Cognitive and motor functional activity in non-demented community-dwelling essential tremor cases.
Many investigators have observed mild cognitive deficits in essential tremor (ET), yet the functional significance of these deficits is unclear. Also, there are very few data in which functional activity in ET has been divided into cognitively based activities (remembering appointments) versus motor-based activities (writing cheques). The authors (1) compared functional level in ET cases versus controls, assessing functional activities that are cognitively based and those that are dependent upon both motor and cognitive factors, and (2) determined whether lower mini mental status test scores in ET cases have a functional correlate. In a population-based study of people > or = 65 years in central Spain (NEDICES), a 37-item version of the Mini-Mental State Examination (37-MMSE) and an 11-item version of the Pfeffer Functional Activities Questionnaire (FAQ) were administered to non-demented ET cases and controls. The FAQ was 55.5% higher (ie, lower function) in 208 cases than 3616 controls (2.8+/-4.8 vs 1.8+/-4.2, p<0.001). Cases reported more difficulty (ie, higher FAQ scores) with FAQ items that were cognitive measures as well as FAQ items that were cognitive-motor in nature. In cases, a lower 37-MMSE was associated with more difficulty on both cognitively based and cognitive-motor-based FAQ items (p<0.001). In this large, population-based study, ET cases reported more functional difficulty than controls, and this functional difficulty was present in both cognitive and cognitive-motor domains. Lower cognitive test scores were associated with more reported functional difficulty, indicating that lower cognitive test scores in ET, rather than being inconsequential, have a clear clinical-functional correlate.


A healthy bladder: a consensus statement.
A panel of experts in urology, urogynecology, nursing, and behavioral therapy convened in 2010 to discuss the importance of a healthy bladder on overall health. They determined that a consensus statement was necessary to raise awareness among the general public, healthcare providers, payors, and policymakers, with the goals of minimizing the impact of poor bladder health and stimulating primary prevention of bladder conditions. In this statement, 'healthy' bladder function is described, as well as internal and external factors that influence bladder health. It is suggested that primary prevention strategies should be aimed at providing education regarding normal lower urinary tract structures and functioning to the public, including patients and healthcare providers. This education may promote the achievement of optimal bladder health by increasing healthy bladder habits and behaviors, awareness of risk factors, healthcare seeking, and clinician engagement and reducing stigma and other barriers to treatment. Promoting optimal bladder health may reduce the personal, societal and economic impact of bladder conditions, including anxiety and depression and costs associated with conditions or diseases and their treatment. While adopting healthy bladder habits and behaviors and behaviors may improve or maintain bladder health, it is important to recognize that certain symptoms may indicate the presence of conditions that require medical attention; many bladder conditions are treatable with a range of options for most bladder conditions. Lastly, the authors propose clinical directives based on persuasive and convergent research to improve and maintain bladder health. The authors hope that this statement will lead to promotion and achievement of optimal bladder health, which may improve overall health and help minimize the effects of bladder conditions on the public, healthcare professionals, educators, employers, and payors. The advisors are in consensus regarding the recommendations for improving and maintaining bladder health presented herein.


A systematic review and meta-analysis on the influence of biological implant surface coatings on periimplant bone formation.
This systematic review and meta-analysis evaluated the influence of biological implant surface coatings on periimplant bone formation in comparison to an uncoated titanium reference surface in experimental large animal models. The analysis was structured according to the PRISMA criteriae. Of the1077 studies, 30 studies met the inclusion criteriae. Nineteen studies examined the bone implant contact (BIC) and were included in the meta-analysis. Overall, the mean increase in BIC for the test surfaces compared to the reference surfaces was 3.7 percentage points (pp) (95% CI -3.9-11.2, p = 0.339). Analyzing the increase in BIC for specific coated surfaces in comparison to uncoated reference surfaces, inorganic surface coatings showed a significant mean increase in BIC of 14.7 pp (95% CI 10.6-18.9, p < 0.01), extracellular matrix (ECM) surface coatings showed an increase of 10.0 pp (95% CI 4.4-15.6, p < 0.001), and peptide coatings showed a statistical trend with 7.1 pp BIC increase (95% CI -0.8-15.0, p = 0.08). In this review, no statistically significant difference could be found for growth factor surface coatings (observed difference -3.3 pp, 95% CI -16.5-9.9, p = 0.6). All analyses are exploratory in nature. The results show a statistically significant effect of inorganic and ECM coatings on periimplant bone formation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2898-2910, 2016.


Reoperative antireflux surgery for dysphagia.
Troublesome dysphagia is a common indication for redo antireflux surgery (Re-ARS). This study is aimed to analyze the efficacy of Re-ARS in resolving dysphagia and to identify risk factors for persistent or new-onset dysphagia after Re-ARS. A prospectively maintained database was retrospectively reviewed to identify patients after Re-ARS. Dysphagia severity was graded on a scale of 0 to 3 before and after Re-ARS based on responses to a standardized questionnaire. Patients reporting grade 2 or 3 symptoms were considered to have significant dysphagia. Satisfaction was graded using a 10-point analog scale. Between December 2003 and July 2008, 106 patients underwent Re-ARS. Significant preoperative dysphagia was reported by 54 patients, and impaired esophageal motility was noted in 31 patients. Remedial surgery included redo fundoplication (n = 87), Collis gastroplasty with redo fundoplication (n = 16), and takedown of the fundoplication or hiatal closure alone (n = 3). At least 1 year follow-up period (mean 21.8 months) was available for 92 patients. For patients with significant preoperative dysphagia (n = 46), the mean symptom score declined from 2.35 to 0.78 (p < 0.0001). Persistent dysphagia was reported by 13 patients and new-onset dysphagia by 4 patients. No patients reported grade 3 dysphagia after Re-ARS. Dilations were used to treat 11 patients. Multivariate logistic regression analysis identified Collis gastroplasty (p = 0.03; adjusted odds ratio [OR], 5.74) and preoperative dysphagia (p = 0.01; adjusted OR, 6.80) as risk factors for significant postoperative dysphagia. The overall satisfaction score was 8.3, but certain subsets had significantly lower satisfaction scores. These subsets included patients with esophageal dysmotility (7.1; p = 0.04), patients who required Collis gastroplasty (7.0; p = 0.09), and patients with esophageal dysmotility who required Collis gastroplasty (5.0; p < 0.01). Although dysphagia is a common symptom among patients requiring Re-ARS, intervention provides a significant benefit. Patients with preoperative dysphagia, especially those requiring Collis gastroplasty, are at increased risk for persistent dysphagia and decreased satisfaction after Re-ARS.


Providing understanding of the behavior of feedforward neural networks.
The advent of artificial neural networks has stirred the imagination of many in the field of knowledge acquisition. There is an expectation that neural networks will play an important role in automating knowledge acquisition and encoding, however, the problem solving knowledge of a neural network is represented at a subsymbolic level and hence is very difficult for a human user to comprehend. One way to provide an understanding of the behavior of neural networks is to extract their problem solving knowledge in terms of rules that can be provided to users. Several papers which propose extracting rules from feedforward neural networks can be found in the literature, however, these approaches can only deal with networks with binary inputs. Furthermore, certain approaches lack theoretical support and their usefulness and effectiveness are debatable. Upon carefully analyzing these approaches, we propose a method to extract fuzzy rules from networks with continuous-valued inputs. The method was tested using a real-life problem (decision-making by pilots involving combat situations) and found to be effective.


