviewed and evaluated.


Observer rated sleepiness and real road driving: an explorative study.
The aim of the present study was to explore if observer rated sleepiness (ORS) is a feasible method for quantification of driver sleepiness in field studies. Two measures of ORS were used: (1) one for behavioural signs based on facial expression, body gestures and body movements labelled B-ORS, and (2) one based on driving performance e.g. if swerving and other indicators of impaired driving occurs, labelled D-ORS. A limited number of observers sitting in the back of an experimental vehicle on a motorway about 2 hours repeatedly 3 times per day (before lunch, after lunch, at night) observed 24 participant's sleepiness level with help of the two observer scales. At the same time the participant reported subjective sleepiness (KSS), EOG was recorded (for calculation of blink duration) and several driving measure were taken and synchronized with the reporting. Based on mixed model Anova and correlation analysis the result showed that observer ratings of sleepiness based on drivers' impaired performance and behavioural signs are sensitive to extend the general pattern of time awake, circadian phase and time of driving. The detailed analysis of the subjective sleepiness and ORS showed weak correspondence on an individual level. Only 16% of the changes in KSS were predicted by the observer. The correlation between the observer ratings based on performance (D-ORS) and behavioural signs (B-ORS) are high (r = .588), and the B-ORS shows a moderately strong association (r = .360) with blink duration. Both ORS measures show an association (r>0.45) with KSS, whereas the association with driving performance is weak. The results show that the ORS-method detects the expected general variations in sleepy driving in field studies, however, sudden changes in driver sleepiness on a detailed level as 5 minutes is usually not detected; this holds true both when taking into account driving behaviour or driver behavioural signs.


Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion. Altered profile and pregnancy outcome.
Several lines of evidence indicate that immunologic effectors, particularly suppressor T cells and NK cells, may play a role in the pathogenesis of idiopathic repetitive abortions. To investigate the involvement of these immune cell populations, we determined the immunophenotypic characteristics of endometrial leukocytes from nonpregnant recurrent aborters. Habitual aborters with a negative investigation underwent an endometrial biopsy during their secretory phase and were followed prospectively to assess clinical outcome. Endometrial leukocytes were evaluated by two-color flow cytometric analysis. The percentage of endometrial CD8+ T lymphocytes was significantly decreased in recurrent aborters, and their CD4:CD8 ratio was increased. In contrast, the proportion of B lymphocytes (CD20+) was strikingly increased in these patients' endometria. The proportion of NK cells was identical in recurrent aborters and normal controls, but the CD16-CD56 bright NK cell subset, which is predominant in normal decidua and endometrium, was significantly decreased in favor of an important contingent of CD16+CD56 dim NK cells in all habitual aborters. Repetitive aborters who had normal CD8+ and CD20+ cell numbers and a normal CD4:CD8 ratio subsequently underwent successful pregnancies, while patients with continuing abortions presented lymphoid populations observed in the habitual aborters group. In conclusion, endometrial lymphocytes of recurrent spontaneous aborters harbor a distinct immunophenotypic profile that antedates implantation and suggests that endometrial immunologic conditions are intrinsically altered in recurrent aborters. Also, the prognostic impact of CD8 and CD20 expression supports their predominant role in the development of fetal tolerance. Finally, a role for NK cells in the abortion process is suggested by their altered subsets in all repetitive aborters.


A 0.35 μm sub-ns wake-up time ON-OFF switchable LVDS driver-receiver chip I/O pad pair for rate-dependent power saving in AER bit-serial links.
This paper presents a low power switchable current mode driver/receiver I/O pair for high speed serial transmission of asynchronous address event representation (AER) information. The sparse nature of AER packets (also called events) allows driver/receiver bias currents to be switched off to save power. The on/off times must be lower than the bit time to minimize the latency introduced by the switching mechanism. Using this technique, the link power consumption can be scaled down with the event rate without compromising the maximum system throughput. The proposed technique has been implemented on a typical push/pull low voltage differential signaling (LVDS) circuit, but it can easily be extended to other widely used current mode standards, such as current mode logic (CML) or low-voltage positive emitter-coupled logic (LVPECL). A proof of concept prototype has been fabricated in 0.35 μm CMOS incorporating the proposed driver/receiver pair along with a previously reported switchable serializer/deserializer scheme. At a 500 Mbps bit rate, the maximum event rate is 11 Mevent/s for 32-bit events. In this situation, current consumption is 7.5 mA and 9.6 mA for the driver and receiver, respectively, while differential voltage amplitude is ±300 mV. However, if event rate is lower than 20-30 Kevent/s, current consumption has a floor of 270 μA for the driver and 570 μA for the receiver. The measured ON/OFF switching times are in the order of 1 ns. The serial link could be operated at up to 710 Mbps bit rate, resulting in a maximum 32-bit event rate of 15 Mevent/s . This is the same peak event rate as that obtained with the same SerDes circuits and a non-switched driver/receiver pair.


