The iron-chelating potential of silybin in patients with hereditary haemochromatosis.
Milk thistle contains silybin, which is a potential iron chelator. We aimed to determine whether silybin reduced iron absorption in patients with hereditary haemochromatosis. In this crossover study, on three separate occasions, 10 patients who were homozygous for the C282Y mutation in the HFE gene (and fully treated) consumed a vegetarian meal containing 13.9 mg iron with: 200 ml water; 200 ml water and 140 mg silybin (Legalon Forte); or 200 ml tea. Blood was drawn once before, then 0.5, 1, 2, 3 and 4 h after the meal. Consumption of silybin with a meal resulted in a reduction in the postprandial increase in serum iron (AUC±s.e.) compared with water (silybin 1726.6±346.8 versus water 2988.8±167; P<0.05) and tea (silybin 1726.6±346.8 versus tea 2099.3±223.3; P<0.05). In conclusion, silybin has the potential to reduce iron absorption, and this deserves further investigation, as silybin could be an adjunct in the treatment of haemochromatosis.


Contribution of cytochrome P450 4A isoforms to renal functional response to inhibition of nitric oxide production in the rat.
20-Hydroxyeicosatetraenoic acid (20-HETE), a major renal eicosanoid, regulates renal function and contributes to renal responses following withdrawal of nitric oxide (NO). However, the role of 20-HETE-synthesizing isoforms in renal function resulting from NO inhibition is unknown. The present study evaluated the role of cytochrome (CYP)4A1, -4A2 and -4A3 isoforms on renal function in the presence and absence of NO. Antisense oligonucleotides (ASODN) to CYP4A1, -4A2 and -4A3 reduced 20-HETE synthesis and downregulated the expression of CYP4A isoforms in renal microsomes. Nomega-L-nitromethyl arginine ester (L-NAME, 25 mg kg(-1)), an inhibitor of NO production, increased mean arterial blood pressure (MABP, Delta = +18 to 26 mmHg), reduced renal blood flow (RBF, Delta = -1.8 to 2.9 ml min(-1)), increased renal vascular resistance (RVR, Delta = +47 to 54 mmHg ml(-1) min(-1)), reduced glomerular filtration rate (GFR), but increased sodium excretion (UNaV). ASODN to CYP4A1 and -4A2 but not -4A3 reduced basal MABP and RVR and increased basal GFR, while ASODN to CYP4A2 significantly reduced basal UNaV suggesting a differential role for CYP4A isoforms in the regulation of renal function. ASODN to CYP4A2 but not -4A1 or -4A3 blunted the increase in MABP by L-NAME (38 +/- 9 %, P < 0.05). ASODN to CYP4A1, -4A2 and -4A3 attenuated the reduction in RBF and the consequent increase in RVR by L-NAME with a potency order of CYP4A2 = CYP4A1 > CYP4A3. ASODN to CYP4A1 and -4A2 but not -4A3 attenuated L-NAME-induced reduction in GFR, but ASODN to all three CYP4A isoforms blunted the L-NAME-induced increase in UNaV (CYP4A3 > CYP4A1 >> CYP4A2). We conclude from these data that CYP4A isoforms contribute to different extents to basal renal function. Moreover, CYP4A2 contributes greatest to haemodynamic responses while CYP4A3 contributes greatest to tubular responses following NO inhibition. We therefore propose that NO differentially regulates the function of CYP4A1, -4A2, and -4A3 isoforms in the renal vasculature and the nephron.


Building resilient societies after COVID-19: the case for investing in maternal, neonatal, and child health.
Resilient societies respond rapidly and effectively to health challenges and the associated economic consequences, and adapt to be more responsive to future challenges. Although it is only possible to recognise resilience retrospectively, the COVID-19 pandemic has occurred at a point in human history when, uniquely, sufficient knowledge is available on the early-life determinants of health to indicate clearly that a focus on maternal, neonatal, and child health (MNCH) will promote later resilience. This knowledge offers an unprecedented opportunity to disrupt entrenched strategies and to reinvest in MNCH in the post-COVID-19 so-called new normal. Furthermore, analysis of the short-term, medium-term, and longer-term consequences of previous socioeconomic shocks provides important insights into those domains of MNCH, such as neurocognitive development and nutrition, for which investment will generate the greatest benefit. Such considerations apply to high-income countries (HICs) and low-income and middle-income countries (LMICs). However, implementing appropriate policies in the post-COVID-19 recovery period will be challenging and requires political commitment and public engagement.


Cost analysis of a major burn.
A retrospective review was undertaken of 26 patients admitted to Middlemore Hospital between January 1986 to July 1989 with burns totalling more than 30% of total body surface area. An attempt was made to estimate the total cost of successful inpatient management of a major burn using known and assumed values. The new schedule of interboard hospital charges was also employed for greater accuracy. The 20 survivors had a mean initial hospital stay of 68.7 days at a cost of between $37,077 and $40,702 (1989 values) and $46,069 (1991 values). This latter figure equates to an average cost of $647 per patient per day or, alternatively, $927 per % burn. Suggestions to reduce costs and improve treatment include: earlier excision and grafting; the establishment of a regional skin bank and keratinocyte culture facility to aid wound closure; and guidelines on antibiotic prescribing.


Lipid droplet binding thalidomide analogs activate endoplasmic reticulum stress and suppress hepatocellular carcinoma in a chemically induced transgenic mouse model.
Hepatocellular carcinoma (HCC) is the most frequent and aggressive primary tumor of the liver and it has limited treatment options. In this study, we report the in vitro and in vivo effects of two novel amino-trifluoro-phtalimide analogs, Ac-915 and Ac-2010. Both compounds bind lipid droplets and endoplasmic reticulum membrane, and interact with several proteins with chaperone functions (HSP60, HSP70, HSP90, and protein disulfide isomerase) as determined by affinity chromatography and resonant waveguide optical biosensor technology. Both compounds inhibited protein disulfide isomerase activity and induced cell death of different HCC cells at sub or low micromolar ranges detected by classical biochemical end-point assay as well as with real-time label-free measurements. Besides cell proliferation inhibiton, analogs also inhibited cell migration even at 250 nM. Relative biodistribution of the analogs was analysed in native tissue sections of different organs after administration of drugs, and by using fluorescent confocal microscopy based on the inherent blue fluorescence of the compounds. The analogs mainly accumulated in the liver. The effects of Ac-915 and Ac-2010 were also demonstrated on the advanced stages of hepatocarcinogenesis in a transgenic mouse model of N-nitrosodiethylamine (DEN)-induced HCC. Significantly less tumor development was found in the livers of the Ac-915- or Ac-2010-treated groups compared with control mice, characterized by less liver tumor incidence, fewer tumors and smaller tumor size. These results imply that these amino-trifluoro-phthalimide analogs could serve potent clinical candidates against HCC alone or in combination with dietary polyunsaturated fatty acids.


Abdominal weakness, bulge, or hernia after DIEP flaps: An algorithm of management, prevention, and surgical repair with classification.
This study analyzes abdominal weakness, hernia, and bulge following deep inferior epigastric perforator (DIEP) flap breast reconstruction. Abdominal wall morbidities are categorized, and an algorithm for management is provided. A retrospective review of 644 patients who underwent abdominal based flap breast reconstruction between 2009 and 2018 and met selection criteria was performed. Bulge and hernia were evaluated on exam and then by imaging and/or operative exploration. The incidence of abdominal weakness was evaluated by BREAST-Q™ data. Risk factors were analyzed. Of the 644 patients, 23 (3.6%) had a clinically significant bulge or hernia on exam postoperatively. Developing an abdominal wound postoperatively and sacrificing nerves both correlated with an increased incidence of bulge or hernia (p < 0.05). The use of lateral row perforators, keeping the umbilicus, higher BMI, and the use of biological mesh in the initial abdominal wall repair trended toward an increased incidence of bulge or hernia; however, these data were not statistically significant. Seven percent of patients who answered the BREAST-Q™ reported abdominal weakness. Patients in the umbilicus sacrificing cohort had an increased incidence of weakness (p < 0.05). Abdominal wounds, nerve sacrificing procedures and obesity correlated with an increased incidence of weakness; these data were not statistically significant. A classification and algorithm for treatment of functional abdominal wall morbidity after DIEP flap is provided. Abdominal wall morbidity is classified as: type 1 - abdominal weakness; type 2 - smaller, unilateral abdominal bulge; and type 3 - true abdominal hernia or large bilateral bulge. An algorithm of treatment is presented, which includes physical therapy and surgical repair recommendations.


Healthcare resource use and costs of varicella and its complications: A systematic literature review.
Varicella is a highly contagious disease caused by the varicella zoster virus (VZV). While the disease is usually mild, severe complications can occur requiring costly hospitalization. A thorough understanding of the healthcare resource use (HCRU) and costs of varicella is needed to inform health-economic models of preventive strategies. A systematic literature review was carried out to retrieve relevant publications between 1999 and 2021, reporting HCRU and cost outcomes for varicella and its complications. Data were extracted and stratified according to pre-specified age groups and complication categories. Costs were re-based to a $US2020 footing using both purchasing power parity and the medical component of consumer price indexes. Data were summarized descriptively due to high heterogeneity in study design and outcome reporting. Forty-four publications fulfilled the inclusion and exclusion criteria of which 28 were conducted in Europe, 6 in Middle East and Asia, 5 in South America, 3 in North America, and 2 in multiple regions. Primary healthcare visits accounted for 30% to 85% of total direct costs. Hospitalization costs varied between $1,308 and $38,268 per episode depending on country, complication type, and length of stay, contributing between 2% and 60% to total direct costs. Indirect costs, mostly driven by workdays lost, accounted for approximately two-thirds of total costs due to varicella. The management of varicella and related complications can lead to substantial HCRU and costs for patients and the healthcare system. Additional research is needed to further characterize the varicella-associated economic burden and its broader impact from a societal standpoint.


A common gene exclusion mechanism used by two chemosensory systems.
Sensory coding strategies within vertebrates involve the expression of a limited number of receptor types per sensory cell. In mice, each vomeronasal sensory neuron transcribes monoallelically a single V1R pheromone receptor gene, chosen from a large V1R repertoire. The nature of the signals leading to this strict receptor expression is unknown, but is apparently based on a negative feedback mechanism initiated by the transcription of the first randomly chosen functional V1R gene. We show, in vivo, that the genetic replacement of the V1rb2 pheromone receptor coding sequence by an unrelated one from the odorant receptor gene M71 maintains gene exclusion. The expression of this exogenous odorant receptor in vomeronasal neurons does not trigger the transcription of odorant receptor-associated signalling molecules. These results strongly suggest that despite the different odorant and vomeronasal receptor expression sites, function and transduction cascades, a common mechanism is used by these chemoreceptors to regulate their transcription.