A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring.
Epidemiological and animal studies suggest that diet-induced epigenetic modifications in early life can contribute to development of the metabolic syndrome in adulthood. We previously reported features of the metabolic syndrome in adult offspring of rats fed a diet rich in animal fat during pregnancy and suckling. We now report a study to compare the relative effects of high-fat feeding during 1) pregnancy and 2) the suckling period in the development of these disorders. As observed previously, 6-mo-old female offspring of fat-fed dams suckled by the same fat-fed dams (OHF) demonstrated raised blood pressure, despite being fed a balanced diet from weaning. Female offspring of fat-fed dams "cross fostered" to dams consuming a control diet during suckling (OHF/C) demonstrated raised blood pressure compared with controls (OC) [systolic blood pressure (SBP; mmHg) means +/- SE: OHF/C, 132.5 +/- 3.0, n = 6 vs. OC, 119.0 +/- 3.8, n = 7, P < 0.05]. Female offspring of controls cross fostered to dams consuming the fat diet (OC/HF) were also hypertensive [SBP (mmHg) 131.0 +/- 2.5 mmHg, n = 6 vs. OC, P < 0.05]. Endothelium-dependent relaxation (EDR) of male and female OHF and OHF/C mesenteric small arteries was similar and blunted compared with OC (P < 0.001). OC/HF arteries showed profoundly impaired EDR (OC/HF vs. OHF, P < 0.001). OHF/C and OC/HF demonstrated hyperinsulinemia and increased adiposity. Features of the metabolic syndrome in adult offspring of fat-fed rats can be acquired both antenatally and during suckling. However, exposure during pregnancy confers adaptive protection against endothelial dysfunction induced by maternal fat feeding during suckling.


Pollination networks of oil-flowers: a tiny world within the smallest of all worlds.
1. In the Neotropics, most plants depend on animals for pollination. Solitary bees are the most important vectors, and among them members of the tribe Centridini depend on oil from flowers (mainly Malpighiaceae) to feed their larvae. This specialized relationship within 'the smallest of all worlds' (a whole pollination network) could result in a 'tiny world' different from the whole system. This 'tiny world' would have higher nestedness, shorter path lengths, lower modularity and higher resilience if compared with the whole pollination network. 2. In the present study, we contrasted a network of oil-flowers and their visitors from a Brazilian steppe ('caatinga') to whole pollination networks from all over the world. 3. A network approach was used to measure network structure and, finally, to test fragility. The oil-flower network studied was more nested (NODF = 0.84, N = 0.96) than all of the whole pollination networks studied. Average path lengths in the two-mode network were shorter (one node, both for bee and plant one-mode network projections) and modularity was lower (M = 0.22 and four modules) than in all of the whole pollination networks. Extinctions had no or small effects on the network structure, with an average change in nestedness smaller than 2% in most of the cases studied; and only two species caused coextinctions. The higher the degree of the removed species, the stronger the effect and the higher the probability of a decrease in nestedness. 4. We conclude that the oil-flower subweb is more cohesive and resilient than whole pollination networks. Therefore, the Malpighiaceae have a robust pollination service in the Neotropics. Our findings reinforce the hypothesis that each ecological service is in fact a mosaic of different subservices with a hierarchical structure ('webs within webs').


High spatial resolution analysis of the distribution of sulfate reduction and sulfide oxidation in hypoxic sediment in a eutrophic estuary.
Bottom hypoxia and consequential hydrogen sulfide (H2S) release from sediment in eutrophic estuaries is a major global environmental issue. We investigated dissolved oxygen, pH and H2S concentration profiles with microsensors and by sectioning sediment cores followed by colorimetric analysis. The results of these analyses were then compared with the physicochemical properties of the bottom water and sediment samples to determine their relationships with H2S production in sediment. High organic matter and fine particle composition of the sediment reduced the oxidation-reduction potential, stimulating H2S production. Use of a microsensor enabled measurement of H2S concentration profiles with submillimetre resolution, whereas the conventional sediment-sectioning method gave H2S measurements with a spatial resolution of 10 mm. Furthermore, microsensor measurements revealed H2S consumption occurring at the sediment surface in both the microbial mat and the sediment anoxic layer, which were not observed with sectioning. This H2S consumption prevented H2S release into the overlying water. However, the microsensor measurements had the potential to underestimate H2S concentrations. We propose that a combination of several techniques to measure microbial activity and determine its relationships with physicochemical properties of the sediment is essential to understanding the sulfur cycle under hypoxic conditions in eutrophic sediments.


Different angiogenesis modes and endothelial responses in implanted porous biomaterials.
An in vivo experimental model based on implanting porous biomaterials to study angiogenesis was proposed. In the implanted porous polyvinyl alcohol, three major modes of angiogenesis, sprouting, intussusception and splitting, were found. By electron microscopy and three-dimensional simulation of the angiogenic vessels, we investigated the morphological characteristics of the three modes and paid special attention to the initial morphological difference between intussusception and splitting, and it was confirmed that the endothelial abluminal invagination and intraluminal protrusion are pre-representations of intussusception and splitting, respectively. Based on immunohistochemical analysis of HIF-1α, VEGF and Flt-1 expressions, it was demonstrated that the dominant mode of angiogenesis is related to the local hypoxic condition, and that there is difference in the response of endothelial cells to hypoxia-induced VEGF between sprouting and splitting. Specifically, in the biomaterials implanted for 3 days, the higher expression and gradient of VEGF induced by severe hypoxia in the avascular area caused sprouting of the peripheral capillaries, and in the biomaterial implanted for 9 days, with moderate hypoxia, splitting became a dominant mode. Whether on day 3 or day 9, Flt-1 expression in sprouting endothelia was significantly higher than that in splitting endothelia, which indicates that sprouting is caused by the strong response of endothelial cells to VEGF, while splitting is associated with their weaker response. As a typical experimental example, these results show the effectiveness of the porous biomaterial implantation model for studying angiogenesis, which is expected to become a new general model.


An evaluation of the International Monetary Fund's claims about public health.
The International Monetary Fund's recent claims concerning its impact on public health are evaluated against available data. First, the IMF claims that health spending either does not change or increases with IMF-supported programs, but there is substantial evidence to the contrary. Second, the IMF claims to have relaxed strict spending requirements in response to the 2008-9 financial crisis, but there is no evidence supporting this claim, and some limited evidence from the Center for Economic Policy Research contradicting it. Third, the IMF states that wage ceilings on public health are no longer part of its explicit conditionalities to poor countries, as governments can choose how to achieve public spending targets; but in practice, ministers are left with few viable alternatives than to reduce health budgets to achieve specific IMF-mandated targets, so the result effectively preserves former policy. Fourth, the IMF's claim that it has increased aid to poor countries also seems to be contradicted by its policies of diverting aid to reserves, as well as evidence that a very small fraction of the Fund's new lending in response to the financial crisis has reached poor countries. Finally, the IMF's claim that it follows public health standards in tobacco control contrasts with its existing policies, which fail to follow the guidelines recommended by the World Bank and World Health Organization. The authors recommend that the IMF (1) become more transparent in its policies, practices, and data to allow improved independent evaluations of its impact on public health (including Health Impact Assessment) and (2) review considerable public health evidence indicating a negative association between its current policies and public health outcomes.


Bootstrapping of gene-expression data improves and controls the false discovery rate of differentially expressed genes.
The ordinary-, penalized-, and bootstrap t-test, least squares and best linear unbiased prediction were compared for their false discovery rates (FDR), i.e. the fraction of falsely discovered genes, which was empirically estimated in a duplicate of the data set. The bootstrap-t-test yielded up to 80% lower FDRs than the alternative statistics, and its FDR was always as good as or better than any of the alternatives. Generally, the predicted FDR from the bootstrapped P-values agreed well with their empirical estimates, except when the number of mRNA samples is smaller than 16. In a cancer data set, the bootstrap-t-test discovered 200 differentially regulated genes at a FDR of 2.6%, and in a knock-out gene expression experiment 10 genes were discovered at a FDR of 3.2%. It is argued that, in the case of microarray data, control of the FDR takes sufficient account of the multiple testing, whilst being less stringent than Bonferoni-type multiple testing corrections. Extensions of the bootstrap simulations to more complicated test-statistics are discussed.


The energy divide: Integrating energy transitions, regional inequalities and poverty trends in the European Union.
Energy poverty can be understood as the inability of a household to secure a socially and materially necessitated level of energy services in the home. While the condition is widespread across Europe, its spatial and social distribution is highly uneven. In this paper, the existence of a geographical energy poverty divide in the European Union (EU) provides a starting point for conceptualizing and exploring the relationship between energy transitions - commonly described as wide-ranging processes of socio-technical change - and existing patterns of regional economic inequality. We have undertaken a comprehensive analysis of spatial and temporal trends in the national-scale patterns of energy poverty, as well as gas and electricity prices. The results of our work indicate that the classic economic development distinction between the core and periphery also holds true in the case of energy poverty, as the incidence of this phenomenon is significantly higher in Southern and Eastern European EU Member States. The paper thus aims to provide the building blocks for a novel theoretical integration of questions of path-dependency, uneven development and material deprivation in existing interpretations of energy transitions.


Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst.
The transcription factor Oct4 is required in vitro for establishment and maintenance of embryonic stem cells and for reprogramming somatic cells to pluripotency. In vivo, it prevents the ectopic differentiation of early embryos into trophoblast. Here, we further explore the role of Oct4 in blastocyst formation and specification of epiblast versus primitive endoderm lineages using conditional genetic deletion. Experiments involving mouse embryos deficient for both maternal and zygotic Oct4 suggest that it is dispensable for zygote formation, early cleavage and activation of Nanog expression. Nanog protein is significantly elevated in the presumptive inner cell mass of Oct4 null embryos, suggesting an unexpected role for Oct4 in attenuating the level of Nanog, which might be significant for priming differentiation during epiblast maturation. Induced deletion of Oct4 during the morula to blastocyst transition disrupts the ability of inner cell mass cells to adopt lineage-specific identity and acquire the molecular profile characteristic of either epiblast or primitive endoderm. Sox17, a marker of primitive endoderm, is not detected following prolonged culture of such embryos, but can be rescued by provision of exogenous FGF4. Interestingly, functional primitive endoderm can be rescued in Oct4-deficient embryos in embryonic stem cell complementation assays, but only if the host embryos are at the pre-blastocyst stage. We conclude that cell fate decisions within the inner cell mass are dependent upon Oct4 and that Oct4 is not cell-autonomously required for the differentiation of primitive endoderm derivatives, as long as an appropriate developmental environment is established.


Impaired central mediation of the arterial baroreflex in chronic renal hypertension.
After 6 wk of renal hypertension in rabbits, the arterial baroreflex control of heart rate (HR) is impaired but the baroreflex control of lumbar sympathetic nerve activity ( LSNA ) is preserved. This selective impairment may reflect a predominant abnormality in the baroreceptors. In this study, we tested the hypothesis that renal hypertension of longer duration may impair baroreflex control of LSNA through a defect in the central nervous system mediation of the reflex. Four months after induction of renal hypertension, baroreflex responses were determined during increases in arterial pressure with intravenous phenylephrine or decreases in pressure with vena caval occlusion under chloralose-urethan anesthesia. Reflex control of LSNA and HR was impaired markedly in hypertensive rabbits. Reflex inhibition of LSNA and HR in response to afferent electrical stimulation of the left aortic depressor nerve (all arterial baroreceptor afferents cut) was attenuated in hypertensive in contrast to normotensive rabbits. This attenuation was noted when the medullated fibers only were stimulated or when both medullated and nonmedullated fibers were stimulated. We conclude that baroreflex control of LSNA that is preserved after 6 wk of hypertension is impaired after 4 mo of hypertension. The impairment reflects an abnormality in the central nervous system mediation of the reflex.


Age-related difference in susceptibility of Apc(Min/+) mice towards the chemopreventive efficacy of dietary aspirin and curcumin.
The nonsteroidal anti-inflammatory drug aspirin and the spice curcumin retard adenoma formation when administered long-term to Apc(Min/+) mice, a model of human familial adenomatous polyposis coli. Both agents interfere with cyclooxygenase activity. When aspirin is administered to Apc(Min/+) mice only postweaning, but not before, it is inefficacious, while curcumin given postweaning is active. Here the hypothesis was tested that dietary aspirin (0.05%) or curcumin (0.2%) prevent or delay adenoma formation in offsprings when administered to Apc(Min/+) mothers and up to the end of weaning, but not afterwards. Whereas curcumin was without effect when administered in this way, aspirin reduced numbers of intestinal adenomas by 21%. When aspirin given up to the end of weaning was combined with curcumin administered from the end of weaning for the rest of the animals' lifetime, intestinal adenoma numbers were reduced by 38%. The combination was not superior to intervention postweaning with curcumin alone. These results show that aspirin exerts chemopreventive activity in the Apc(Min/+) mouse during tumour initiation/early promotion, while curcumin is efficacious when given at a later stage of carcinogenic progression. Thus, the results suggest that in this mouse model aspirin and curcumin act during different 'windows' of neoplastic development.


Timing and original features of flagellum assembly in trypanosomes during development in the tsetse fly.
Trypanosoma brucei exhibits a complex life-cycle alternating between tsetse flies and mammalian hosts. When parasites infect the fly, cells differentiate to adapt to life in various tissues, which is accompanied by drastic morphological and biochemical modifications especially in the proventriculus. This key step represents a bottleneck for salivary gland infection. Here, we monitored flagellum assembly in trypanosomes during differentiation from the trypomastigote to the epimastigote stage, i.e. when the nucleus migrates to the posterior end of the cell, by using three-dimensional electron microscopy (focused ion beam scanning electron microscopy, FIB-SEM) and immunofluorescence assays. The combination of light and electron microscopy approaches provided structural and molecular evidence that the new flagellum is assembled while the nucleus migrates towards the posterior region of the body. Two major differences with well-known procyclic cells are reported. First, growth of the new flagellum begins when the associated basal body is found in a posterior position relative to the mature flagellum. Secondly, the new flagellum acquires its own flagellar pocket before rotating on the left side of the anterior-posterior axis. FIB-SEM revealed the presence of a structure connecting the new and mature flagellum and serial sectioning confirmed morphological similarities with the flagella connector of procyclic cells. We discuss the potential function of the flagella connector in trypanosomes from the proventriculus. These findings show that T. brucei finely modulates its cytoskeletal components to generate highly variable morphologies.


Effects of delta9-tetrahydrocannabinol and cannabinol in man.
The interaction of delta9-tetrahydrocannabinol (delta9-THC) and cannabinol (CBN) was studied in man. Five male volunteers were given placebo, 50 mg CBN, 25 mg delta9-THC, 12.5 mg delta9-THC + 25 mg CBN, and 25 mg delta9-THC + 50 mg CBN (orally). Administrations were spaced 1 week apart. With physiological measures, delta9-THC produced an increase in heart rate while CBN did not. When combined, no change of the delta9-THC effect occurred. No changes occurred on the electrocardiogram, blood pressure, or body temperature. With psychophysical measures no changes occurred in pain thresholds or skin sensitivity as a function of drug treatment. In time estimates of the passage of 1 minute, delta9-THC alone produced underestimates of the passage of 1 minute and CBN alone had no effect. In combination the two drugs had a tendency to produce significant overestimates and underestimates of the passage of 1 minute. On a 66-item adjective-pair drug reaction scale, the volunteers reported feeling drugged, drunk, dizzy, and drowsy under the delta9-THC condition, but not under the CBN condition. With combined drug treatment, volunteers reported feeling more drugged, drunk, dizzy, and drowsy than under the delta9-THC condition alone. None of the drug treatments produced significant changes on other items which included items on perception, emotion, cognition and sociability. It appears that CBN increases the effect of delta9-THC on some aspects of physiological and psychological processes, but that these effects are small and cannot account for the greater potency which has been reported when plant material is used.


Mutagenic bypass of the butadiene-derived 2'-deoxyuridine adducts by polymerases eta and zeta.
Butadiene is a ubiquitous environmental chemical carcinogen that when activated to its monoepoxide intermediate can react with the N3 position of cytosine, resulting in two stereoisomeric adducted bases that rapidly deaminate to N3 2'-deoxyuridine lesions. We have previously shown that replication of DNAs containing these adducts through mammalian cells resulted in approximately 97% mutagenicity, predominantly C to T transitions. Since replicative DNA polymerases were blocked by these lesions in vitro, translesional polymerases were assessed for their ability to bypass these adducts. While polymerases iota, kappa and zeta were significantly blocked one nucleotide prior to the lesion, pol eta incorporated nucleotides opposite the adducts with a preference for insertion of a G or A. Following polymerase dissociation and reassociation, pol eta was also able to extend primers with mispaired termini opposite the lesions, with extensions from the A and T mismatched primer termini being the most efficient. Pol zeta was also able to extend primers containing all mismatched nucleotides opposite the lesions, with the most efficient extension occurring off of the A mismatched primer.