Capturing epidermal stemness for regenerative medicine.
The skin is privileged because several skin-derived stem cells (epithelial stem cells from epidermis and its appendages, mesenchymal stem cells from dermis and subcutis, melanocyte stem cells) can be efficiently captured for therapeutic use. Main indications remain the permanent coverage of extensive third degree burns and healing of chronic cutaneous wounds, but recent advances in gene therapy technology open the door to the treatment of disabling inherited skin diseases with genetically corrected keratinocyte stem cells. Therapeutic skin stem cells that were initially cultured in research or hospital laboratories must be produced according strict regulatory guidelines, which ensure patients and medical teams that the medicinal cell products are safe, of constant quality and manufactured according to state-of-the art technology. Nonetheless, it does not warrant clinical efficacy and permanent engraftment of autologous stem cells remains variable. There are many challenges ahead to improve efficacy among which to keep telomere-dependent senescence and telomere-independent senescence (clonal conversion) to a minimum in cell culture and to understand the cellular and molecular mechanisms implicated in engraftment. Finally, medicinal stem cells are expansive to produce and reimbursement of costs by health insurances is a major concern in many countries.


Molecular and cellular characterization of imexon-resistant RPMI8226/I myeloma cells.
Imexon is an aziridine-containing iminopyrrolidone with selective growth-inhibitory potency for multiple myeloma. Our previous research indicates that imexon induces mitochondrial alterations, oxidative stress, and apoptosis. This drug represents an interesting model drug with a nonmyelosuppressive profile to study the basic mechanisms leading to antitumor activity and resistance. The major purpose of this study was to characterize an imexon-resistant RPMI8226/I cell line that was developed from RPMI8226 cells by continuous exposure to imexon. No significant differences were observed in the sensitivity to several cytotoxic drugs, including mitoxantrone, mitomycin C, melphalan, methotrexate, cytarabine, cisplatin, vincristine, and paclitaxel, in the imexon-resistant cells. However, RPMI8226/I cells were cross-resistant to arsenic trioxide, doxorubicin, fluorouracil, etoposide, irinotecan, and especially IFN-alpha. The data from DNA microarray and Western blot analyses indicated that the levels of antiapoptotic proteins Bcl-2 and thioredoxin-2, which reside mainly in the mitochondria, are increased in RPMI8226/I cells. In addition, increased levels of lung resistance protein were detected in imexon-resistant cells. Expression of P-glycoprotein was not detected in RPMI8226/I cells. No loss of mitochondrial membrane potential or increase in the levels of reactive oxygen species was observed in RPMI8226/I cells after exposure to imexon; however, the levels of glutathione are increased in the RPMI8226/I cells. Transmission electron microscopy revealed significant changes in the mitochondrial morphology of RPMI8226/I cells, whereas no ultrastructural changes were observed in other cellular compartments. Imexon-resistant RPMI8226/I myeloma cells appear to have a unique mechanism of resistance that is associated with morphological alterations of mitochondria, increased protection against oxidative stress, elevated levels of glutathione, and enhanced expression of antiapoptotic mitochondrial proteins.


The CHA2DS2-VASc score and in-hospital mortality in patients with COVID-19: A multicenter retrospective cohort study.
Coronavirus disease 2019 (COVID-19) is an infectious disease that was first reported in December 2019 in Wuhan, China, and has since spread rapidly around the world, resulting in the ongoing COVID-19 pandemic. The CHA2DS2-VASc score is a well-validated risk stratification tool for predicting stroke in atrial fibrillation (AFib), as well as morbidity and mortality in several entities. The aim of this study was to evaluate the relationship between the CHA2DS2-VASc score and in-hospital mortality in patients with COVID-19, regardless of AFib. This multicenter, retrospective study included a total of 349 patients with COVID-19 who were hospitalized between March 15 and April 15, 2020. The CHA2DS2-VASc score of each patient was calculated. Mortality outcomes were followed up until April 25, 2020. The CHA2DS2-VASc score was significantly higher in non-survivor COVID-19 patients than in survivor COVID-19 patients (p<0.001). Forward stepwise logistic regression analysis demonstrated that a CHA2DS2-VASc score of ≥3 (odds ratio [OR]: 12.613, 95% confidence interval [CI]: 3.092-51.451; p<0.001), and the leukocyte count (OR: 1.327, 95% CI: 1.145-1.538; p<0.001), C-reactive protein level (OR: 1.010, 95% CI: 1.002-1.018; p=0.012), and ferritin level (OR: 1.005, 95% CI: 1.003-1.007; p<0.001) on admission were independent predictors of in-hospital mortality of COVID-19 patients. The CHA2DS2-VASc score predicted in-hospital mortality in patients with COVID-19, regardless of AFib.