Sarcopenia and sarcopenic leg as potential risk factors for acute osteoporotic vertebral fracture among older women.
Sarcopenia-related falls and fractures among women with osteoporosis are becoming an emerging problem because of rapid aging worldwide. We aimed to investigate the association between sarcopenia, given by the muscle mass of the arms and legs, and osteoporotic vertebral fracture (OVF) among female patients. This cross-sectional study examined 216 women with fresh OVF (OVF group) diagnosed by magnetic resonance imaging and 1,608 women from an outpatient clinic who did not have a OVF [non-fracture (NF) group]. We performed whole-body dual-energy X-ray absorptiometry to analyze body composition, including skeletal muscle mass index (SMI; lean mass/height2) and bone mineral density (BMD). We used stepwise logistic regression analysis to determine the risk factors associated with OVF. After controlling for age, the OVF group showed lower appendicular SMI (5.62 vs. 5.97 kg/m2, P < 0.001), lower arm SMI (1.36 vs. 1.42 kg/m2, P = 0.004), lower leg SMI (4.27 vs. 4.55 kg/m2, P < 0.001), and higher prevalence of sarcopenia (42.3 vs. 25.9 %, P < 0.001), compared with the NF group. Reduced leg muscle mass and presence of sarcopenia were independent risk factors for acute OVF in multivariate analysis (odds ratio = 1.4, P = 0.002; odds ratio = 1.96, P < 0.001, respectively). We found higher prevalence of sarcopenia and lower leg muscle mass among patients with acute OVF compared with patients who did not have an OVF. These results suggest that sarcopenia may be a risk factor for OVF.


Towards New Drug Targets? Function Prediction of Putative Proteins of Neisseria meningitidis MC58 and Their Virulence Characterization.
Neisseria meningitidis is a Gram-negative aerobic diplococcus, responsible for a variety of meningococcal diseases. The genome of N. meningitidis MC58 is comprised of 2114 genes that are translated into 1953 proteins. The 698 genes (∼35%) encode hypothetical proteins (HPs), because no experimental evidence of their biological functions are available. Analyses of these proteins are important to understand their functions in the metabolic networks and may lead to the discovery of novel drug targets against the infections caused by N. meningitidis. This study aimed at the identification and categorization of each HP present in the genome of N. meningitidis MC58 using computational tools. Functions of 363 proteins were predicted with high accuracy among the annotated set of HPs investigated. The reliably predicted 363 HPs were further grouped into 41 different classes of proteins, based on their possible roles in cellular processes such as metabolism, transport, and replication. Our studies revealed that 22 HPs may be involved in the pathogenesis caused by this microorganism. The top two HPs with highest virulence scores were subjected to molecular dynamics (MD) simulations to better understand their conformational behavior in a water environment. We also compared the MD simulation results with other virulent proteins present in N. meningitidis. This study broadens our understanding of the mechanistic pathways of pathogenesis, drug resistance, tolerance, and adaptability for host immune responses to N. meningitidis.


The mechanism of action of 17-hydroxy-11-dehydrocorticosterone (compound E) and of the adrenocorticotropic hormone in experimental hypersensitivity in rabbits.
The concurrent administration of compound E at a daily dosage of 2 mg. per kg. to rabbits receiving daily intracutaneous injections of crystalline egg albumin markedly inhibited the development of anaphylactic hypersensitivity of the Arthus type. ACTH, when given at a similar dosage, produced a much less marked effect. Both hormones suppressed circulating antibody and as with the Arthus reaction, the suppression produced by compound E was much greater than that obtained with ACTH. When treatment with compound E was started following sensitization, there was a rapid decline in circulating antibody and, if the pretreatment serum antibody was low, there was also a progressive decrease in skin reactivity, becoming negative after 5 days of treatment. When the pretreatment serum antibody concentration was great, so that by the termination of treatment the antibody concentration was still above the level ordinarily sufficient for a maximal skin response, the Arthus reaction was unaffected by treatment. These considerations as well as the failure of compound E to inhibit the systemic passive Arthus reaction suggest that the inhibitory effect of compound E and ACTH on the development of experimental hypersensitivity results from the hormonal reduction of circulating antibody. Treatment with compound E had no effect on the rate of disappearance of circulating antibody in the passively immunized rabbit. This finding suggests that ACTH and compound E reduce circulating antibody by inhibiting antibody formation rather than by promoting antibody destruction. The question is raised as to whether the marked lymphoid atrophy produced by these hormones may be related to the interference with antibody production.


Bulges in left-handed G-quadruplexes.
G-quadruplex (G4) DNA structures with a left-handed backbone progression have unique and conserved structural features. Studies on sequence dependency of the structures revealed the prerequisites and some minimal motifs required for left-handed G4 formation. To extend the boundaries, we explore the adaptability of left-handed G4s towards the existence of bulges. Here we present two X-ray crystal structures and an NMR solution structure of left-handed G4s accommodating one, two and three bulges. Bulges in left-handed G4s show distinct characteristics as compared to those in right-handed G4s. The elucidation of intricate structural details will help in understanding the possible roles and limitations of these unique structures.


Activation of a diverse set of genes during the tobacco resistance response to TMV is independent of salicylic acid; induction of a subset is also ethylene independent.
Through differential screening of a cDNA library, we cloned six groups of genes that are expressed relatively early in the inoculated leaves of tobacco resisting infection by tobacco mosaic virus (TMV). Induction of all these genes was subsequently detected in the uninoculated leaves; thus, their expression is associated with the development of both local and systemic acquired resistance. Exogenously applied salicylic acid (SA) was observed to induce these genes transiently. However, analyses with transgenic NahG plants, which are unable to accumulate SA, demonstrated that expression of these genes in TMV-inoculated leaves is mediated via an SA-independent pathway. Because the expression kinetics of these genes differ from those associated with the well-characterized pathogenesis-related protein (PR-1) and phenylalanine ammonia-lyase (PAL) genes, we propose that they belong to a group which we designate SIS, for SA-independent, systemically induced genes. Interestingly, the expression of several SIS genes in the uninoculated leaves of TMV-infected NahG plants was delayed and/or reduced, raising the possibility that SA is involved in activating some of these genes in systemic tissue. Most of the SIS genes were induced by exogenous ethylene. However, analyses of infected NahG plants treated with ethylene action and/or synthesis inhibitors indicated that the TMV-induced expression of several SIS genes is independent of ethylene as well as SA.


[Redirection and consolation in hamadryas baboons].
Post-conflict interactions between victims and non-involved group members was investigated in the troop of hamadryas baboons, Papio hamadryas. Observations were done in the Russian Primate Center, Adler in 1996-1997. Redirected aggression, initiation of affiliation from the side of victims towards third parties and consolation were registered during this study. The analyses was done on 445 PC-MC pairs of animals, represented different social classes (harem male-female pairs, harem females, relations, females from different harems, male-male pairs, female-subadult pairs). The attracted-pairs method and the time-rule method were used. Redirected aggression was practiced mainly by male aggressees. It was typical for victims, both males and females, to initiate affiliative interactions with third parties soon after the conflict. Consolation was practiced by hamadryas baboons, but it was limited to harem male-female pairs only. Special affiliative patterns were used by male-consoler. This is the first case, when consolation was demonstrated in baboons.


miR-371-5p down-regulates pre mRNA processing factor 4 homolog B (PRPF4B) and facilitates the G1/S transition in human hepatocellular carcinoma cells.
Increasing evidence has lent support to the notion that miRNAs regulate hepatocellular carcinoma (HCC) cell proliferation by directly targeting cell cycle-related genes. Among these genes, we identified PRPF4B, a CDK-like kinase, as a new target of miR-371-5p. Over-expression of miR-371-5p and knockdown of PRPF4B promotes cell growth by accelerating the G1/S transition in HCC cell lines. Moreover, miR-371-5p promotes tumor growth of QGY-7703 cells in vivo. Conversely, inhibition of miR-371-5p yields an opposing effect. Ectopic expression of PFPF4B abolishes the malignant phenotypes caused by miR-371-5p. Furthermore, contrary to PRPF4B, miR-371 was up-regulated in HCC tissues. Collectively, we highlight the significance of miR-371-5p and PRPF4B in cell cycle progression and hepatocarcinogenesis.


Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis.
Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4+ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR). A prospective study of the phenotype and the function of major CD4+ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew. Compared with control subjects, patients with GCA and patients with PMR had a decreased frequency of Treg cells and Th1 cells, whereas the percentage of Th17 cells was significantly increased. Furthermore, an analysis of temporal artery biopsy specimens obtained from patients affected by GCA for whom biopsy results were positive demonstrated massive infiltration by Th17 and Th1 lymphocytes without any Treg cells. After glucocorticoid treatment, the percentages of circulating Th1 and Th17 cells decreased, whereas no change in the Treg cell frequency was observed. The frequency of CD161+CD4+ T cells, which are considered to be Th17 cell precursors, was similar in patients and control subjects. However, these cells highly infiltrated GCA temporal artery biopsy specimens, and their ability to produce interleukin-17 in vitro was significantly enhanced in patients with GCA and patients with PMR and was correlated with a decrease in the phosphorylated form of STAT-1. This study is the first to demonstrate that the frequency of Treg cells is decreased in patients with GCA and patients with PMR, and that CD161+CD4+ T lymphocytes, differentiated into Th1 cells and Th17 cells, are involved in the pathogenesis of GCA and PMR.


P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis.
TP53 also known as p53 is a tumor suppressor gene mutated in a variety of cancers. P53 is involved in cell cycle, apoptosis and DNA repair mechanisms and is thus tightly controlled by many regulators. Recently, strategies to treat cancer have focused on the development of MDM2 antagonists to induce p53 stabilization and restore cell death in p53 non-mutated cancers. However, some of these molecules display adverse effects in patients including induction of thrombocytopenia. In the present study, we have explored the effect of SAR405838 not only on human megakaryopoiesis but also more generally on hematopoiesis. We compared its effect to MI-219 and Nutlin, which are less potent MDM2 antagonists than SAR405838. We found that all these compounds induce a deleterious effect on all types of hematopoietic progenitors, as well as on erythroid and megakaryocytic differentiation. Moreover, they inhibit both early and late stages of megakaryopoiesis including ploidization and proplatelet formation. In conclusion, MDM2 antagonists induced a major hematopoietic defect in vitro as well as an inhibition of all stages of megakaryopoiesis that may account for in vivo thrombocytopenia observed in treated patients.