Patients' satisfaction with anatomic polyurethane implants.
This paper presents patients satisfaction using anatomical polyurethane breast implants. We performed surgery on 525 patients, 370 of which were primary and 155 were secondary to various causes such as capsular contracture, ruptured implants, volume changes, and incorrect positioning of the implant. The advantages of silicone polyurethane covers shown high level of patient satisfaction, low incidence of capsular contracture, and absence of implant rotation, and late seroma.


Cardiac injuries in car occupants in fatal motor vehicle collisions--an autopsy-based study.
Motor vehicle accidents contribute widely to population morbidity and mortality around the world, and cardiac injuries are a major factor determining outcome. Autopsy reports from 380 motor vehicle occupants who died in motor vehicle crashes in Adelaide, Australia, and Hamburg, Germany, over a 6-year period were reviewed, analysing the presence and type of cardiac injuries and their correlation with factors such as crash type, presence of seatbelt/airbag and vehicle speed as well as with the presence of other injuries which might predict the presence of cardiac injuries in a clinical setting. 21.1% had cardiac injuries identified macroscopically autopsy or histology. Cardiac injuries were the only cause of death or contributed to a fatal outcome in 76% of these cases. Sternal fractures and left-sided serial rib fractures were predictive of cardiac injury.


Nutrient deficiencies before and after sleeve gastrectomy.
Obesity is associated with nutritional deficiencies. Bariatric surgery could worsen these deficiencies. Fewer nutritional deficiencies would be seen after sleeve gastrectomy compared to the Roux-en-Y gastric bypass, but sleeve gastrectomy would also cause further deterioration of the deficiencies. The aim of this study was to determine the amount of pre-operative nutrient deficiencies in sleeve gastrectomy patients and assess the evolution of the nutritional status during the first post-operative year. Four hundred seven sleeve gastrectomy patients were assigned to a standardized follow-up program. Data of interest were weight loss, pre-operative nutrient status and evolution of nutrient deficiencies during the first post-operative year. Deficiencies were supplemented when found. Two hundred patients completed blood withdrawal pre-operatively and in the first post-operative year. pre-operatively, 5 % of the patients were anemic, 7 % had low serum ferritin and 24 % had low folic acid. Hypovitaminosis D was present in 81 %. Vitamin A had excessive levels in 72 %. One year post-operatively, mean excess weight loss was 70 %. Anemia was found in 6 %. Low-ferritin levels were found in 8 % of the patients. Folate deficiency decreased significantly and hypovitaminosis D was still found in 36 %. In this study, a considerable amount of patients suffered from a deficient micronutrient status pre-operatively. One year after surgery, micronutrient deficiencies persisted or were found de novo in a considerable amount of patients, despite significant weight loss and supplementation. Significant reductions were seen only for folate and vitamin D.


Changes in serum adipokine levels during pioglitazone treatment for nonalcoholic steatohepatitis: relationship to histological improvement.
Thiazolidinedione (TZD) therapy improves liver histology in nonalcoholic steatohepatitis (NASH) through a mechanism possibly related to its insulin-sensitizing or anti-inflammatory activity. This study was conducted to assess changes in serum levels of selected adipokines and proinflammatory cytokines and to relate these changes to the improved liver histology resulting from pioglitazone therapy for NASH. Serum samples from 18 patients with NASH obtained at day 0 and week 48 of therapy during an open-label study of pioglitazone were tested for adiponectin, leptin, interleukin (IL)-1a, IL-6, and tumor necrosis factor (TNF)-alpha levels. Paired liver biopsy specimens were scored (0-4) for steatosis, parenchymal inflammation, cell injury, and fibrosis. Adiponectin levels increased from 3.7 to 10.3 mug/mL at week 48 (P < .01); the levels of the other cytokines were unchanged: TNF-alpha, 9.1 vs 8.8 pg/mL; IL-1a, 3.9 vs 3.4 pg/mL; IL-6, 19.4 vs 13.4 pg/mL; and leptin, 24.8 vs 29.6 ng/mL (P > .05 for all). Pioglitazone therapy was associated with improvements in steatosis (2.5 vs 1.0), parenchymal inflammation (3.3 vs 2.1), cell injury (2.2 vs 0.9), and fibrosis (2.0 vs 1.4). The change in adiponectin level was associated with the improvement in steatosis (P = .03) as well as in a summary NASH activity index score (P = .01). Changes in IL-1, IL-6, TNF-alpha, and leptin levels did not correlate with improvements in the histological features. Improvements in liver histology during TZD therapy may be modulated by an adiponectin-mediated effect on insulin sensitivity and hepatic fatty acid metabolism rather than by changes in proinflammatory cytokines.


New Preparative Approaches for Micro and Nano Drug Delivery Carriers.
The full success of pharmacological therapies is strongly depending on the use of suitable, efficient and smart drug delivery systems (DDSs). Thus DDSs development is one of the main challenges in pharmaceutical industry both to achieve tailored carrier systems based on drug features and to promote manufacturing innovations to reduce energetic resources, emissions, wastes and risks. Main functions of an ideal DDS are: to protect loaded active molecules from degradation in physiological environments; to deliver them in a controlled manner and towards specific organs or tissues, to allow the maintenance of drug concentration within therapeutic window. Smart features, such as those able to induce active molecule release upon the occurrence of specific physiological stimuli, are also desirable. Under the manufacturing point of view, the current industrial scenery is obliged to respond to the increasing market requirements and to the mandatory rules in sustainable productions such as raw material and energy savings. In this work a general framework on drug delivery systems preparation techniques is presented. In particular two sections on innovation in preparative approaches carried out are detailed. These latter involve the use of microwave and ultrasonic energy applied in the production of polymeric and lipidic delivery systems on micro- and nanometric scale. The novelties of these preparative approaches are emphasized and examples of developed drug delivery carriers, loaded with vitamins and drug mimicking siRNA, are shown.


Soy as an endocrine disruptor: cause for caution?
Endocrine disrupting compounds (EDCs) alter the function of the endocrine system and consequently cause adverse health effects. Phytoestrogens, natural plant compounds abundantly found in soy and soy products, behave as weak estrogen mimics or as antiestrogens. They are considered to be EDCs, and have some beneficial effects on health, including reducing the risk of breast cancer and improving metabolic parameters. However, the supporting evidence that consumption of phytoestrogens is beneficial is indirect and inconsistent. Lifetime exposure to estrogenic substances, especially during critical periods of development, has been associated with formation of malignancies and several anomalies of the reproductive systems. Phytoestrogen consumption in infants, through soy-based formulas, is of particular concern. Prospective epidemiological studies for the evaluation of the effect of phytoestrogens alone, and in combination with other estrogenic chemicals, are lacking, yet possible adverse effects should not be taken lightly.


Total energy expenditure in captive capuchins (Sapajus apella).
Primates have markedly lower total energy expenditure (TEE; kcal/day) than other placental mammals, expending approximately 50% less energy for their mass than non-primate eutherians. However, little is known regarding interspecific variation of energy expenditure within platyrrhine primates. We investigated TEE in captive tufted capuchins (Sapajus apella, n = 8, ages 7-36), a frugivorous platyrrhine, to compare TEE with other placental mammals and primates. We tested the hypothesis that large-brained capuchins would exhibit greater TEE than other platyrrhines that are less encephalized. We used the doubly labeled water (DLW) method to measure TEE over 7-11 days, during which physical activity data were recorded via focal observation. TEE was strongly correlated with fat free mass, but sex, age, and rates of walking and climbing were not correlated with variation in TEE in multivariate analyses controlling for fat free mass. We found evidence that daily physical activity was negatively correlated with body fat percentage. Capuchin TEE was similar (P = 0.67) to other, less encephalized platyrrhines (Callithrix and Alouatta) and 54% lower than other placental mammals, in analyses controlling for body mass. These results suggest that brain size and physical activity do not necessarily influence variation in daily energy expenditure across primate species.