Interaction of Developmental Venous Anomalies with Resting-State Functional MRI Measures.
Functional MR imaging of the brain, used for both clinical and neuroscientific applications, relies on measuring fluctuations in blood oxygenation. Such measurements are susceptible to noise of vascular origin. The purpose of this study was to assess whether developmental venous anomalies, which are frequently observed normal variants, can bias fMRI measures by appearing as true neural signal. Large developmental venous anomalies (1 in each of 14 participants) were identified from a large neuroimaging cohort (n = 814). Resting-state fMRI data were decomposed using independent component analysis, a data-driven technique that creates distinct component maps representing aspects of either structured noise or true neural activity. We searched all independent components for maps that exhibited a spatial distribution of their signals following the topography of developmental venous anomalies. Of the 14 developmental venous anomalies identified, 10 were clearly present in 17 fMRI independent components in total. While 9 (52.9%) of these 17 independent components were dominated by venous contributions and 2 (11.8%) by motion artifacts, 2 independent components (11.8%) showed partial neural signal contributions and 5 independent components (29.4%) unambiguously exhibited typical neural signal patterns. Developmental venous anomalies can strongly resemble neural signal as measured by fMRI. They are thus a potential source of bias in fMRI analyses, especially when present in the cortex. This could impede interpretation of local activity in patients, such as in presurgical mapping. In scientific studies with large samples, developmental venous anomaly confounds could be mainly addressed using independent component analysis-based denoising.


A simplified predictive control algorithm for disturbance rejection.
Model predictive control (MPC) offers several advantages for control of chemical processes. However, the standard MPC may do a poor job in suppressing the effects of certain disturbances. This shortcoming is mainly due to the assumption that disturbances remain constant over the prediction horizon. In this paper, a simple disturbance predictor (SDP) is developed to provide predictions of the unmodeled deterministic disturbances for a simplified MPC algorithm. The prediction is developed by curve fitting of the past information. A tuning parameter is employed to handle a variety of disturbance dynamics and a procedure is presented to find an optimum value of the tuning parameter online. A comparison is made with the commonly used disturbance prediction on three example problems. The results show that an improved regulatory performance and zero offset can be achieved under both regular and ramp output disturbances by using the proposed disturbance predictor.


Evaluating annotations of an Agilent expression chip suggests that many features cannot be interpreted.
While attempting to reanalyze published data from Agilent 4 x 44 human expression chips, we found that some of the 60-mer olignucleotide features could not be interpreted as representing single human genes. For example, some of the oligonucleotides align with the transcripts of more than one gene. We decided to check the annotations for all autosomes and the X chromosome systematically using bioinformatics methods. Out of 42683 reporters, we found that 25505 (60%) passed all our tests and are considered "fully valid". 9964 (23%) reporters did not have a meaningful identifier, mapped to the wrong chromosome, or did not pass basic alignment tests preventing us from correlating the expression values of these reporters with a unique annotated human gene. The remaining 7214 (17%) reporters could be associated with either a unique gene or a unique intergenic location, but could not be mapped to a transcript in RefSeq. The 7214 reporters are further partitioned into three different levels of validity. Expression array studies should evaluate the annotations of reporters and remove those reporters that have suspect annotations. This evaluation can be done systematically and semi-automatically, but one must recognize that data sources are frequently updated leading to slightly changing validation results over time.


Restricted Spread of Tomato spotted wilt virus in Thrips-Resistant Pepper.
ABSTRACT Spread of Tomato spotted wilt virus (TSWV) and population development of its vector Frankliniella occidentalis were studied on the pepper accessions CPRO-1 and Pikante Reuzen, which are resistant and susceptible to thrips, respectively. Viruliferous thrips were released on plants of each accession (nonchoice tests) or on plants in a 1:1 mixture of both accessions (choice tests) in small cages containing 8 or 16 plants. Significantly fewer CPRO-1 plants became infected in the primary infection phase in both tests. In the nonchoice test, virus infection of the resistant plants did not increase after the initial infection, but all plants eventually became infected when mixtures of both cultivars were challenged in the secondary infection phase. Secondary spread of TSWV from an infected resistant or susceptible source plant was significantly slower to resistant plants than to susceptible plants, independent of source plant phenotype. The restricted introduction and spread of TSWV in the thrips-resistant cultivar was confirmed in a large-scale greenhouse experiment. The restricted and delayed TSWV spread to plants of the resistant accession in both the cage and the greenhouse experiment was explained by impeded thrips population development. The results obtained indicate that thrips resistance may provide a significant protection to TSWV infection, even when the crop is fully susceptible to the virus.