Intracranial Hemorrhages on Extracorporeal Membrane Oxygenation: Differences Between COVID-19 and Other Viral Acute Respiratory Distress Syndrome.
Extracorporeal membrane oxygenation (ECMO) is a potentially lifesaving procedure in acute respiratory distress syndrome (ARDS) due to COVID-19. Previous studies have shown a high prevalence of clinically silent cerebral microbleeds in patients with COVID-19. Based on this fact, together with the hemotrauma and the requirement of therapeutic anticoagulation on ECMO support, we hypothesized an increased risk of intracranial hemorrhages (ICHs). We analyzed ICH occurrence rate, circumstances and clinical outcome in patients that received ECMO support due to COVID-19-induced ARDS in comparison to viral non-COVID-19-induced ARDS intracerebral hemorrhage. Multicenter, retrospective analysis between January 2010 and May 2021. Three tertiary care ECMO centers in Germany and Switzerland. Two-hundred ten ARDS patients on ECMO support (COVID-19, n = 142 vs viral non-COVID, n = 68). None. Evaluation of ICH occurrence rate, parameters of coagulation and anticoagulation strategies, inflammation, and ICU survival. COVID-19 and non-COVID-19 ARDS patients showed comparable disease severity regarding Sequential Organ Failure Assessment score, while the oxygenation index before ECMO cannulation was higher in the COVID group (82 vs 65 mm Hg). Overall, ICH of any severity occurred in 29 of 142 COVID-19 patients (20%) versus four of 68 patients in the control ECMO group (6%). Fifteen of those 29 ICH events in the COVID-19 group were classified as major (52%) including nine fatal cases (9/29, 31%). In the control group, there was only one major ICH event (1/4, 25%). The adjusted subhazard ratio for the occurrence of an ICH in the COVID-19 group was 5.82 (97.5% CI, 1.9-17.8; p = 0.002). The overall ICU mortality in the presence of ICH of any severity was 88%. This retrospective multicenter analysis showed a six-fold increased adjusted risk for ICH and a 3.5-fold increased incidence of ICH in COVID-19 patients on ECMO. Prospective studies are needed to confirm this observation and to determine whether the bleeding risk can be reduced by adjusting anticoagulation strategies.


The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs.
Extrapyramidal signs (EPS) are common in Alzheimer disease (AD) and increase in prevalence as AD advances. The neuropathologic substrate responsible for EPS in AD remains to be fully characterized. Subjects had a clinical diagnosis of AD confirmed by neuropathologic examination. EPS during life were documented by clinical methods assessing bradykinesia, cogwheel rigidity, rest tremor, and parkinsonian gait. Subjects with EPS and previous neuroleptic exposure were excluded. Twenty-eight subjects were in the EPS group and 104 subjects were without EPS. Neuron loss, alpha-synuclein (ASYN)-labeled pathology, and tau-labeled pathology in the substantia nigra were measured using semiquantitative techniques such that higher scores represented increased pathologic burden. Presence of nigral ASYN-labeled pathology was more common (50 vs 28.9%; p < 0.05) in the EPS group than in those without EPS. There was more nigral neuron loss in the EPS group (1.50 vs 1.11 in no-EPS group; p < 0.05). Tau-labeled burden was not different by group comparisons; however, EPS onset at later stages of dementia severity was associated with increased tau-labeled pathology (Kendall tau-B = 0.48, p < 0.01) and this association remained after controlling for dementia severity at death. Additionally, moderate to severe tau burden was more common in the subgroup with "pure AD" (definite AD without other neuropathology) with EPS (81.8%) than cases without EPS (49.0%; p < 0.05). Four subjects with EPS (14.3%) had little to no significant nigral pathologic changes. Clinically detected extrapyramidal signs (EPS) in Alzheimer disease (AD) are associated with substantia nigra pathology including alpha-synuclein aggregation, hyperphosphorylated tau accumulation, and neuron loss that may account for the increasing prevalence of EPS as AD progresses. In some cases, limited nigral pathology suggests extranigral factors in the clinical symptoms of EPS.


Association of Stress, Glucocorticoid Receptor, and FK506 Binding Protein Gene Polymorphisms With Internalizing Disorders Among HIV-Infected Children and Adolescents From Kampala and Masaka Districts-Uganda.
Children and adolescents living with human immunodeficiency virus (CA-HIV) suffer a considerable burden of internalizing disorders (IDs; depressive and anxiety disorders). Environmental and genetic factors have been reported to influence the vulnerability to IDs in western settings; however, their role among African populations remains inadequately explored. We investigated the individual and interactive effects of stress and single-nucleotide polymorphisms within the FK506 binding protein 5 (rs1360780) and glucocorticoid receptor (rs10482605) genes on ID status in a cohort of CA-HIV in Uganda. We genotyped rs10482605 (309 cases and 315 controls) and rs1360780 (350 cases and 335 controls) among CA-HIV with and without IDs using Kompetitive Allele-Specific PCR. Socio-demographic variables, as well as allele and genotype distributions, were compared between cases and controls using chi-square tests. Genotypes were assessed for Hardy-Weinberg equilibrium. Composite indices of recent and chronic stress classes were also generated. A hierarchical cluster analysis was used to generate cutoff points within each of the indices of recent and chronic stress. Logistic regression was used to assess the association between IDs and each of recent stress, chronic stress, and the investigated genotypes. The interaction effect of chronic/recent stress on the association between each of the polymorphisms and IDs was determined using a likelihood ratio test. We observed no significant association between IDs and rs1360780 and rs10482605 polymorphisms within the FKBP5 and glucocorticoid receptor genes, respectively (P > 0.050). Severe recent stress increased the vulnerability to IDs among CA-HIV (P = 0.001). We did not observe any gene-environment effect on vulnerability to IDs in this population. These findings support the currently held opinion that polymorphisms at single genetic loci only contribute a very small effect to the genetic vulnerability to IDs.


Physical activity changes predict abdominal fat change in midlife women.
The influence of physical activity (PA) changes on risk of abdominal fat gain in midlife women has not been studied using objective measures and controlling for potentially confounding variables. Changes in PA were assessed within a prospective cohort of 233 middle-age (40 +/- 3 years), nonobese, nonsmoking, primarily Caucasian women by using accelerometers, worn continuously for 7 consecutive days at baseline and again at a 20 month follow-up. Weighed food intake diaries were completed on concurrent days. Bod Pod assessed total body fat. Abdominal fat was measured by abdominal circumference at the umbilicus. Women who decreased PA gained abdominal fat across 20 months, while women who increased PA (F = 4.82, P = .009) did not. Change in PA remained an independent predictor of abdominal fat change after adjusting for potential confounders, including changes in total body fat and total energy intake. Compared with women who maintained or decreased PA, women who increased PA had approximately half the risk (RR = 0.52, 95% CI: 0.27, 0.98) of gaining abdominal fat. Increasing daily physical activity may attenuate risk of abdominal fat gain in middle-age women independent of changes in total body fat or energy intake.


Complications of Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy: An Observational Study.
Regional citrate anticoagulation (RCA) is the recommended anticoagulation modality for continuous renal replacement therapy (CRRT). RCA was associated with a low rate of complications in randomized controlled trials. However, little is known about the type and rate of complications in real life. We sought to describe complications associated with RCA in comparison with those associated with heparin anticoagulation. In our institution, RCA has been the default anticoagulation modality for CRRT in all patients without contraindications since 2013. We have retrospectively reviewed all consecutive patients who received CRRT between January and December 2016 in our institution. For each CRRT session, we have assessed circuit duration, administered dose, as well as therapy-associated complications. Those parameters were compared according to whether the circuit was run in continuous veno-venous hemodialysis (CVVHD) mode with RCA or continuous veno-venous hemofiltration (CVVH) mode with heparin anticoagulation. We analyzed 691 CRRT sessions in 121 patients. Of those 400 (57.9%) were performed in CVVHD-RCA mode and 291 (42.1%) in CVVH-Heparin Mode. Compared with -CVVH-Heparin mode, CVVHD-RCA mode was associated with a longer circuit lifespan (median duration 54.9 interquartile range [IQR 44.6] vs. 15.3 h [IQR 22.4], p < 0.0001). It was associated with a higher rate of metabolic acidosis 77 (20.2%) vs. 18 (7.2%), (p < 0.0001), alkalosis 186 (48.7%) vs. 43 (17.1%), (p= 0.0001), and hypocalcemia 96 (25.07%) vs. 26 events (10.79%), p < 0.0001. However, the majority of these alterations were of benign or moderate severity. Only one possible citrate intoxication was observed. CVVHD-RCA was associated with a much longer circuit life but an increased rate of minor metabolic complications, in particular acid-base derangements. Some of these complications might have been prevented by therapy adaptation. Medical and nursing staff education is of major importance in the implementation of an RCA protocol.


Isolation by distance and vicariance drive genetic structure of a coral reef fish in the Pacific Ocean.
We studied the genetic diversity of a coral reef fish species to investigate the origin of the differentiation. A total of 727 Acanthurus triostegus collected from 15 locations throughout the Pacific were analyzed for 20 polymorphic loci. The genetic structure showed limited internal disequilibrium within each population; 3.7% of the loci showed significant Hardy-Weinberg disequilibrium, mostly associated with Adh*, and we subsequently removed this locus from further analysis of geographic pattern. The genetic structure of A. triostegus throughout the tropical Pacific Ocean revealed a strong geographic pattern. Overall, there was significant population differentiation (multilocus F(ST) = 0.199), which was geographically structured according to bootstraps of neighbor-joining analysis on Nei's unbiased genetic distances and AMOVA analysis. The genetic structure revealed five geographic groups in the Pacific Ocean: western Pacific (Guam, Philippines, Palau, and Great Barrier Reef); central Pacific (Solomons, New Caledonia, and Fiji); and three groups made up of the eastern populations, namely Hawaiian Archipelago (north), Marquesas (equatorial), and southern French Polynesia (south) that incorporates Clipperton Island located in the northeastern Pacific. In addition, heterozygosity values were found to be geographically structured with higher values grouped within Polynesian and Clipperton populations, which exhibited lower population size. Finally, the genetic differentiation (F(ST)) was significantly correlated with geographic distance when populations from the Hawaiian and Marquesas archipelagos were separated from all the other locations. These results show that patterns of differentiation vary within the same species according to the spatial scale, with one group probably issued from vicariance, whereas the other followed a pattern of isolation by distance. The geographic pattern for A. triostegus emphasizes the diversity of the evolutionary processes that lead to the present genetic structure with some being more influential in certain areas or according to a particular spatial scale.