Cyclodiene insecticide, DDE, DDT, arsenic, and mercury contamination of big brown bats (Eptesicus fuscus) foraging at a Colorado Superfund site.
Rocky Mountain Arsenal (RMA) National Wildlife Area, near Denver, Colorado, is a Superfund site contaminated by past military and industrial uses, including pesticide manufacturing. From an ecosystem standpoint, the most critical contaminants at RMA are certain cyclodiene insecticides and metabolites, p,p'-DDE, p,p'-DDT, arsenic, and mercury. Bats are important ecosystem components that can be impacted by persistent contaminants because of their position in the food chain and their potential longevity and thus duration of exposure. Big brown bats (Eptesicus fuscus) were captured (n = 51) while foraging at RMA in the summers of 1997 and 1998 for determination of concentrations of contaminants of concern in carcasses, brains, and stomach contents. Adult females (n = 15) were also tracked by radiotelemetry to determine locations of nearest maternity roosts for sampling of guano for contaminant analysis and inspection for potential contaminant-induced mortality. Bats captured while foraging at RMA had measurable quantities of dieldrin and DDE in masticated insect samples from stomach contents and significantly higher concentrations of dieldrin, DDE, DDT, and mercury (juveniles) in carcasses than big brown bats (n = 26) sampled at a reference area 80 km to the north. Concentrations of dieldrin and DDE in brains of bats captured while foraging at RMA were also greater than in bats from the reference area, but not high enough to suggest mortality. Maximum concentrations of DDE, DDT, and cyclodienes in brains of big brown bats were found in adult males from RMA. Guano from the two closest known roosts had significantly higher concentrations of dieldrin, DDE, and mercury than guano from two roosts at the reference area. Dieldrin concentrations in carcasses of bats from RMA were highest in juveniles, followed by adult males and adult females. DDE concentrations in carcasses were lowest in adult females at both sites and highest in adult males at RMA. No contaminant-related mortality was obvious at the small maternity colonies near RMA. Big brown bats show higher contamination than most other mammals previously sampled at this site. Concentrations and proportions of samples with detectable residues of dieldrin in carcasses of big brown bats from RMA were similar to or exceeded reports for this species from elsewhere in the United States some 25 years ago, prior to or just following restrictions on use of this compound.


Power Up for Health: Pilot Study Outcomes of a Diabetes Prevention Program for Men from Disadvantaged Neighborhoods.
There is a significant evidence base for the Diabetes Prevention Program, a lifestyle intervention to prevent onset of type 2 diabetes among high-risk individuals; however, translation of this intervention for men has been challenging. This report presents outcomes of the pilot study of an adapted 16-week diabetes prevention program entitled " Power Up for Health." The study goal was to better engage men of color with prediabetes from disadvantaged neighborhoods of New York City. It was implemented at five different recreation centers located in predominantly low-income neighborhoods across New York City. The curriculum was facilitated by male lifestyle coaches only; one group was conducted in Spanish. Primary outcome was weight loss from baseline to 16 weeks. Other measures included lifestyle activities, depressive symptoms, and self-reported health status. Men ( N = 47) were screened by telephone. Of the 29 eligible men who began the program, 25 attended at least 4 sessions (52% non-Latino Black, 32% Latino, mean age 51.7 ± SD 9.9 years, mean body mass index 35 ± SD 6.9 kg/m2). End of program outcomes ( n = 23) varied by site and included a mean weight loss of 3.8% (9.7 lbs); 3 of the 5 sites had a mean weight loss of 5.6%, meeting the national goal of 5%-7%. Men ( n = 23) attended a mean of 11.6 of 16 sessions. Improvement in depressive symptoms, healthy eating and exercise, and health status were also seen. While recruitment was challenging with many lessons learned, the adapted men's diabetes prevention program shows promise of success for participants and their coaches.


Aging and Systemic Lupus Erythematosus - Immunosenescence and Beyond.
The lifespan of humans has increased drastically over the last decades; considerable effort has been applied to delineate the mechanisms behind aging in order to find strategies for longevity. As the benefits of the gained knowledge might extend to diseases, where accelerated aging is suspected, the role of aging in the systemic autoimmune disease Systemic Lupus Erythematosus (SLE) is of particular interest. In this review the immunological similarities of SLE and aging are analyzed on three levels: the clinical, the cellular and the molecular, in order to find possible common pathological mechanisms. Common clinical features (e.g. increased infection rates, incidence of tumors and cardiovascular diseases) of SLE-patients and elderly individuals and shared characteristics of immuno-senescence and SLE are identified. These similarities are strongest in the adaptive immune system, where terminally differentiated T-cells and an immunological risk profile are found in both conditions. Also the aging innate immune system has overlapping features with SLE, exemplified by a generally lowered phagocytic capacity. However, great disparities between the aging immune system and SLE become apparent on a closer look, affecting numbers, phenotype and function of most immune cells, ranging from NETosis by granulocytes to the mechanisms underlying abnormal IL-2 production by T-cells. On the molecular level, also the increased presence of aging mechanisms like telomere attrition, DNA damage, autophagy and the characteristics of the mTOR pathway in SLE, possibly contributing to the shared changes on the cellular and clinical level are elaborated. The possible implications thereof concern existing (hydroxychloroquine, rapamycine, Glucocorticoids) as well as novel therapeutic strategies targeting more specific pathways which might rapidly reach the clinical arena. Overall a differential view on the similarities of aging and SLE and possible consequences is presented.


Protective Effect of Korean Red Ginseng against Aflatoxin B1-Induced Hepatotoxicity in Rat.
Korean red ginseng (KRG), the steamed root of Panax ginseng Meyer, has a variety of biological properties, including anti-inflammatory, antioxidant and anticancer effects. Aflatoxin B1 (AFB1) produced by the Aspergillus spp. causes acute hepatotoxicity by lipid peroxidation and oxidative DNA damage, and induces liver carcinoma in humans and laboratory animals. This study was performed to examine the protective effects of KRG against hepatotoxicity induced by AFB1 using liver-specific serum marker analysis, histopathology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. In addition, to elucidate the possible mechanism of hepatoprotective effects, superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde were analyzed. Rats were treated with 250 mg/kg of KRG (KRG group) or saline (AFB1 group) for 4 weeks and then received 150 μg/kg of AFB1 intraperitoneally for 3 days. Rats were sacrificed at 12 h, 24 h, 48 h, 72 h, or 1 wk after AFB1 treatment. In the KRG pre-treatment group, serum alanine aminotransferase, aspartate aminotransferase, and malondialdehyde levels were low, but superoxide dismutase, catalase, and glutathione peroxidase activities were high as compared to the AFB1 alone group. Histopathologically, AFB1 treatment induced necrosis and apoptosis in hepatocytes, and led to inflammatory cells infiltration in the liver. KRG pre-treatment ameliorated these changes. These results indicate that KRG may have protective effects against hepatotoxicity induced by AFB1 that involve the antioxidant properties of KRG.


Treatment with novel oral anticoagulants: indications, efficacy and risks.
To summarize data relevant to novel oral anticoagulants (nOACs), mainly apixaban, dabigatran and rivaroxaban, as alternatives to vitamin K antagonists (VKAs). RE-LY was the first contemporaneous study to compare a nOAC, dabigatran, with dose-adjusted warfarin, for prevention of stroke and systemic embolism in atrial fibrillation. Since then multiple studies have compared nOACs to warfarin for acute (RE-COVER, RECOVER-II, EINSTEIN-DVT and EINSTEIN-PE) and extended treatment of venous thromboembolism (VTE) (AMPLIFY-EXT, RE-MEDY and RE-SONATE). Additional studies have examined stroke prevention in atrial fibrillation (ARISTOTLE and ROCKET-AF). We do not examine, in depth, use of nOACs in coronary artery disease. nOACs are an acceptable alternative to VKAs in certain situations - these are at least as effective as warfarin for secondary prevention of VTE and for prevention of stroke and systemic embolism in patients with atrial fibrillation. These compare favorably with warfarin with respect to their rate of fatal and major bleeding. However, special attention should be given when using these drugs in certain patient populations, in particular in patients with renal insufficiency, those receiving additional antithrombotic therapy, those with questionable compliance, patients of child bearing potential and those with a high risk of gastrointestinal bleeding.