The pathology of extracranial scalp and skull masses in young children.
Extracranial subcutaneous masses involving the scalp and/or skull in young children are uncommon lesions that get excised by the neurosurgeon. Although the most common reported lesion is the dermoid cyst, our experience suggests that the spectrum of pathology in these lesions can present diagnostic challenges to the pathologist. We reviewed 30 consecutive extracranial masses from 29 patients between July 1998 and June 2003. Hematoxylin and eosin-stained sections were reviewed in all cases, and immunohistochemistry was performed in select cases. Twenty-three were within the scalp, 5 involved the scalp and skull and 2 were within the limits of the inner and outer tables of the skull. There were 8 dermoid cysts, 2 epidermoid cysts, 6 post-traumatic lesions including 3 calcified cephalhematomas and 3 pseudocysts, 5 vascular lesions including 3 capillary hemangiomas, 1 venous angioma and 1 lymphangioma, 2 cases of cranial fasciitis and 1 case each of benign teratoma, deep granuloma annulare, benign fibrous histiocytoma, congenital melanocytic nevus, hamartoma with ectopic meningothelial elements, cutaneous hyalinised ectopic meningioma and a meningocele with a fibrohistiocytic reaction. No lesions have recurred or exhibited malignant features. Surgical pathologists and neuropathologists should be aware that the differential diagnosis of "lumps and bumps on babie's heads" is quite varied and can be histologically challenging.


Characterisation of re-entrant circuit (or rotational activity) in vitro using the HL1-6 myocyte cell line.
Fibrillation is the most common arrhythmia observed in clinical practice. Understanding of the mechanisms underlying its initiation and maintenance remains incomplete. Functional re-entries are potential drivers of the arrhythmia. Two main concepts are still debated, the "leading circle" and the "spiral wave or rotor" theories. The homogeneous subclone of the HL1 atrial-derived cardiomyocyte cell line, HL1-6, spontaneously exhibits re-entry on a microscopic scale due to its slow conduction velocity and the presence of triggers, making it possible to examine re-entry at the cellular level. We therefore investigated the re-entry cores in cell monolayers through the use of fluorescence optical mapping at high spatiotemporal resolution in order to obtain insights into the mechanisms of re-entry. Re-entries in HL1-6 myocytes required at least two triggers and a minimum colony area to initiate (3.5 to 6.4 mm2). After electrical activity was completely stopped and re-started by varying the extracellular K+ concentration, re-entries never returned to the same location while 35% of triggers re-appeared at the same position. A conduction delay algorithm also allows visualisation of the core of the re-entries. This work has revealed that the core of re-entries is conduction blocks constituted by lines and/or groups of cells rather than the round area assumed by the other concepts of functional re-entry. This highlights the importance of experimentation at the microscopic level in the study of re-entry mechanisms.


Sonoelastography as a diagnostic tool in the assessment of musculoskeletal alterations: a systematic review.
Elasticity imaging is a relatively new ultrasound-based technique for investigating musculoskeletal injury. Sonoelastography (SEL), the most commonly used technique, allows determination of the elastic properties of tissue by applying pressure. To critically evaluate the literature regarding the use of SEL in the diagnosis of tendon and muscle alterations. This review includes a systematic literature search performed on major electronic databases. Eight articles were included. The GRADE approach was used to evaluate the quality of evidence presented in the included articles and the strength of their recommendations. The results on human tendon disorders showed that the SEL findings correlated extremely well with conventional ultrasound (US) findings as well as with magnetic resonance imaging (MRI) and clinical examination. In some articles SEL was found to be even more sensitive than conventional ultrasound and in addition capable of identifying subclinical alterations that conventional ultrasound could not. For skeletal muscle, a close correlation between SEL and US and MRI was found, although there is only one article on the topic. SEL was found to be able to distinguish between healthy and diseased muscles and was potentially more sensitive in identifying early dystrophic changes than US or MRI. Based on this critical evaluation of the literature, SEL seems to be at least as feasible as US and MRI for assessing tendon alterations and able to identify subclinical tendon alterations not visible with conventional US. The findings in the reviewed articles suggest that SEL could become a supplementary imaging technique in the assessment of musculoskeletal alterations, potentially superior to US and MRI. Until more studies are available, SEL has to be viewed as an experimental examination without sufficient supporting evidence to be used as a routine examination equivalent to US and MRI.