Assessment of readiness of academic emergency departments in the central region of Saudi Arabia to receive a sick child.
We sought to assess the readiness of general emergency departments (EDs) in academic hospitals in the central region of the Kingdom of Saudi Arabia (KSA) to manage pediatric patients using an international tool: The American Academy of Pediatrics, American College of Emergency Physicians, and Emergency Nurses Association guidelines, which include facilities, personnel, safety, and other components. We assessed eligible centers during multiple visits from January 2016 to May 2016 in which we inspected the EDs and conducted interviews with their respective leadership in which we independently recorded our observations. We meet afterward to reach a consensus. Four centers were eligible for enrollment out of eight. 437,548 patient visits were recorded in 2015 in four academic EDs served by 176 beds. 193 parameters as well as basic demographic data were evaluated. The average travel time from an academic ED to an affiliated pediatric ED was 4.2 min (standard deviation: 1.25). Only two centers had a dedicated pediatric resuscitation bed and none had a separate pediatric crash cart. Overall performance for all centers was 53% in all test parameters. Average scores were 75% for administration and staffing and 49.6% for equipment and medications. None of the centers had a weighing scale or a hypothermia monitor, and all centers neither had policies for family-centered care nor care of children during disasters. Evaluation of academic EDs in the central region of the KSA using an international tool revealed low overall scores with critical components needed for pediatric emergency care missing.


Factor analysis for survival time prediction with informative censoring and diverse covariates.
Fulfilling the promise of precision medicine requires accurately and precisely classifying disease states. For cancer, this includes prediction of survival time from a surfeit of covariates. Such data presents an opportunity for improved prediction, but also a challenge due to high dimensionality. Furthermore, disease populations can be heterogeneous. Integrative modeling is sensible, as the underlying hypothesis is that joint analysis of multiple covariates provides greater explanatory power than separate analyses. We propose an integrative latent variable model that combines factor analysis for various data types and an exponential proportional hazards (EPH) model for continuous survival time with informative censoring. The factor and EPH models are connected through low-dimensional latent variables that can be interpreted and visualized to identify subpopulations. We use this model to predict survival time. We demonstrate this model's utility in simulation and on four Cancer Genome Atlas datasets: diffuse lower-grade glioma, glioblastoma multiforme, lung adenocarcinoma, and lung squamous cell carcinoma. These datasets have small sample sizes, high-dimensional diverse covariates, and high censorship rates. We compare the predictions from our model to three alternative models. Our model outperforms in simulation and is competitive on real datasets. Furthermore, the low-dimensional visualization for diffuse lower-grade glioma displays known subpopulations.


Separation behavior of short single- and double-stranded DNA in 1 micron and 100 nm glass channels.
Micro- and nanofluidic lab-on-chip technology offers the unique capability of high-resolution separation, identification, and manipulation of biomolecules with broad applications in chemistry, biology, and medicine. In this work, we probe the effects of ionic strength on separation of ss- and dsDNA within 1 micron and 100 nm-deep glass channels. Separation behavior of DNA is influenced by a number of parameters, including ionic strength, melting temperature, strand length, strand conformation, and channel size. Specifically, we find a shift in the observed mobility of 10-bp (base pair) dsDNA for different ionic strengths due to changes in kinetic parameters, underlying the importance of these considerations when working with short DNA. For 50-base DNA, the electrophoretic mobility difference between ss- and dsDNA increases as the ionic strength increases due to changes in conformation of the ssDNA. Finally, we find that decreasing channel size decreases the absolute electrophoretic mobility of 10- and 20-bp ss- and dsDNA, due to both hydrodyamic confinement and electric double layer (EDL) interactions. We hypothesize that about 4% mobility reduction is due to hydrodynamic confinement, which is observed at all ionic strengths, and further reduction is due to EDL interactions between the DNA and the channel walls, only observed at low ionic strengths.


Combinatorial determinants of tissue-specific transcription in B cells and macrophages.
A tripartite domain of the immunoglobulin mu heavy-chain gene enhancer that activates transcription in B cells contains binding sites for PU.1, Ets-1, and a leucine zipper-containing basic helix-loop-helix factor. Because PU.1 is expressed only in B cells and macrophages, we tested the activity of a minimal mu enhancer fragment in macrophages by transient transfections. The minimal mu enhancer activated transcription in macrophages, and the activity was dependent on all three sites. Analysis of mutated enhancers, in which spacing and orientation of the ETS protein binding sites had been changed, suggested that the mechanisms of enhancer activation were different in B cells and macrophages. Thus, ETS protein binding sites may be combined in different ways to generate tissue-specific transcription activators. Despite the activity of the minimal enhancer in macrophages, a larger mu enhancer fragment was inactive in these cells. We propose that formation of the nucleoprotein complex that is formed on the minimal enhancer in macrophages cannot be helped by the neighboring muE elements that are essential for activity of the monomeric enhancer.


Statistical inference of regulatory networks for circadian regulation.
We assess the accuracy of various state-of-the-art statistics and machine learning methods for reconstructing gene and protein regulatory networks in the context of circadian regulation. Our study draws on the increasing availability of gene expression and protein concentration time series for key circadian clock components in Arabidopsis thaliana. In addition, gene expression and protein concentration time series are simulated from a recently published regulatory network of the circadian clock in A. thaliana, in which protein and gene interactions are described by a Markov jump process based on Michaelis-Menten kinetics. We closely follow recent experimental protocols, including the entrainment of seedlings to different light-dark cycles and the knock-out of various key regulatory genes. Our study provides relative network reconstruction accuracy scores for a critical comparative performance evaluation, and sheds light on a series of highly relevant questions: it quantifies the influence of systematically missing values related to unknown protein concentrations and mRNA transcription rates, it investigates the dependence of the performance on the network topology and the degree of recurrency, it provides deeper insight into when and why non-linear methods fail to outperform linear ones, it offers improved guidelines on parameter settings in different inference procedures, and it suggests new hypotheses about the structure of the central circadian gene regulatory network in A. thaliana.


Oxidative stress: a key contributor to diabetic cardiomyopathy.
Diabetes and its associated complications are major known health disorders. Diabetes mellitus increases the risk of cardiovascular morbidity and mortality by promoting cardiomyopathy. It appears to arise as a result of the diabetic state, at times independent of vascular or valvular pathology. It manifests initially as asymptomatic diastolic dysfunction, which progresses to symptomatic heart failure. The compliance of the heart wall is decreased and contractile function is impaired. The pathophysiology of diabetic cardiomyopathy is incompletely understood but appears to be multifactorial in origin. Several hypotheses have been proposed, including oxidative stress, inflammation, endothelial dysfunction, metabolic derangements, abnormalities in ion homeostasis, alterations in structural proteins, and interstitial fibrosis. Amongst these various mechanisms, an increase in reactive oxygen species, leading to oxidative stress, has received significant experimental support. This review focuses on the role of oxidative stress in the pathogenesis of diabetic cardiomyopathy and the potential of antioxidant therapy.


Impact of spectral resolution of in situ ocean color radiometric data in satellite matchups analyses.
The spectral resolution requirements for in situ remote sensing reflectanceRRS measurements aiming at supporting satellite ocean color validation and System Vicarious Calibration (SVC) were investigated. The study, conducted using sample hyperspectral RRS from different water types, focused on the visible spectral bands of the ocean land color imager (OLCI) and of the Plankton, Aerosol, Cloud, ocean Ecosystem (PACE) satellite sensors. Allowing for a ±0.5% maximum difference between in situ and satellite derived RRS solely due to the spectral band characteristics of the in situ radiometer, a spectral resolution of 1 nm for SVC of PACE is needed in oligotrophic waters. Requirements decrease to 3 nm for SVC of OLCI. In the case of validation activities, which exhibit less stringent uncertainty requirements with respect to SVC, a maximum difference of ±1% between in situ and satellite derived data indicates the need for a spectral resolution of 3 nm for both OLCI and PACE in oligotrophic waters. Conversely, spectral resolutions of 6 nm for PACE and 9 nm for OLCI appear to satisfy validation activities in optically complex waters.


Directional responding of C57BL/6J mice in the Morris water maze is influenced by visual and vestibular cues and is dependent on the anterior thalamic nuclei.
Recent findings indicate that rats navigate in spatial tasks such as the Morris water maze (MWM) using a local cue-based reference frame rather than a distal cue-based reference frame. Specifically, rats swim in a particular direction to a location relative to pool-based cues, rather than to an absolute location defined by room-based cues. Neural mechanisms supporting this bias in rodents for relative responding in spatial tasks are not yet understood. Anterior thalamic neurons discharge according to the current directional heading of the animal. The contribution of head direction (HD) cell activity to navigation has been difficult to elucidate. We found that male C57BL/6J mice trained for 4 or 7 d in the MWM exhibited an overwhelming preference for swimming in a direction relative to pool-based cues over absolute responding during a platform-less probe test. Rotation of extramaze cues caused a corresponding rotation of the direction mice swam during the probe test, suggesting that both pool- and room-based reference frames guide platform search. However, disorienting the mice before the probe test disturbed relative responding. Therefore, relative responding is guided by both internal and external cue sources. Selective inactivation of anterior thalamic nuclei (ATN) by microinfusion of muscimol or fluorophore-conjugated muscimol caused a near complete shift in preference from relative to absolute responding. Interestingly, inactivation of the dorsal CA1 region of the hippocampus did not affect relative responding. These data suggest that ATN, and HD cells therein, may guide relative responding in the MWM, a task considered by most to reflect hippocampal processing.