Plasma membrane-located purine nucleotide transport proteins are key components for host exploitation by microsporidian intracellular parasites.
Microsporidia are obligate intracellular parasites of most animal groups including humans, but despite their significant economic and medical importance there are major gaps in our understanding of how they exploit infected host cells. We have investigated the evolution, cellular locations and substrate specificities of a family of nucleotide transport (NTT) proteins from Trachipleistophora hominis, a microsporidian isolated from an HIV/AIDS patient. Transport proteins are critical to microsporidian success because they compensate for the dramatic loss of metabolic pathways that is a hallmark of the group. Our data demonstrate that the use of plasma membrane-located nucleotide transport proteins (NTT) is a key strategy adopted by microsporidians to exploit host cells. Acquisition of an ancestral transporter gene at the base of the microsporidian radiation was followed by lineage-specific events of gene duplication, which in the case of T. hominis has generated four paralogous NTT transporters. All four T. hominis NTT proteins are located predominantly to the plasma membrane of replicating intracellular cells where they can mediate transport at the host-parasite interface. In contrast to published data for Encephalitozoon cuniculi, we found no evidence for the location for any of the T. hominis NTT transporters to its minimal mitochondria (mitosomes), consistent with lineage-specific differences in transporter and mitosome evolution. All of the T. hominis NTTs transported radiolabelled purine nucleotides (ATP, ADP, GTP and GDP) when expressed in Escherichia coli, but did not transport radiolabelled pyrimidine nucleotides. Genome analysis suggests that imported purine nucleotides could be used by T. hominis to make all of the critical purine-based building-blocks for DNA and RNA biosynthesis during parasite intracellular replication, as well as providing essential energy for parasite cellular metabolism and protein synthesis.


Simulating acoustic scattering from atmospheric temperature fluctuations using a k-space method.
This paper describes a numerical method for simulating far-field scattering from small regions of inhomogeneous temperature fluctuations. Such scattering is of interest since it is the mechanism by which acoustic wind velocity profiling devices (Doppler SODAR) receive backscatter. The method may therefore be used to better understand the scattering mechanisms in operation and may eventually provide a numerical test-bed for developing improved SODAR signals and post-processing algorithms. The method combines an analytical incident sound model with a k-space model of the scattered sound close to the inhomogeneous region and a near-to-far-field transform to obtain far-field scattering patterns. Results from two test case atmospheres are presented: one with periodic temperature fluctuations with height and one with stochastic temperature fluctuations given by the Kolmogorov spectrum. Good agreement is seen with theoretically predicted far-field scattering and the implications for multi-frequency SODAR design are discussed.


Action of the methylxanthines on the pituitary and pituitary-dependent hormones.
High doses of caffeine produce a stresslike neuroendocrine response in rats. This response is characterized by increased serum corticosterone, beta-endorphin, and decreased serum growth hormone and TSH. There is no effect on prolactin. Curiously, another common stimulant, amphetamine, produces a similar endocrine response in rats. Like caffeine, amphetamine decreases serum TSH [36], increases serum corticosterone [37], and has little effect on serum prolactin [38]. Perhaps amphetamine and caffeine as stimulants activate the same neurotransmitter systems and hence have similar endocrine effects. In man, typically consumed oral doses of caffeine have little or no endocrine effects. A person must consume 500 mg caffeine (equivalent to 5 cups of coffee) in one sitting for there to be any possible endocrine effects. Under these circumstances the endocrine changes that might occur would be limited to slight elevations in plasma ACTH, beta-endorphin, and cortisol.


A spontaneous mutation involving Kcnq2 (Kv7.2) reduces M-current density and spike frequency adaptation in mouse CA1 neurons.
The M-type K+ current [IK(M)] activates in response to membrane depolarization and regulates neuronal excitability. Mutations in two subunits (KCNQ2 and KCNQ3; Kv7.2 and Kv7.3) that underlie the M-channel cause the human seizure disorder benign familial neonatal convulsions (BFNC), presumably by reducing IK(M) function. In mice, the Szt1 mutation, which deletes the genomic DNA encoding the KCNQ2 C terminus and all of CHRNA4 (nicotinic acetylcholine receptor alpha4 subunit) and ARFGAP-1 (GTPase-activating protein that inactivates ADP-ribosylation factor 1), reduces seizure threshold, and alters M-channel pharmacosensitivity. Genomic deletions affecting the C terminus of KCNQ2 have been identified in human families with BFNC, and truncation of the C terminus prevents proper KCNQ2/KCNQ3 channel assembly in Xenopus oocytes. We showed previously that Szt1 mice have a reduced baseline seizure threshold and altered sensitivity to drugs that act at the M-channel. Specifically, the proconvulsant M-channel blocker linopirdine and anticonvulsant enhancer retigabine display increased and decreased potency, respectively, in Szt1 mice. To investigate the effects of the Szt1 mutation on IK(M) function explicitly, perforated-patch electrophysiology was performed in CA1 pyramidal neurons of the hippocampus in brain slices prepared from C57BL/6J-Szt1/+ and control C57BL/6J+/+ mice. Our results show that Szt1 reduces both IK(M) amplitude and current density, inhibits spike frequency adaptation, and alters many aspects of M-channel pharmacology. This is the first evidence that a naturally occurring Kcnq2 mutation diminishes the amplitude and function of the native neuronal IK(M), resulting in significantly increased neuronal excitability. Finally, the changes in single-cell biophysical properties likely underlie the altered seizure threshold and pharmacosensitivity reported previously in Szt1 mice.


Variations in vascular mortality trends, 2001-2010, among 1.3 million women with different lifestyle risk factors for the disease.
Vascular disease mortality has declined rapidly in most Western countries, against a background of improved treatments and falling prevalence of smoking, but rising obesity. We examined whether this decline differed by lifestyle risk factors for vascular disease. During 2001-2010, there were 9241 vascular disease deaths in a prospective study of 1.3 million women in middle age, about one-quarter of all UK women in the eligible age range (50-64 years in 1996-2001). We estimated percentage declines in mortality from coronary heart disease, cerebrovascular disease and other vascular diseases, overall and by age, smoking, alcohol consumption, adiposity, physical activity, socioeconomic status and age at leaving school. Over 10 years, coronary heart disease mortality fell by half (52%), cerebrovascular disease mortality by two-fifths (42%) and other vascular disease mortality by one-fifth (22%). Lean women experienced greater declines in coronary heart disease mortality than overweight or obese women (70%, 48% and 26%, respectively; P < 0.001 for heterogeneity) and women in the highest and middle thirds of socioeconomic status experienced greater declines in other (non-coronary, non-cerebrovascular) vascular disease mortality than women in the lowest third (41% and 42% and -9%, respectively; P = 0.001). After accounting for multiple testing, there were no other significant differences in vascular mortality trends by any lifestyle risk factor, including by smoking status. Vascular disease mortality trends varied in this cohort by adiposity and socioeconomic status, but not by smoking status or other lifestyle risk factors. Prevention and treatment of vascular disease appear not to have been equally effective in all subgroups of UK women.


The role of value orientations in curricular decision making: a rationale for teachers' goals and expectations.
This research examined the role of value orientations in curricular decision making from the perspective of high school physical education teachers and students. Educational value orientations served as the theoretical base for the research. Teachers who exhibited one of two paired orientations, disciplinary mastery/learning process (DM/LP) or ecological integration/social reconstruction (EI/SR), were interviewed to examine the extent to which their value orientations influenced their stated (a) goals for student learning, and (b) expectations for academic performance and behavior. Students were also interviewed to investigate the extent to which they acknowledged these goals and expectations. Data were analyzed using constant comparison. Results suggested that goals and expectations of DM/LP and EI/SR teachers were distinctly different and that comments from students in the EI/SR teachers' classes did not reflect their teachers' goals and expectations. Dynamical system theory was used to conceptualize value orientations as attractors within the educational ecosystem. Teachers working from weak EI/SR value attractors may be limited by learner, instructional, and contextual constraints.