Incivility in nursing education: a descriptive study of definitions and prevalence.
Evidence suggests that incivility on American college campuses, ranging from insulting remarks and verbal abuse to violence, is a serious and growing concern. Faculty and students are often unsure how to address these behaviors. Therefore, 32 (88.9%) nursing faculty and 324 (69.4%) nursing students at one university completed a survey to gather their perceptions of student and faculty behaviors that may be considered uncivil. Student behaviors most frequently reported as uncivil by faculty included making disapproving groans, making sarcastic remarks or gestures, not paying attention in class, dominating class discussions, using cell phones during class, and cheating on examinations. The majority of faculty reported that uncivil student behaviors occurred rarely or sometimes. Examples of faculty behaviors considered uncivil by students included canceling class without warning, being unprepared for class, not allowing open discussion, being disinterested or cold, belittling or taunting students, delivering fast-paced lectures, and not being available outside of class. Students perceived incivility as a moderate problem in the nursing academic environment. It is imperative that nurse educators help students and faculty cope effectively with these behaviors; the authors discuss strategies to do so.


Lithium - a continuing story in the treatment of bipolar disorder.
To review the literature on the use of lithium in the treatment of bipolar disorder and highlight the evidence base supporting its efficacy and safety. A selective literature review. Lithium is widely believed to be effective against acute mania, acute bipolar depression and in relapse prevention to either mania or depression. In fact, the data supporting efficacy in acute treatment are less impressive than is often claimed, whereas for relapse prevention and suicide prevention no other agent has comparable depth of support. Lithium is best described as the bench mark treatment for bipolar disorder, rather than the gold standard, because only a minority of patients show major clinical benefit. There is a developing need for further trials against new alternatives and in combination studies. Lithium has a continuing important role in the clinical management of bipolar disorder. Its under-utilization in North America reflects opinion rather than evidence and the demonstrated anti-suicide effects should help to reignite interest in its use.


Implications for prediction and hazard assessment from the 2004 Parkfield earthquake.
Obtaining high-quality measurements close to a large earthquake is not easy: one has to be in the right place at the right time with the right instruments. Such a convergence happened, for the first time, when the 28 September 2004 Parkfield, California, earthquake occurred on the San Andreas fault in the middle of a dense network of instruments designed to record it. The resulting data reveal aspects of the earthquake process never before seen. Here we show what these data, when combined with data from earlier Parkfield earthquakes, tell us about earthquake physics and earthquake prediction. The 2004 Parkfield earthquake, with its lack of obvious precursors, demonstrates that reliable short-term earthquake prediction still is not achievable. To reduce the societal impact of earthquakes now, we should focus on developing the next generation of models that can provide better predictions of the strength and location of damaging ground shaking.


Thermostable peroxidase-polylysine films for biocatalysis at 90 degrees C.
Cross-linked films of poly(l-lysine) (PLL) and enzymes covalently linked to surfaces provided remarkable thermostability, enabling biocatalysis at 90 degrees C. Soret spectra, circular dichroism, and voltammetry showed that PLL films containing peroxidases or myoglobin were stable for up to 9 h at 90 degrees C, while the same enzymes in solution denatured completely within 20 min. Biocatalytic reduction of t-BuOOH with enzyme-PLL films, using rotating disk voltammetry, provided Michaelis kcat/Km values. Results showed that horseradish peroxidase (HRP)-PLL is 3-fold more active than soybean peroxidase (SBP)-PLL at 25 degrees C, but SBP-PLL is slightly more active at 90 degrees C. SBP-PLL films had 8-fold larger kcat/Km values at 90 degrees C compared to 25 degrees C. Oxidation of o-methoxyphenol to 3,3'-dimethoxy-4,4'-biphenoquinone by peroxidase-PLL-coated silica colloids gave better yields at 90 degrees C than 25 degrees C, suggesting increasing catalytic efficiency and selectivity at the higher temperature. These biocolloids were reusable with little loss of activity at 90 degrees C.


Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.


Prevalence of problematic mobile phone use in British adolescents.
The problematic use of mobile phones among adolescents has not been widely studied. There are very few instruments for assessing potential technological addiction to mobile phones, or for categorizing different types of users or uses. The most widely used scale is the Mobile Phone Problem Use Scale (MPPUS), which is used to study adult populations, and has been applied in various forms in international contexts. The aims of this study were to adapt the Spanish version of this scale (MPPUSA) to British adolescents, and then to estimate the prevalence of possible problematic users. A questionnaire was administered to a sample of 1,529 secondary school pupils aged between 11 and 18 years, with 1,026 completed questionnaires being collected. The analysis showed that the factor and construct validity and reliability were comparable to those obtained in previous studies. The prevalence of problematic users among the students was 10%, and the typical problematic user tended to be an adolescent between 11 and 14 years old, studying in a public school, who considered themselves to be an expert user of this technology, who made extensive use of his/her mobile phone, and who attributed the same problem of use among their peers. These users presented notable scores in all the symptoms covered by the scale used to assess problematic use. In conclusion, the adaptation of the MPPUSA as a screening scale for British adolescents presents good sensitivity and specificity for detecting the main addictive symptoms proposed in this validated version.