Interactions between NCR+ILC3s and the Microbiome in the Airways Shape Asthma Severity.
Asthma is a heterogeneous disease whose development is shaped by a variety of environmental and genetic factors. While several recent studies suggest that microbial dysbiosis in the gut may promote asthma, little is known about the relationship between the recently discovered lung microbiome and asthma. Innate lymphoid cells (ILCs) have also been shown recently to participate in asthma. To investigate the relationship between the lung microbiome, ILCs, and asthma, we recruited 23 healthy controls (HC), 42 patients with non-severe asthma, and 32 patients with severe asthma. Flow cytometry analysis showed severe asthma associated with fewer natural cytotoxicity receptor (NCR)+ILC3s in the lung. Similar changes in other ILC subsets, macrophages, and monocytes were not observed. The asthma patients did not differ from the HC in terms of the alpha and beta-diversity of the lung and gut microbiomes. However, lung function correlated positively with both NCR+ILC3 frequencies and microbial diversity in the lung. Sputum NCR+ILC3 frequencies correlated positively with lung microbiome diversity in the HC, but this relationship was inversed in severe asthma. Together, these data suggest that airway NCR+ILC3s may contribute to a healthy commensal diversity and normal lung function.


Clinical Competencies in Advanced Practice Respiratory Therapy Education: Is It Time to Entrust the Learner?
The field of clinical education in health care has undergone several paradigm shifts in regards to its original theoretical frameworks across multiple healthcare professions. One of the most common evaluation and assessment tools undergoing equal amounts of change and research is competency-based education. In that vein, the respiratory care profession is also experiencing similar challenges to better asses and evaluate clinical competency. One of the emerging professional directions in respiratory care is the establishment of the advanced practice respiratory therapist (APRT) at the graduate level. This new advanced degree profession currently relies on competency-based education as an evaluation and assessment framework to fulfill the competency domains required by the professions accrediting agency, the Commission on Accreditation for Respiratory Care (CoARC). Since advanced practice, respiratory therapists will be considered advanced practice providers, a more robust assessment tool should be considered to assess and evaluate their clinical performance. The purpose of this article is to establish a higher evaluation and assessment framework, the Entrustable Professional Activity (EPA) tool. Entrusting the learner to be competent practitioners involves many aspects of practice skills, tasks, and other intangible areas such as behaviors and critical thinking that may not typically part of a competency-based education framework. We thus propose a sample EPA framework that is aligned with current CoARC APRT core competencies and a recommendation for an implementation strategy to assist the respiratory care community at large.


Bounded uncertainty and climate change economics.
It has been argued recently that the combination of risk aversion and an uncertainty distribution of future temperature change with a heavy upper tail invalidates mainstream economic analyses of climate change policy. A simple model is used to explore the effect of imposing an upper bound on future temperature change. The analysis shows that imposing even a high bound reverses the earlier argument and that the optimal policy, as measured by the willingness to pay to avoid climate change, is relatively insensitive to this bound over a wide range.


Safety and efficacy of the simultaneous administration of udenafil and an alpha-blocker in men with erectile dysfunction concomitant with BPH/LUTS.
We evaluated the clinical efficacy and safety of administering udenafil (5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)-pyrimidin-7-one) in patients with comorbid benign prostatic hyperplasia (BPH) and erectile dysfunction (ED). One hundred and twenty patients who had been undergoing stable alpha-blocker therapy for BPH were enrolled in this trial and they were administered 100 mg udenafil for 8 weeks. Changes in blood pressure (BP), heart rate (HR), the international prostatic symptom score (IPSS) and the international index of ED (IIEF-5) were evaluated every 4 weeks. At end point, there was no significant change in BP and HR, whereas the lower urinary tract symptoms (LUTS) and ED improved significantly compared with baseline (IPSS 14.3-11.5, IIEF-5 11.95-18.32, P<0.05). Most patients were tolerant to the treatment and there was no evidence of additional side effects related to coadministration. The coadministration of udenafil and an alpha-blocker in patients with comorbid BPH and ED was safe and gave significant improvements in both LUTS and ED.


Transcription of G-protein coupled receptors in corporeal smooth muscle is regulated by the endogenous neutral endopeptidase inhibitor sialorphin.
Several reports suggest that the rat Vcsa1 gene is down-regulated in models of erectile dysfunction. The Vcsa protein product sialorphin is an endogenous neutral endopeptidase inhibitor and its down-regulation could result in prolonged activation of G-protein activated signaling pathways by their peptide agonists. We investigated whether Vcsa1 down-regulation could result in an adaptive change in GPCR (G-protein coupled receptor) expression. Gene expression in cultured rat corporeal smooth muscle cells following treatment with siRNA directed against Vcsa1 or the neutral endopeptidase gene was analyzed using microarray and quantitative reverse transcriptase-polymerase chain reaction. In rats Vcsa1 is one of the most down-regulated genes following bilateral transection of the cavernous nerves. In that animal model we also investigated whether Vcsa1 down-regulation was accompanied by similar changes in gene expression in corporeal smooth muscle cells in which Vcsa1 was knocked down in vitro. Microarray analysis and quantitative reverse transcriptase-polymerase chain reaction demonstrated that corporeal smooth muscle cells treated in vitro with siRNA against Vcsa1 resulted in GPCR up-regulation as a functional group. In contrast, treatment of corporeal smooth muscle cells that lowered neutral endopeptidase activity resulted in decreased GPCR expression. These results suggest that the peptide product of Vcsa1, sialorphin, can effect GPCR expression by acting on neutral endopeptidase. In animals with bilaterally transected cavernous nerves the decreased Vcsa1 expression is accompanied by increased GPCR expression in cavernous tissue. These experiments suggest that the mechanism by which Vcsa1 modulates erectile function is partly mediated through changes in GPCR expression.


[Consequences and complications of obesity].
Obesity increases the risk of metabolic complications such as diabetes, dyslipidemia, systemic hypertension and cardiovascular disease. These are mainly responsible for the increased mortality of obese people. Other metabolic consequences of obesity are: gallstones, steatosis of the liver and the polycystic ovary syndrome. Beside the body mass index the distribution of body fat is important. Centralized obesity, as measured by the waist-to-hip circumference ratio (WHR), is associated with increased mortality and morbidity. Insulin resistance and hyperinsulinaemia seem to play a central role in the pathogenesis of this association. Obesity has not only metabolic complications. There is a relationship between obesity and impaired respiratory function. Furthermore is obesity a risk factor for osteoarthrosis of the knee, the hip and even the hand and for pulmonary embolism and venous thrombosis. Obesity can also lead to psycho-social problems such as depression, social discrimination and isolation.


Management of non-transfusion-dependent thalassemia: a practical guide.
Despite their transfusion-independence, non-transfusion-dependent thalassemia (NTDT) patients experience a variety of serious clinical complications that require prompt and comprehensive management. Transfusion therapy may still be an important part of management of this disease, in cases of acute stress, to support growth and development in childhood, or to prevent clinical morbidities stemming from ineffective erythropoiesis or hemolytic anemia. Although splenectomy is associated with improvements in hemoglobin levels, it leads to several short- and long-term adverse events, warranting caution in application of this intervention. Fetal hemoglobin induction therapy has been evaluated in non-randomized studies, with benefits extending beyond hematologic improvements to lowering morbidity risk. Effective and safe iron chelation therapy is now available for NTDT patients in whom iron overload develops, irrespective of transfusions, due to increased intestinal absorption, ultimately leading to clinically high iron burden levels and subsequent morbidity. Optimal management of NTDT patients requires a holistic approach targeting all hallmarks of the disease to ensure favorable patient outcomes.


Modulation of Anopheles gambiae Epsilon glutathione transferase activity by plant natural products in vitro.
Elevated glutathione transferase (GST) E2 activity is associated with DDT resistance in the mosquito Anopheles gambiae. The search for chemomodulators that inhibit the function of AgGSTE2 would enhance the insecticidal activity of DDT. Therefore, we examined the interaction of novel natural plant products with heterologously expressed An. gambiae GSTE 2 in vitro. Five of the ten compounds, epiphyllocoumarin (Tral-1), knipholone anthrone, isofuranonaphthoquinones (Mr 13/2, Mr13/4) and the polyprenylated benzophenone (GG1) were shown to be potent inhibitors of AgGSTE2 with IC(50) values of 1.5 microM, 3.5 microM, 4 microM, 4.3 microM and 4.8 microM respectively. Non-competitive inhibition was obtained for Tral 1 and GG1 with regards to GSH (K(i) of 0.24 microM and 0.14 microM respectively). Competitive inhibition for Tral1 was obtained with CDNB (K(i) = 0.4 microM) whilst GG1 produced mixed type of inhibition. The K(i) and K(i)' for GSH for Tral-1 and GG1 were 0.2 microM and 0.1 microM respectively. These results suggest that the novel natural plant products, particularly Tral-1, represent potent AgGSTE2 in vitro inhibitors.


Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens.
When dendritic cells (DCs) encounter signals associated with infection or inflammation, they become activated and undergo maturation. Mature DCs are very efficient at presenting antigens captured in association with their activating signal but fail to present subsequently encountered antigens, at least in vitro. Such impairment of MHC class II (MHC II) antigen presentation has generally been thought to be a consequence of down-regulation of endocytosis, so it might be expected that antigens synthesized by the DCs themselves (for instance, viral antigens) would still be presented by mature DCs. Here, we show that DCs matured in vivo could still capture and process soluble antigens, but were unable to present peptides derived from these antigens. Furthermore, presentation of viral antigens synthesized by the DCs themselves was also severely impaired. Indeed, i.v. injection of pathogen mimics, which caused systemic DC activation in vivo, impaired the induction of CD4 T cell responses against subsequently encountered protein antigens. This immunosuppressed state could be reversed by adoptive transfer of DCs loaded exogenously with antigens, demonstrating that impairment of CD4 T cell responses was due to lack of antigen presentation rather than to overt suppression of T cell activation. The biochemical mechanism underlying this phenomenon was the down-regulation of MHC II-peptide complex formation that accompanied DC maturation. These observations have important implications for the design of prophylactic and therapeutic DC vaccines and contribute to the understanding of the mechanisms causing immunosuppression during systemic blood infections.


Sensitive Oligodeoxynucleotide Synthesis Using Dim and Dmoc as Protecting Groups.
In traditional oligodeoxynucleotide (ODN) synthesis, phosphate groups are protected with the 2-cyanoethyl group, and amino groups are protected with acyl groups. At the end of ODN synthesis, deprotection is achieved with strong bases and nucleophiles. Therefore, traditional technologies are not suitable for the synthesis of ODNs containing sensitive functionalities. To address the problem, we report the use of Dim and Dmoc groups, which are based on the 1,3-dithian-2-yl-methyl function, for phosphate and amine protection for the solid phase ODN synthesis. Using the new Dim-Dmoc protection, deprotection was achieved under mild oxidative conditions without using any strong bases and nucleophiles. As a result, the new technology is suitable for the synthesis of ODNs containing sensitive functions. To demonstrate feasibility, seven 20-mer ODNs including four that contain sensitive ester and alkyl chloride groups were synthesized, purified with RP HPLC, and characterized with MALDI-TOF MS and enzyme digestion essays. High purity ODNs were obtained.