Suppression of bladder epithelial cytokine responses by uropathogenic Escherichia coli.
Urinary tract infections are most commonly caused by uropathogenic strains of Escherichia coli (UPEC), which invade superficial bladder epithelial cells via a type 1 pilus-dependent mechanism. Inside these epithelial cells, UPEC organisms multiply to high numbers to form intracellular bacterial communities, allowing them to avoid immune detection. Bladder epithelial cells produce interleukin-6 (IL-6) and IL-8 in response to laboratory strains of E. coli in vitro. We investigated the ability of UPEC to alter epithelial cytokine signaling by examining the in vitro responses of bladder epithelial cell lines to the cystitis strains UTI89 and NU14. The cystitis strains induced significantly less IL-6 than did the laboratory E. coli strain MG1655 from 5637 and T24 bladder epithelial cells. The cystitis strains also suppressed epithelial cytokine responses to exogenous lipopolysaccharide (LPS) and to laboratory E. coli. We found that insertional mutations in the rfa and rfb operons and in the surA gene all abolished the ability of UTI89 to suppress cytokine induction. The rfa and rfb operons encode LPS biosynthetic genes, while surA encodes a periplasmic cis-trans prolyl isomerase important in the biogenesis of outer membrane proteins. We conclude that, in this in vitro model system, cystitis strains of UPEC have genes encoding factors that suppress proinflammatory cytokine production by bladder epithelial cells.


House infestation dynamics and feeding sources of Triatoma dimidiata in central Veracruz, Mexico.
Chagas disease is endemic in the state of Veracruz, Mexico, and we investigated here the dynamics of house infestation by Chagas disease vectors to understand disease transmission and design effective control interventions. Bug collections in 42 rural villages confirmed the widespread distribution of Triatoma dimidiata in central Veracruz. Unexpectedly, collection data further indicated a clear pattern of seasonal infestation by mostly adult bugs. Analysis of feeding sources with a polymerase chain reaction-heteroduplex assay indicated a frequent feeding on humans, in agreement with the high seroprevalence previously observed. Feeding sources also confirmed a significant dispersal of bugs between habitats. High dispersal capabilities and seasonal infestation may thus be a shared characteristic of several of the T. dimidiata sibling species from this complex. It would thus be critical to adapt vector control interventions to this behavior to improve their efficacy and sustainability, as the control of T. dimidiata has been notoriously challenging.


Treatment with bevacizumab plus carboplatin for recurrent malignant glioma.
To estimate overall survival (OS), progression-free survival (PFS), imaging responses, and toxicities of bevacizumab plus carboplatin for the treatment of recurrent malignant glioma. The secondary objective was to estimate the agreement between postcontrast T1-weighted and T2-weighted magnetic resonance imaging. A retrospective analysis of 9 patients who received bevacizumab (10 mg/kg intravenously) and carboplatin (AUC 5 intravenously) for recurrent malignant glioma (World Health Organization grades III and IV) is presented. Eight of 9 patients received this regimen at first recurrence. The median age and Karnofsky performance score were 51 years and 70, respectively. For the 5 patients with grade III gliomas, the median PFS was 126 days, whereas median OS was not attained at 517 days of follow-up. Six-month PFS was 40%, whereas 6-month OS was 60%. For the 4 patients with grade IV gliomas, the median PFS was 216 days, whereas the median OS was not attained at 482 days of follow-up. Six-month PFS was 50%, whereas 6-month OS was 75%. The agreement between contrast-enhanced T1-weighted and T2-weighted images to determine recurrence was moderate (kappa=0.5714). Three patients had grade 3 and 4 toxicities including hyponatremia and thrombocytopenia. Patients who received the combination of bevacizumab plus carboplatin for recurrent malignant glioma had reasonable PFS, OS, and toxicities. The median OS in our series is promising at well over 1 year. Agreement between postcontrast T1- and T2-weighted images is only moderate in the context of bevacizumab therapy.


Vertical nanopillars for highly localized fluorescence imaging.
Observing individual molecules in a complex environment by fluorescence microscopy is becoming increasingly important in biological and medical research, for which critical reduction of observation volume is required. Here, we demonstrate the use of vertically aligned silicon dioxide nanopillars to achieve below-the-diffraction-limit observation volume in vitro and inside live cells. With a diameter much smaller than the wavelength of visible light, a transparent silicon dioxide nanopillar embedded in a nontransparent substrate restricts the propagation of light and affords evanescence wave excitation along its vertical surface. This effect creates highly confined illumination volume that selectively excites fluorescence molecules in the vicinity of the nanopillar. We show that this nanopillar illumination can be used for in vitro single-molecule detection at high fluorophore concentrations. In addition, we demonstrate that vertical nanopillars interface tightly with live cells and function as highly localized light sources inside the cell. Furthermore, specific chemical modification of the nanopillar surface makes it possible to locally recruit proteins of interest and simultaneously observe their behavior within the complex, crowded environment of the cell.


Risedronate in adults with osteogenesis imperfecta type I: increased bone mineral density and decreased bone turnover, but high fracture rate persists.
Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm(2), p = 0.007; mean Z-score, -1.93 vs. -1.58, p = 0.002), with no significant change at TH. P1NP fell by 37% (p = 0.00041), with no significant change in bone ALP (p = 0.15). Bone pain did not change significantly (p = 0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.


Functional Relationship between a Dinoflagellate Host and Its Diatom Endosymbiont.
While we know much about the evolutionary patterns of endosymbiotic organelle origins, we know less about how the actual process unfolded within each system. This is partly due to the massive changes endosymbiosis appears to trigger, and partly because most organelles evolved in the distant past. The dinotoms are dinoflagellates with diatom endosymbionts, and they represent a relatively recent but nevertheless obligate endosymbiotic association. We have carried out deep sequencing of both the host and endosymbiont transcriptomes from two dinotoms, Durinskia baltica and Glenodinium foliaceum, to examine how the nucleocytosolic compartments have functionally integrated. This analysis showed little or no functional reduction in either the endosymbiont or host, and no evidence for genetic integration. Rather, host and endosymbiont seem to be bound to each other via metabolites, such as photosynthate exported from the endosymbiont to the host as indicated by the presence of plastidic phosphate translocators in the host transcriptome. The host is able to synthesize starch, using plant-specific starch synthases, as a way to store imported photosynthate.


Long-term elevation of free fatty acids leads to delayed processing of proinsulin and prohormone convertases 2 and 3 in the pancreatic beta-cell line MIN6.
To explore the role of chronically elevated free fatty acids (FFAs) in the pathogenesis of the hyperproinsulinemia of type 2 diabetes, we have investigated the effect of FFAs on proinsulin processing and prohormone convertases PC2 and PC1/PC3 in MIN6 cells cultured in Dulbecco's modified Eagle's medium with or without 0.5 mmol/l FFA mixture (palmitic acid:oleic acid = 1:2). After 7 days of culture, the percent of proinsulin in FFA-exposed cells was increased (25.9 +/-0.3% intracellular and 75.4 +/- 1.2% in medium vs. 13.5 +/-0.2 and 56.2 +/- 4.1%, respectively, in control cells). The biosynthesis and secretion of proinsulin and insulin were analyzed by comparing the incorporation of [3H]Leu and [35S]Met. In pulse-chase studies, proinsulin-to-insulin conversion was inhibited, and proinsulin in the medium was increased by 50% after 3 h of chase, while insulin secretion was decreased by 50% after FFA exposure. Levels of cellular PC2 and PC3 analyzed by Western blotting were decreased by 23 and 15%, respectively. However, PC2, PC3, proinsulin, and 7B2 mRNA levels were not altered by FFA exposure. To test for an effect on the biosynthesis of PC2, PC3, proinsulin, and 7B2, a protein required for PC2 activation, MIN6 cells were labeled with [35S]Met for 10-15 min, followed by a prolonged chase. Most proPC2 was converted after 6 h of chase in control cells, but conversion was incomplete even after 6 h of chase in FFA-exposed MIN6 cells. Media from chase incubations showed that FFA-exposed cells secreted more proPC2 than controls. Similar inhibitory effects were noted on the processing of proPC3, proinsulin, and 7B2. In conclusion, prolonged exposure of beta-cells to FFAs may affect the biosynthesis and posttranslational processing of proinsulin, PC2, PC3, and 7B2, and thereby contribute to the hyperproinsulinemia of type 2 diabetes. The mechanism of inhibition of secretory granule processing by FFAs may be through changes in Ca2+ concentration, the pH in the secretory granules, and/or other factors that may influence the activation and function of the convertases.