Multivalent fusion protein vaccine for lymphatic filariasis.
Lymphatic filariasis affects approximately 3% of the whole world population. Mass drug administration is currently the major control strategy to eradicate this infection from endemic regions by year 2020. Combination drug treatments are highly efficient in controlling the infection. However, there are no effective vaccines available for human or animal lymphatic filariasis despite the identification of several subunit vaccines. Lymphatic filariasis parasites are multicellular organisms and potentially use multiple mechanisms to survive in the host. Therefore, there is a need to combine two or more vaccine candidate antigens to achieve the desired effect. In this study we combined three well characterized vaccine antigens of Brugia malayi, heat shock protein 12.6 (HSP12.6), Abundant Larval transcript-2 (ALT-2) and tetraspanin large extra cellular loop (TSP-LEL) as a multivalent fusion vaccine. Putative immune individuals carry circulating antibodies against all three antigens. Depletion of these antigen specific antibodies from the sera samples removed the ability of the sera to participate in the killing of B. malayi L3 in an antibody dependent cellular cytotoxicity (ADCC) mechanism. Vaccination trials in mice with a bivalent [HSP12.6+ALT-2 (HA), HSP12.6+TSP-LEL (HT) or TSP-LEL+ALT-2 (TA)] or trivalent [HSP12.6+ALT-2+TSP-LEL (HAT)] vaccines using DNA, protein or heterologous prime boost regimen showed that trivalent HAT vaccine either as protein alone or as heterologous prime boost vaccine could confer significant protection (95%) against B. malayi L3 challenge. Immune correlates of protection suggest a Th1/Th2 bias. These finding suggests that the trivalent HAT fusion protein is a promising prophylactic vaccine against lymphatic filariasis infection in human.


Thoracic involvement in IgG4-related disease in a UK-based patient cohort.
IgG4-related disease (IgG4-RD) is a multi-system fibro-inflammatory disorder with classical histopathological findings, often in the context of elevated serum IgG4 levels. The thoracic manifestations of IgG4-RD are numerous and can mimic several common and better known conditions. The objective of this study was to outline the frequency and nature of thoracic involvement in a prospective cohort of IgG4-RD patients who met defined diagnostic criteria. Over 40% of IgG4-RD patients had clinicoradiological and/or histological evidence of thoracic involvement, predominantly mediastinal lymphadenopathy, the majority associated with multi-system disease outside the chest. Thoracic involvement was associated with a higher serum IgG4 level, potentially representing greater disease activity or spread. Our data highlight the diverse nature of thoracic IgG4-RD, and the importance of knowledge and recognition of the condition among respiratory physicians who are likely to encounter this disease entity on an increasing basis.


Recent advances in catalytic hydrogenation of carbon dioxide.
Owing to the increasing emissions of carbon dioxide (CO(2)), human life and the ecological environment have been affected by global warming and climate changes. To mitigate the concentration of CO(2) in the atmosphere various strategies have been implemented such as separation, storage, and utilization of CO(2). Although it has been explored for many years, hydrogenation reaction, an important representative among chemical conversions of CO(2), offers challenging opportunities for sustainable development in energy and the environment. Indeed, the hydrogenation of CO(2) not only reduces the increasing CO(2) buildup but also produces fuels and chemicals. In this critical review we discuss recent developments in this area, with emphases on catalytic reactivity, reactor innovation, and reaction mechanism. We also provide an overview regarding the challenges and opportunities for future research in the field (319 references).