DNA Methylation Profile of the SREBF2 Gene in Human Fetal Aortas.
Increasing evidence suggests that maternal cholesterol represents an important risk factor for atherosclerotic disease in offspring already during pregnancy, although the underlying mechanisms have not yet been elucidated. Eighteen human fetal aorta samples were collected from the spontaneously aborted fetuses of normal cholesterolemic and hypercholesterolemic mothers. Maternal total cholesterol levels were assessed during hospitalization. DNA methylation profiling of the whole SREBF2 gene CpG island was performed (p value <0.05). The Mann-Whitney U test was used for comparison between the 2 groups. For the first time, our study revealed that in fetal aortas obtained from hypercholesterolemic mothers, the SREBF2 gene shows 4 significant differentially hypermethylated sites in the 5'UTR-CpG island. This finding indicates that more effective long-term primary cardiovascular prevention programs need to be designed for the offspring of mothers with hypercholesterolemia. Further studies should be conducted to clarify the epigenetic mechanisms underlying the association between early atherogenesis and maternal hypercholesterolemia during pregnancy.


Advances on polyphenism in insects.
Polyphenism denotes that one genome produces two or more distinct phenotypes due to environmental inductions. Many cases have been reported in insects, for example, metamorphosis, seasonal polyphenism, the caste of eusocial insects and so on. Polyphenism is one of the most important reasons for insects to survive and thrive, because insects can adapt and use the environmental cues around them in order to avoid predators and reproduce by changing their phenotypes. Polyphenism has received growing attentions, ranging from the earlier description of this phenomenon to the exploration of possible inducing factors. With the recent advent of the genomic era, more and more studies based on next generation sequencing, gene knockout and RNA interference have been reported to reveal the molecular mechanism of polyphenism. In this review, we summarize the progresses of the polyphenism in insects and envision prospects of future researches.


Uptake, metabolism and release of (3H)-adrenaline by human platelets.
1. Measurements were made of the uptake, metabolism and release of [(3)H]-adrenaline by human platelets in citrated plasma or in an artificial medium.2. Radioactive adrenaline was not taken up at 0-2 degrees C. At 37 degrees C there was a slow uptake which continued for at least 5 hours.3. About half of the radioactivity in the platelets was intact adrenaline. The other half was an acidic metabolite from which adrenaline was released by acid hydrolysis.4. The immediate uptake of adrenaline was proportional to its concentration in the plasma up to at least 1 x 10(-5)M. Uptake measured after 1 h also increased linearly with concentration up to about 1 x 10(-4)M but less with higher concentrations. The highest concentration ratio was about 12.5. The concentration of metabolite in the platelets increased with the concentration of added adrenaline only up to about 2 x 10(-4)M.6. The immediate uptake of adrenaline was partially inhibited by phentolamine and dihydroergotamine. Measurement of uptake both immediately and after 1 h showed that the inhibition produced was not increased beyond about 50% by these drugs or by (+/-)-propranolol, chlorpromazine or amitriptyline up to 1 x 10(-4)M.7. Formation of the metabolite was inhibited by pyrogallol, 8-hydroxyquinoline, or tropolone. This inhibition was associated with a corresponding increase in the adrenaline accumulated intact. Formation of the metabolite was not inhibited by monoamine oxidase inhibitors.8. Reserpine caused a small decrease in the uptake of adrenaline radioactivity in 1 h and a great increase in the proportion recovered as metabolite.9. Thrombin caused the release from platelets of intact adrenaline but not of the metabolite.10. Platelets of albino patients with spontaneous haemorrhages accumulated adrenaline radioactivity at the normal rate but this radioactivity was wholly accounted for by metabolite and not released by thrombin.11. After taking up adrenaline, platelets resuspended in artificial medium at 37 degrees C slowly released both adrenaline and its metabolite. At the same time, the intracellular adrenaline was slowly metabolized.12. The Result suggest that human platelets take up adrenaline by two processes, one of which is inhibited by both alpha- and beta-adrenoceptor blocking agents ad well as by phenothiazines; and that in the platelets adrenaline is partly stored in organelles from which, like 5-hydroxytryptamine, it can be specifically released.


Diabetes and elevated urea level predict for uretero-ileal stricture after radical cystectomy and ileal conduit formation.
Benign uretero-ileal anastomotic stricture is a significant complication following radical cystectomy and ileal conduit urinary diversion after radical cystectomy. We examined risk factors for stricture formation to predict those at greatest stricture risk. A retrospective chart review was conducted for patients undergoing radical cystectomy and ileal conduit diversion between 2002 and 2012. Demographic data and patient variables were analyzed to determine risk factors for uretero-ileal stricture using multivariate logistic regression. Over the study period, 133 patients underwent cystectomy and ileal conduit formation, with 14 (10.5%) developing uretero-ileal anastomotic stricture. Diabetes and elevated serum urea level (defined as >7.1 mmol/L) were associated with increased risk for development of uretero-ileal stricture (odds ratio 4.31 and 4.28, respectively; p<0.05 for each). In this patient cohort, diabetes and elevated serum urea level were predictive for the development of uretero-ileal anastomotic stricture. Further prospective study with larger patient samples is required.


Importance of Interface in the Coarse-Grained Model of CNT /Epoxy Nanocomposites.
Interface interactions play a crucial role in determining the thermomechanical properties of carbon nanotubes (CNTs)/polymer nanocomposites. They are, however, poorly treated in the current multi-scale coarse-grained (CG) models. To develop suitable CG models of CNTs/polymer nanocomposites, we demonstrate the importance of two aspects for the first time, that is, preserving the interfacial cohesive energy and reproducing the interface load transfer behavior of all-atomistic (AA) systems. Our simulation results indicate that, for CNTs/polymer nanocomposites, the interface cohesive energy and the interface load transfer of CG models are generally inconsistent with their AA counterparts, revealing significant deviations in their predicted mechanical properties. Fortunately, such inconsistency can be "corrected" by phenomenologically adjusting the cohesive interaction strength parameter of the interface LJ potentials in conjunction with choosing a reasonable degree of coarse-graining of incorporated CNTs. We believe that the problem studied here is general for the development of the CG models of nanocomposites, and the proposed strategy used in present work may be applied to polymer nanocomposites reinforced by other nanofillers.


Lignans from the fruit of Schisandra glaucescens with antioxidant and neuroprotective properties.
Two rare 7,8-seco-lignans (1, 2), three new lignan glycosides (3, 4a, 4b), and 10 known lignans (5-14) were isolated from the fruit of Schisandra glaucescens Diels. The absolute configurations of 1 and 2 were determined by comparing their experimental and calculated electronic circular dichroism spectra. The molecular structures of the new compounds (3, 4a, and 4b), including their absolute configurations, were determined using various spectroscopic methods and hydrolysis reactions. The antioxidant activities of the isolated compounds were tested using 2,2-diphenyl-1-picrylhydrazyl and ferric reducing antioxidant power assays. Compounds 4, 7, 8, 10, 11, and 12 exhibited antioxidant activities of varying potential in both assays. Of these compounds, 7 showed the strongest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity, with IC50 values of 15.7 (150 μM DPPH) and 34.6 μM (300 μM DPPH), respectively, and 4, 12, and 7 displayed higher total antioxidant activities than Trolox in the ferric reducing antioxidant power assay. The neuroprotective effects of these compounds against Aβ25-35-induced cell death in SH-SY5Y cells were also investigated. Compounds 1, 2, 6, 7, 8, 11, and 12 exhibited statistically significant neuroprotective effects against Aβ25-35-induced SH-SY5Y cell death compared with the group treated only with Aβ25-35.


Intestinal intubation in acute, mechanical small-bowel obstruction.
A review of 100 consecutive patients admitted with simple, mechanical small-bowel obstruction secondary to adhesions and treated for at least 24 hours with nonoperative intestinal intubation showed that of 76 patients admitted with partial small-bowel obstruction, 49 (65%) were successfully treated without operation. Of those with complete small-bowel obstruction (CSBO), 18 of 24 (75%) subsequently required surgical intervention; however, six of 24 (25%) were safely treated by nonoperative intubation. The 24-hour delay in surgery for CSBO did not increase morbidity or mortality in the 18 requiring operations. Major indications for surgical intervention were suspected strangulated obstruction or persistent obstruction, which frequently was associated with unsuccessful tube passage. Administration of antibiotics preoperatively was associated with a significant reduction in wound infections in patients requiring resection or enterotomy.


Chronic Dietary Selenomethionine Exposure Induces Oxidative Stress, Dopaminergic Dysfunction, and Cognitive Impairment in Adult Zebrafish (Danio rerio).
The present study was designed to investigate the effects of chronic dietary exposure to selenium (Se) on zebrafish cognition and also to elucidate possible mechanism(s) by which Se exerts its neurotoxicity. To this end, adult zebrafish were exposed to different concentrations of dietary l-selenomethionine (control, 2.3, 9.7, 32.5, or 57.7 μg Se/g dry weight) for 30 days. Cognitive performance of fish was tested using a latent learning paradigm in a complex maze. In addition, we also evaluated oxidative stress biomarkers and the expression of genes involved in dopaminergic neurotransmission in the zebrafish brain. Fish treated with higher dietary Se doses (32.5 and 57.5 μg Se/g) exhibited impaired performance in the latent learning task. The impaired learning was associated with the induction of oxidative stress and altered mRNA expression of dopamine receptors, tyrosine hydroxylase, and dopamine transporter genes in the zebrafish brain. Collectively, our results illustrate that cognitive impairment in zebrafish could be associated with Se-induced oxidative stress and altered dopaminergic neurotransmission in the brain.


Metagenomic analysis revealed beneficial effects of probiotics in improving the composition and function of the gut microbiota in dogs with diarrhoea.
The aim of the present study was to evaluate the effects of probiotics on the composition and function of the gut microbiota in dogs with diarrhoea. Forty dogs with diarrhoea were randomly allocated to the treatment group or control group. Probiotics, containing Lactobacillus casei Zhang, Lactobacillus plantarum P-8, and Bifidobacterium animalis subsp. lactis V9, were only fed to 20 treated dogs for 60 days. The faecal samples of all dogs at day 0 and day 60 were analyzed using a metagenomic approach. The results showed a significantly higher microbial diversity and an obvious change in the structure of the gut microbiota in the treatment group. There was also an increase in the abundance of some beneficial bacteria in differently aged dogs, such as Lactobacillus johnsonii (P < 0.05), Lactobacillus reuteri (P < 0.01), Lactobacillus acidophilus (P < 0.05) and Butyricicoccus pullicaecorum (P < 0.05), and a reduction in the abundance of many opportunistic pathogenic bacteria such as Clostridium perfringens (P < 0.05) and Stenotrophomonas maltophilia (P < 0.05) with the supplementation of probiotics. Intriguingly, the correlated networks among some pathogenic bacteria decreased following the administration of probiotics. Additionally, metagenomic analysis revealed the upregulation of pathways involved in the metabolism of amino acids and biosynthesis of secondary metabolites, accompanied by the downregulation of pathways associated with virulence of pathogenic bacteria and cell signaling, suggesting that probiotics could improve the health of dogs with diarrhoea through regulation of the gut microbiota. Our research provides new information relevant to the treatment of diarrhoea in animals and humans.


Deformities of chironomid larvae and heavy metal pollution: from laboratory to field studies.
Mouthpart deformities of Chironomus riparius larvae (Diptera) have been investigated to evaluate the toxic effects of contamination by heavy metals in the Genna Stream (Central Italy), situated in an area subjected to intensive swine farms (40000 heads). The livestock farming (fertirrigation) contributes to metal pollution of the Genna Stream with an increase of copper, zinc, cadmium, chromium and nickel in the sediments of the downstream stations. The incidence of mentum deformities was very high at all sampling stations, about 56%. The highest values of deformities were found in the intermediate river reach (St. 3: 65%) and in March (66%), mainly due to an increase in severe deformities. The high incidence of severe deformities (30%) is attributed to the high pollution level by heavy metals in the sediments, in particular to copper and zinc, which showed the highest average value at St. 3 and in March. This field study reflected the relationships between sediment metal concentrations and chironomid mouthpart deformities, previously observed in laboratory tests, and highlighted these deformities as toxicity endpoints. This feature paves the way for their use as an effective tool in freshwater bioassessment monitoring programs to evaluate the toxic effects of metal contamination in freshwater ecosystems.


Detection of Cryptosporidium parvum DNA in formed human feces by a sensitive PCR-based assay including uracil-N-glycosylase inactivation.
We developed a PCR-based method that can be used to identify Cryptosporidium parvum in human feces. Fecal oocysts were concentrated by centrifugation on a sodium chloride gradient and filtration on a nitrocellulose filter prior to DNA extraction and PCR amplification of a 452-bp C. parvum-specific DNA sequence with a protocol including dUTP and uracil-N-glycosylase. All samples obtained from naturally infected humans (n = 10), calves (n = 4), and goats (n = 2) were positive. A 100% detection rate was achieved with both formed and solid stools (n = 10) seeded with 1,000 C. parvum oocysts per g. Procedures based on stool concentration by a modified Ritchie method and subsequent oocyst identification by immunofluorescent labeling or acid-fast staining require concentrations of 50,000 to 500,000 oocysts per g to achieve a 100% detection rate with formed stools. The described PCR-based assay thus has a 50- to 500-fold increase in sensitivity compared to those of the methods commonly used to analyze formed feces.


Searching for the best modeling specification for assessing the effects of temperature and humidity on health: a time series analysis in three European cities.
Epidemiological time series studies suggest daily temperature and humidity are associated with adverse health effects including increased mortality and hospital admissions. However, there is no consensus over which metric or lag best describes the relationships. We investigated which temperature and humidity model specification most adequately predicted mortality in three large European cities. Daily counts of all-cause mortality, minimum, maximum and mean temperature and relative humidity and apparent temperature (a composite measure of ambient and dew point temperature) were assembled for Athens, London, and Rome for 6 years between 1999 and 2005. City-specific Poisson regression models were fitted separately for warm (April-September) and cold (October-March) periods adjusting for seasonality, air pollution, and public holidays. We investigated goodness of model fit for each metric for delayed effects up to 13 days using three model fit criteria: sum of the partial autocorrelation function, AIC, and GCV. No uniformly best index for all cities and seasonal periods was observed. The effects of temperature were uniformly shown to be more prolonged during cold periods and the majority of models suggested separate temperature and humidity variables performed better than apparent temperature in predicting mortality. Our study suggests that the nature of the effects of temperature and humidity on mortality vary between cities for unknown reasons which require further investigation but may relate to city-specific population, socioeconomic, and environmental characteristics. This may have consequences on epidemiological studies and local temperature-related warning systems.


[Asphyxiation by suffocation and strangulation in children younger than 15 years of age].
Our aim was to describe non-intentional strangulation or suffocation suffered by children under 15 years of age. Records from the Medical Examiner's Office showed child death by non-intentional strangulation or suffocation from January 1, 1991 to December 31, 2001. A total of 44 suffocations or non-intentional strangulations were registered. Overall mortality was 3.62/1,000,000 persons-year (27.57/1,000,000 in children < 1 year of age, 1.94/1,000,000 in older children); 63.6% were males. Most frequent mechanisms included neck entrapment between bars 18.2%, facial obstruction by bed clothes 15.9%, being covered by rubble, sand, or garbage 15.9%, strangulation by cord, chain, or strip 11.4%, and strangulation by dress or bed clothes 9.1%. Nearly all registered deaths could be prevented by education, supervision, or structural modifications. Strategies should also include obligatory standards for manufacturing and for warnings on labels.


Local Thrombolysis in High-Risk Pulmonary Embolism-13 Years Single-Center Experience.
To evaluate the prognosis after local thrombolysis compared to systemic thrombolysis in high-risk pulmonary embolism. Observational study during 13 years which included 37 patients with high-risk pulmonary embolism treated with local thrombolysis and 36 patients with systemic thrombolysis (streptokinase, 250 000 UI/30 minutes followed by 100 000 UI/h). Cardiogenic shock has totally remitted in the group with local thrombolysis (P = .002). The decrease in pressure gradient between right ventricle and right atrium was comparable in both groups in the acute period (the results being influenced by the higher in-hospital mortality after systemic thrombolysis), but significantly better in the next 24 months follow-up after in situ thrombolysis. Major and minor bleeding did not have significant differences. In hospital, mortality was significantly lower in the group with local thrombolysis (P = .003), but for the next 24 months follow-up, the survival was comparable in both groups. Local thrombolysis, during the hospitalization, was associated with lower mortality rate comparing with systemic thrombolysis. In the next 24 months follow-up, the evolution of residual pulmonary hypertension was significantly better after in situ thrombolysis.


What makes a species common? No evidence of density-dependent recruitment or mortality of the sea urchin Diadema antillarum after the 1983-1984 mass mortality.
A potential consequence of individuals compensating for density-dependent processes is that rare or infrequent events can produce profound and long-term shifts in species abundance. In 1983-1984 a mass mortality event reduced the numbers of the abundant sea urchin Diadema antillarum by 95-99% throughout the Caribbean and western Atlantic. Following this event, the abundance of macroalgae increased and the few surviving D. antillarum responded by increasing in body size and fecundity. These initial observations suggested that populations of D. antillarum could recover rapidly following release from food limitation. In contrast, published studies of field manipulations indicate that this species had traits making it resistant to density-dependent effects on offspring production and adult mortality; this evidence raises the possibility that density-independent processes might keep populations at a diminished level. Decadal-scale (1983-2011) monitoring of recruitment, mortality, population density and size structure of D. antillarum from St John, US Virgin Islands, indicates that population density has remained relatively stable and more than an order of magnitude lower than that before the mortality event of 1983-1984. We detected no evidence of density-dependent mortality or recruitment since this mortality event. In this location, model estimates of equilibrium population density, assuming density-independent processes and based on parameters generated over the first decade following the mortality event, accurately predict the low population density 20 years later (2011). We find no evidence to support the notion that this historically dominant species will rebound from this temporally brief, but spatially widespread, perturbation.


Prognostic factors predicting survival in the treatment of retroperitoneal sarcoma.
Retroperitoneal soft tissue sarcomas are rare tumours. The management of these tumours has been difficult because of low resectability and a high recurrence rate. A retrospective review of a prospectively compiled database of 32 consecutive patients with retroperitoneal sarcomas treated at Oulu University Hospital between 1977 and 1996 was performed. The resectability rate of primary tumours was 75%, and 44% of the patients underwent radical resection. The recurrence rate after radical resection was 57% and the resectability rate for recurrent tumours after radical primary operation, 50%. The actuarial overall 5-year survival rate was 31%, 10-year survival rate 19% and median survival 36 months. In univariate analysis the principal factors associated with prognosis were radical resection, recurrent disease, pre-operative loss of weight and histological tumour grade. Complete excision of the primary tumour was the only significant predictor of survival in multivariate analysis. Complete resection of retroperitoneal sarcoma continues to be the most important prognostic factor. The inefficiency of adjuvant therapy, the high recurrence rate and the very low chance of curing the patient after recurrence make the prognosis of these patients poor.


Review of Practice-Based Research: A Guide for Clinicians.
Reviews the book, Practice-Based Research: A Guide for Clinicians edited by R. Trent Codd III. As illuminated in this new book, clinicians are at the forefront of mental health care. They have the proverbial front row view of treatment implementation. Therefore, clinicians are ideally suited, compared with academic researchers, to conduct research that yields a quick and meaningful impact on the medical field. Therefore, clinicians conducting practice-based research are well situated to identify and answer questions of practical importance and direct impact on the medical field. This five-chapter, 13-article guidebook brings to light that the field of mental health faces a scientist-practitioner gap. Hopefully, this book achieves its intention: to improve the caliber of treatments delivered and research conducted, thereby helping the ultimate recipients of both-the patients. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Vaginal reconstruction after extended radical pelvic surgery for cancer: comparison of two techniques.
An immediate partial or total vaginal reconstruction is frequently proposed in cases of exenterative or extended radical pelvic surgery for cancer treatment. One of the main complications after this reconstruction is the vagina obliteration caused by the healing process. This study compares the results of two different reconstructive techniques, particularly focusing on general complications and the risk of vaginal occlusion. A transversus rectus abdominis musculoperitoneal (TRAMP) composite flap has been performed in five cases, and an inverted inferior transverse rectus abdominis musculocutaneous flap (TRAM) has been used in another five cases. Recovery was uneventful in eight cases. One patient (case 5) developed an aortofemoral embolism requiring a bilateral transfemoral embolectomy and heparin administration. Another patient (case 9) experienced severe peritonitis because of the partial leak of the rectal anastomosis, and therefore a Mikulicz's colostomy was performed. Four patients who underwent the TRAMP flap developed a complete closure of the neovagina. In one patient with a TRAMP flap, a severe shortening (2 cm) of the neovagina occurred. Five patients out of five who underwent a reconstruction with a TRAM flap had a stable length of the neovagina (6 to 12 cm) and no shrinkage in diameter occurred, even though a vaginal stent was not used. The conventional inferior TRAM flap with a skin paddle seems to better maintain a stable length of the neovagina than the TRAMP composite flap with peritoneum.