Improved Early Recognition of Coronavirus Disease-2019 (COVID-19): Single-Center Data from a Shanghai Screening Hospital.
In December 2019, an outbreak of a novel coronavirus disease (COVID-19; previously known as 2019-nCoV) was reported in Wuhan, Hubei province, China, which has subsequently affected more than 200 countries worldwide including Europe, North America, Oceania, Africa and other places. The number of infected people is rapidly increasing, while the diagnostic method of COVID-19 is only by nucleic acid testing. To explain the epidemiological characteristics, clinical features, imaging manifestations and to judge diagnostic value of COVID-19 by analyzing the clinical data of COVID-19 suspected and confirmed patients in a non-outbreak, Shanghai, China. To clarify the early epidemiology and clinical characteristics about COVID-19. Cross-sectional, single-center case reports of the 86 patients screened at Zhoupu Hospital in Pudong New District, Shanghai, China, from January 23 to February 16, 2020. Epidemiology, demography, clinical, laboratory and chest CTs were collected and analyzed. The screened patients were divided into COVID-19 and non-COVID-19 based on nucleic acid test results. Of the 86 screened patients, 11 were confirmed (12.8%) by nucleic acid testing (mean age 40.73 ± 11.32, 5 males). No significant differences were found in clinical symptoms including fever, cough, dyspnea, sore throat, and fatigue (P > 0.05). No statistical difference was observed in plasma C-reactive protein (CRP) between the two groups (COVID-19 and non-COVID-19 ) of patients (P = 0.402), while the white blood cell count and lymphocyte count of the confirmed patients were slightly lower than those of the suspected patients (P < 0.05). Some non-COVID-19 chest CTs also showed subpleural lesions, such as ground-glass opacities (GGO) combined with bronchiectasis; or halo nodules distributed under the pleura with focal GGO; consolidation of subpleural distribution or combined with air bronchi sign and vascular bundle sign, etc. The early clinical manifestations and imaging findings of COVID-19 are not characteristic in non-outbreak areas. Etiological testing should be performed as early as possible for clinically suspected patients.


Mammalian BEX, WEX and GASP genes: coding and non-coding chimaerism sustained by gene conversion events.
The identification of sequence innovations in the genomes of mammals facilitates understanding of human gene function, as well as sheds light on the molecular mechanisms which underlie these changes. Although gene duplication plays a major role in genome evolution, studies regarding concerted evolution events among gene family members have been limited in scope and restricted to protein-coding regions, where high sequence similarity is easily detectable. We describe a mammalian-specific expansion of more than 20 rapidly-evolving genes on human chromosome Xq22.1. Many of these are highly divergent in their protein-coding regions yet contain a conserved sequence motif in their 5' UTRs which appears to have been maintained by multiple events of concerted evolution. These events have led to the generation of chimaeric genes, each with a 5' UTR and a protein-coding region that possess independent evolutionary histories. We suggest that concerted evolution has occurred via gene conversion independently in different mammalian lineages, and these events have resulted in elevated G+C levels in the encompassing genomic regions. These concerted evolution events occurred within and between genes from three separate protein families ('brain-expressed X-linked' [BEX], WWbp5-like X-linked [WEX] and G-protein-coupled receptor-associated sorting protein [GASP]), which often are expressed in mammalian brains and associated with receptor mediated signalling and apoptosis. Despite high protein-coding divergence among mammalian-specific genes, we identified a DNA motif common to these genes' 5' UTR exons. The motif has undergone concerted evolution events independently of its neighbouring protein-coding regions, leading to formation of evolutionary chimaeric genes. These findings have implications for the identification of non protein-coding regulatory elements and their lineage-specific evolution in mammals.


Evidence for allelic heterogeneity in familial early-onset Alzheimer's disease.
Age of onset was examined for 139 members of 30 families affected by early-onset AD. Most (77%) of the variance of age of onset derived from differences between rather than within families. The constancy of age of onset within families was also observed in an analysis restricted to families derived from a population-based epidemiological study with complete ascertainment of early-onset AD. Furthermore, we observed clustering of age of onset within those families that support linkage to the predisposing locus on chromosome 21. Our data are compatible with the view that allelic heterogeneity at the AD locus may account for the similarity in age of onset within families. This finding may be of value for scientific studies of AD as well as for genetic counselling.


Oral Administration of Peptide-Based Drugs: Beyond Lipinski's Rule.
The use of peptides in therapy presents several limitations, from physicochemical characteristics to inadequate pharmacokinetic profiles for oral absorption. As peptides are gaining importance in the therapeutic arsenal, there is an increasing need to rationalize the main characteristics of this compound class in the market. Therefore, we performed an extensive analysis of all known peptide drugs and clinical candidates based on their peptide features, physicochemical and structural properties, and correlated these with their administration route and therapeutic classes. Peptide drugs are widely distributed across drug and pharmacological space, covering several therapeutic areas with structural diversity and complexity, distributed between groups of cyclic and linear compounds. Although structural and physicochemical properties are clear within these groups, we counter the consensus that cyclic peptides have better oral availability than linear peptides, as most of the orally administrated peptides have linear structures. This study and review furnishes information that could support peptide drug design, with a new cutoff of known descriptors that go beyond the Rule of Five.