Processed foods: contributions to nutrition.
Both fresh and processed foods make up vital parts of the food supply. Processed food contributes to both food security (ensuring that sufficient food is available) and nutrition security (ensuring that food quality meets human nutrient needs). This ASN scientific statement focuses on one aspect of processed foods: their nutritional impacts. Specifically, this scientific statement 1) provides an introduction to how processed foods contribute to the health of populations, 2) analyzes the contribution of processed foods to "nutrients to encourage" and "constituents to limit" in the American diet as recommended by the Dietary Guidelines for Americans, 3) identifies the responsibilities of various stakeholders in improving the American diet, and 4) reviews emerging technologies and the research needed for a better understanding of the role of processed foods in a healthy diet. Analyses of the NHANES 2003-2008 show that processed foods provide both nutrients to encourage and constituents to limit as specified in the 2010 Dietary Guidelines for Americans. Of the nutrients to encourage, processed foods contributed 55% of dietary fiber, 48% of calcium, 43% of potassium, 34% of vitamin D, 64% of iron, 65% of folate, and 46% of vitamin B-12. Of the constituents to limit, processed foods contributed 57% of energy, 52% of saturated fat, 75% of added sugars, and 57% of sodium. Diets are more likely to meet food guidance recommendations if nutrient-dense foods, either processed or not, are selected. Nutrition and food science professionals, the food industry, and other stakeholders can help to improve the diets of Americans by providing a nutritious food supply that is safe, enjoyable, affordable, and sustainable by communicating effectively and accurately with each other and by working together to improve the overall knowledge of consumers.


Scaffold nucleoporins Nup188 and Nup192 share structural and functional properties with nuclear transport receptors.
Nucleocytoplasmic transport is mediated by nuclear pore complexes (NPCs) embedded in the nuclear envelope. About 30 different proteins (nucleoporins, nups) arrange around a central eightfold rotational axis to build the modular NPC. Nup188 and Nup192 are related and evolutionary conserved, large nucleoporins that are part of the NPC scaffold. Here we determine the structure of Nup188. The protein folds into an extended stack of helices where an N-terminal 130 kDa segment forms an intricate closed ring, while the C-terminal region is a more regular, superhelical structure. Overall, the structure has distant similarity with flexible S-shaped nuclear transport receptors (NTRs). Intriguingly, like NTRs, both Nup188 and Nup192 specifically bind FG-repeats and are able to translocate through NPCs by facilitated diffusion. This blurs the existing dogma of a clear distinction between stationary nups and soluble NTRs and suggests an evolutionary relationship between the NPC and the soluble nuclear transport machinery. DOI:http://dx.doi.org/10.7554/eLife.00745.001.


A simple and accurate model for prediction of cancer-specific mortality in patients treated with surgery for primary penile squamous cell carcinoma.
Cancer-specific mortality (CSM) of patients with primary penile squamous cell carcinoma (PPSCC) may be quite variable. Recently, a nomogram was developed to provide standardized and individualized mortality predictions. Unfortunately, it relies on a large number (n = 8) of specific variables that are unavailable in routine clinical practice. We attempted to develop a simpler prediction rule with at least equal accuracy in predicting CSM after surgical removal of PPSCC. The predictive rule was developed on a cohort of 856 patients identified in the 1988 to 2004 Surveillance, Epidemiology and End Results (SEER) database. The predictors consisted of age, race, SEER stage (localized versus regional versus metastatic), tumor grade, type of surgery (excisional biopsy, partial penectomy, and radical penectomy), and of lymph node status (pN0 versus pN1-3 versus pNx). A look-up table based on Cox regression model-derived coefficients was used for prediction of 5-year CSM. The predictive rule accuracy was tested using the Harrell's modification of the area under the receiver operating characteristics curve. SEER stage and histologic grade achieved independent predictor status and qualified for inclusion in the model. The model achieved 73.8% accuracy for prediction of CSM at 5 years after surgery. Both predictors achieved independent predictor status in competing risk regression models addressing CSM, where other cause mortality was controlled for. Despite equivalent accuracy, our predictive rule predicting 5-year CSM in patients with PPSCC is substantially less complex (2 versus 8 variables) than the previously published model.


Visual gait analysis: the development of a clinical assessment and scale.
To develop and evaluate a four-point scale visual gait assessment form, the Rivermead Visual Gait Assessment (RVGA), for clinical use with patients with neurological deficits. Preliminary clinical testing of reliability, validity and sensitivity to change. Patients were recruited from the Rivermead Rehabilitation Centre (RRC), a centre specializing in rehabilitation for patients with neurological disease. Ten inpatients were assessed by up to seven physiotherapists for the main reliability study, and eight different patients were also assessed by two raters one week apart. Twenty outpatients with multiple sclerosis (MS) who were receiving physiotherapy to improve their mobility and 27 inpatients with various neurological conditions were also assessed and the data used to examine validity, re iability and sensitivity to change. The other comparative measures used were walking time, stride length, step length asymmetry, balance and the Rivermead Mobility Index. Inter-rater reliability between multiple raters was reasonable both for the global scores from the gait assessment form (Kendall's coefficient of concordance; p < 0.001), and for individual items (complete agreement occurred on 63.8% of all observations). There was a significant correlation between the global RVGA score and the various criterion measures (r = 0.53-0.79; p < 0.001) and between change in the RVGA score and change in walking time in patients who received treatment (r = 0.68; p < 0.01). The RVGA provides the clinician with a clinical assessment of the quality of gait which may be used in conjunction with other measures to inform and monitor the value of physiotherapy treatment for people with MS and stroke, and possibly other neurological deficits.


Dose-effect relations and responsive regulation of treatment duration: the good enough level.
This study examined rates of improvement in psychotherapy as a function of the number of sessions attended. The clients (N=1,868; 73.1% female; 92.4% White; average age=40), who were seen for a variety of problems in routine primary care mental health practices, attended 1 to 12 sessions, had planned endings, and completed the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) at the beginning and end of their treatment. The percentage of clients achieving reliable and clinically significant improvement (RCSI) on the CORE-OM did not increase with number of sessions attended. Among clients who began treatment above the CORE-OM clinical cutoff (n=1,472), the RCSI rate ranged from 88% for clients who attended 1 session down to 62% for clients who attended 12 sessions (r=-.91). Previously reported negatively accelerating aggregate curves may reflect progressive ending of treatment by clients who had achieved a good enough level of improvement.


Disease Outcome of Ulcerative Colitis in an Era of Changing Treatment Strategies: Results from the Dutch Population-Based IBDSL Cohort.
In the past decades, treatment options and strategies for ulcerative colitis [UC] have radically changed. Whether these developments have altered the disease outcome at population level is yet unknown. Therefore, we evaluated the disease outcome of UC over the past two decades in the South-Limburg area of The Netherlands. In the Dutch population-based IBDSL cohort, three time cohorts were defined: cohort 1991-1997 [cohort A], cohort 1998-2005 [cohort B], and cohort 2006-2010 [cohort C]. The colectomy and hospitalisation rates were compared between cohorts by Kaplan-Meier survival analyses. Hazard ratios [HR] for early colectomy [within 6 months after diagnosis], late colectomy [beyond 6 months after diagnosis], and hospitalisation were calculated using Cox regression models. In total, 476 UC patients were included in cohort A, 587 patients in cohort B, and 598 patients in cohort C. Over time, an increase in the use of immunomodulators [8.1%, 22.8% and 21.7%, respectively, p < 0.01] and biological agents [0%, 4.3% and 10.6%, respectively, p < 0.01] was observed. The early colectomy rate decreased from 1.5% in cohort A to 0.5% in cohort B [HR 0.14; 95% confidence interval 0.04-0.47], with no further decrease in cohort C [0.3%, HR 0.98; 95% confidence interval 0.20-4.85]. Late colectomy rate remained unchanged over time [4.0% vs 5.2% vs 3.6%, respectively, p = 0.54]. Hospitalisation rate was also similar among cohorts [22.3% vs 19.5% vs 18.3%, respectively, p = 0.10]. Over the past two decades, a reduction in early colectomy rate was observed, with no further reduction in the most recent era. Late colectomy rate and hospitalisation rate remained unchanged over time.


The burden of respiratory syncytial virus bronchiolitis on a pediatric inpatient service.
Respiratory syncytial virus bronchiolitis is the single leading cause of pediatric admissions for infants in the first year of life, presenting regularly in epidemic proportions in the winter months and impacting in major way on pediatric inpatient services. To quantitate the burden of RSV disease on a pediatric service with the purpose of providing a database for proper health planning and resource allocation. We conducted a prospective 5 year study of documented RSV infections in a single pediatric service. RSV disease was confirmed by direct immunofluorescence testing of nasal swabs from all hospitalized cases of bronchiolitis. On average, 147 17 cases of RSV bronchiolitis were admitted annually in the November-March RSV season, representing 7%-9% of admissions and 10%-14% of hospital days. There was a consistent male preponderance of admissions (55-64%) and 15-23% of admissions were patients less than 1 month old. In peak months RSS ses accounted for as many of 40% of the hospitalized infants and was the leading cause of over-occupancy (up to 126%) in the pediatric ward during the winter. RSV infection is a major burden for pediatric inpatient services during the winter season. This recurrent and predictable "epidemic," which regularly leads to over-occupancy, requires increased manpower (nursing) and resources (beds, pulse oximeters) to facilitate proper care. Since this annual event is not a surprise nor an unexpected peak, but rather a cyclical predictable epidemiological phenomeon, proper planning and allocation of services are crucial.