Outcomes of noncardiac surgical procedures in children and adults with congenital heart disease. Mayo Perioperative Outcomes Group.
To assess the outcomes and risk factors for morbidity associated with anesthesia and noncardiac surgical procedures in children and adults with congenital heart disease. We conducted a retrospective cohort study of the 6-year period from January 1987 through November 1992 at one of the Mayo-affiliated hospitals in Rochester, Minnesota. In all children and adults 50 years of age or younger with congenital heart disease who underwent one or more noncardiac surgical or diagnostic procedures and anesthesia, we analyzed the risk factors for 30-day perioperative morbidity and mortality. The overall frequency of complications among the 276 patients who underwent 480 noncardiac surgical procedures and anesthesia was 5.8% (28 of 480), and only 1 patient died intraoperatively. Major risk factors univariately associated with complications for the first procedures (15 of 276 patients or 5.4%) included the presence of cyanosis (P = 0.002), current treatment for congestive heart failure (P<0.001), poor general health (P<0.001), and younger age at the time of the procedure (P = 0.027). Procedures performed on the respiratory and nervous systems also were associated with high frequencies of complications. Complications in patients undergoing ambulatory surgical procedures were infrequent (1.7%). The frequency of perioperative complications in children and adults who have congenital heart disease and undergo noncardiac surgical procedures and anesthesia is low. Patients who have pulmonary hypertension, congestive heart failure, or cyanosis and children with congenital heart disease who are younger than 2 years of age have an increased frequency of perioperative morbidity.


Evidence for a unifocal origin in familial ovarian cancer.
The purpose of this investigation was to determine the pattern of loss of heterozygosity in multiple tumor sites from familial ovarian cancer cases. If ovarian cancer arises focally in one ovary and then metastasizes to other sites, a similar pattern should be seen in all tumor sites. However, if ovarian cancer arises multifocally throughout the peritoneal cavity, a different pattern of loss would be expected among the different sites. The presence or absence of loss of specific alleles for 9 loci on chromosomes 1, 6, 11, 13, 16, and 17 was determined in multiple tumor sites from 12 familial ovarian cancer cases. The frequency of loss of heterozygosity was as follows: chromosome 17 (100%), chromosome 13 (82%), chromosome 6 (80%), chromosome 16 (73%), chromosome 1 (57%), and chromosome 11 (22%). In every case an identical pattern was present for at least one locus. In four cases loss of the same allele was present in tumor from the ovary and all metastatic sites for all informative loci. In the remaining eight cases loss of the same allele for one to five (mean three) loci was detected. The pattern of loss of heterozygosity in the 12 familial ovarian cancers included in this investigation favors a unifocal origin of disease. A dual primary origin could not be absolutely excluded in 3 cases. High frequencies on chromosomes 17q and 13 suggest that loss of whole or part of these chromosomes is important in ovarian carcinogenesis.


[Opinion survey about purchasing nonprescription drugs over the internet in remote islands--survey among internet-literate inhabitants].
The revised Pharmaceutical Affairs Act that came into force in June 2009 prohibits the sales of nonprescription drugs by mail. However, as a provisional measure, regular users and inhabitants of remote islands that do not have pharmacies or drug stores would be able to purchase nonprescription drugs by mail for two years. However, this regulation is now being discussed from the perspectives of safety and convenience. The purpose of this study was to conduct a survey on the purchasing of nonprescription drugs over the Internet by inhabitants of remote islands belonging to Goto City in Nagasaki prefecture. The results showed that approximately 78.0% of the Internet-literate respondents living on large islands (with pharmacies, drug stores, and pharmacists, e.g., Fukue-shima), 65.4% of the Internet-literate respondents living on small islands scattered around large islands (where pharmacies, drug stores, and pharmacists are not located, e.g., Mae-shima) had purchased necessities except nonprescription drugs, but the rate of purchasing nonprescription drugs over the Internet was approximately less than 10%. The results of this survey suggest that it is not necessary to purchase nonprescription drugs over the Internet. However, owing to a small but significant minority of inhabitants who need to purchase nonprescription drugs over the Internet, there is an urgent need for establishing an optimum system for supplying medicinal products to remote islands.


Inactive plasma renin exhibits sex difference in mice.
1. The plasma concentration of inactive renin was two- to three-fold higher in male than in female mice independently of whether mice of strains with low (BALB/c) or high (Theiller) content of active renin in the submandibular salivary glands were studied. 2. Removal of the submandibular glands did not affect the high plasma concentration of inactive renin in male mice. 3. Inactive plasma renin decreased over several days after castration of normal and sialoadenectomized male mice to the same levels as those found in normal female mice. 4. Treatment of these castrated male mice with testosterone increased and normalized inactive plasma renin independently of whether the submandibular glands had been previously removed or not. 5. Testosterone treatment of sialoadenectomized female mice increased inactive renin to the same levels as those found in normal male mice. 6. Our findings suggest that the sex difference in inactive plasma renin in mice may be explained by an increased secretion of inactive renin in male mice stimulated by androgens. 7. Since we have recently found that inactive plasma renin in male mice is mainly of renal origin, this increased secretion is most likely located to the kidneys.