Borderline personality disorder: resource utilisation costs in Ireland.
Borderline personality disorder (BPD) is characterised by recurring crises, hospitalisations, self-harm, suicide attempts, addictions, episodes of depression, anxiety and aggression and lost productivity. The objective of this study is to determine the use of direct health care resources by persons with BPD in Ireland and the corresponding costs. This prevalence-based micro-costing study was undertaken on a sample of 196 individuals with BPD attending publicly funded mental health services in Ireland. All health care costs were assessed using a resource utilisation questionnaire completed by mental health practitioners. A probabilistic sensitivity analysis, using a Monte Carlo simulation, was performed to examine uncertainty. Total direct healthcare cost per individual was €10 844 annually (ranging from 5228 to 20 609). Based on a prevalence of 1% and an adult population (18-65 years) of 2.87 million, we derived that there were 28 725 individuals with BPD in Ireland. Total yearly cost of illness was calculated to be up to €311.5 million. There is a dearth of data on health care resource use and costs of community mental health services in Ireland. The absence of this data is a considerable constraint to research and decision-making in the area of community mental health services. This paper contributes to the limited literature on resource use and costs in community mental health services in Ireland. The absence of productivity loss data (e.g. absenteeism and presenteeism), non-health care costs (e.g. addiction treatment), and indirect costs (e.g. informal care) from study participants is a limitation of this study.


[Autonomic nervous function of vertiginous patients--assessment by spectral analysis of heart rate variability].
Autonomic nervous function in 68 vertiginous patients and 33 controls was studied using power spectral analysis of heart rate variability. First, a system was developed which computes the power spectral density (PSD) of beat-to-beat heart intervals using a continuous non-invasive finger blood pressure recording obtained with the FINAPRESS device. A fast-Fourier transform algorithm was used to compute the PSD. In frequencies up to 0.5 Hz, the PSD of heart rate variability contains three major components: a low frequency (P1), a middle frequency (P2) and a high frequency (P3). Each component was normalized by dividing the absolute values by total power (T), and then used as an index of each component. Second, the effects of passive tilt, respiratory frequency and specific pharmacological sympathetic or parasympathetic blockade on the indices of these components were evaluated in the control group. The following results were obtained. 1. During passive tilt, the normalized power of P2 was increased, whereas that of P3 was decreased. 2. The peak frequency of P3 was consistent with the frequency of respiration. 3. Sympathetic blockade decreased the normalized power of P2, whereas parasympathetic blockade decreased the normalized power of P3. From these results, I concluded that the normalized power of P2 and P3 are quantitative markers of sympathetic and vagal nervous activities, respectively. Third, the results of spectral analysis in patients were compared with those in controls. The following characteristics of autonomic nervous function in vertiginous patients were noted. 1. The normalized power of P3 in patients was lower than that in controls, suggesting that parasympathetic nervous activity at rest was suppressed in patients. 2. The increase of normalized power of P2 with passive tilt was suppressed in patients, suggesting suppression of sympathetic response to passive tilt. 3. In patients with Meniere's disease, during the active period of vertigo attacks, the normalized power of P2, which is an index of sympathetic activity, was higher than that in the intervals between vertigo attacks. Fourth, with caloric stimulation in the control group, an increase of the normalized power of P2 was observed during or after the stimulation, which suggests that vestibular stimulation increases sympathetic activity. I therefore suggest the following: 1. Decreased parasympathetic activity and suppression of sympathetic response were present in the vertiginous patients. 2. Sympathetic activity was increased by vertigo attacks in the patients with Meniere's disease.


Upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol, resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and electrophilic stress.
Resveratrol (3,4',5-trihydroxystilbene), a polyphenolic compound found in mulberries, grapes and red wine has been demonstrated to be capable of protecting against oxidative cardiovascular pathophysiology. However, the underlying cellular and biochemical mechanisms remain to be elucidated. This study was undertaken to determine if resveratrol could upregulate endogenous antioxidants and phase 2 enzymes in cultured aortic smooth muscle cells (ASMCs), and if such increased cellular defenses could provide protection against oxidative and electrophilic vascular cell injury. Incubation of rat ASMCs with resveratrol at low micromolar concentrations resulted in a significant induction of a scope of cellular antioxidants and phase 2 enzymes in a concentration- and/or time-dependent fashion. These cytoprotective factors include superoxide dismutase, catalase, glutathione, glutathione reductase, glutathione peroxidase, glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase-1 (NOQ1). Notably, induction of catalase, GST, and NOQ1 was most remarkable among the above resveratrol-inducible antioxidants and phase 2 enzymes. Moreover, resveratrol treatment also significantly increased the mRNA expression of catalase, GSTA1, and NQO1 in a time-dependent manner. Pretreatment of ASMCs with resveratrol afforded a remarkable protection against xanthine oxidase (XO)/xanthine- or 4-hydroxy-2-nonenal-induced cytotoxicity, as assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Resveratrol pretreatment also led to a marked reduction in intracellular accumulation of reactive oxygen species in ASMCs after incubation with XO/xanthine. Taken together, this study demonstrates that a scope of key endogenous antioxidants and phase 2 enzymes in cultured ASMCs can be upregulated by resveratrol at low micromolar concentrations, and that such chemically-elevated cellular defenses rendered cells increased resistance to oxidative and electrophilic stress. The results of this study thus suggested a new mechanism, which might contribute to the cardiovascular protective effects of resveratrol.


Global, Regional and Country-Specific Burden of Ischaemic Stroke, Intracerebral Haemorrhage and Subarachnoid Haemorrhage: A Systematic Analysis of the Global Burden of Disease Study 2017.
Stroke is a leading cause of death and disability in globally and particularly in low- and middle-income countries, and this burden is increasing. The burden of stroke pathological subtypes varies in terms of incidence, disability and mortality. Previous Global Burden of Diseases, Injuries, and Risk Factors Studies (GBD) reports did not provide separate global burden and trends estimates for haemorrhagic stroke by primary intracerebral haemorrhage (PICH) and subarachnoid haemorrhage (SAH). To summarise the GBD 2017 findings for the burden and 27-year trends for ischaemic stroke (IS), intracerebral haemorrhage and SAH by age, sex and country income level in 21 world regions and associated risk factors. Data on stroke incidence, prevalence, mortality and disability-adjusted life-years (DALY) lost and the burden of IS, PICH and SAH were derived from all available datasets from the GBD 2017 studies. Data were analysed in terms of absolute numbers and age-standardised rates per 100,000 (95% uncertainty interval [UI]), with estimates stratified by age, sex and economic development level by the World Bank classification. We also analysed changes in the patterns of incidence, mortality and DALYs estimates between 1990 and 2017. In 2017, there were 11.9 million incident (95% UI 11.1-12.8), 104.2 million prevalent (98.6-110.2), 6.2 million fatal (6.0-6.3) cases of stroke and 132.1 million stroke-related DALYs (126.5-137.4). Although stroke incidence, prevalence, mortality and DALY rates declined from 1990 to 2017, the absolute number of people who developed new stroke, died, survived or remained disabled from stroke has almost doubled. The bulk of stroke burden (80% all incident strokes, 77% all stroke survivors, 87% of all deaths from stroke and 89 of all stroke-related DALYs) in 2017 was in low- to middle-income countries. Globally in 2017, IS constituted 65%, PICH -26% and SAH -9% of all incident strokes. The latest GBD estimates of stroke burden in 195 countries supersede previous GBD stroke burden findings and provide most accurate data for stroke care planning and resource allocation globally, regionally and for 195 countries. Stroke remains the second leading cause of deaths and disability worldwide. The increased stroke burden continues to exacerbate a huge pressure on people affected by stroke, their families and societies. It is imperative to develop and implement more effective primary prevention strategies to reduce stroke burden and its impact.


Complete complex conjugate resolved heterodyne swept-source optical coherence tomography using a dispersive optical delay line.
Swept-source optical coherence tomography (SSOCT) provides a substantial sensitivity advantage over its time-domain counterpart, but suffers from a reduced imaging depth range due to sensitivity falloff and complex conjugate ambiguity. Heterodyne complex conjugate-resolved SSOCT (HCCR-SSOCT) has been previously demonstrated as a technique to completely resolve the complex conjugate ambiguity, effectively doubling the falloff limited imaging depth, without the reduction in imaging speed associated with other CCR techniques. However, previous implementations of this technique have employed expensive and lossy optical modulators to provide the required differential phase modulation. In this paper, we demonstrate the use of a dispersive optical delay line (D-ODL) as the reference arm of an OCT system to realize HCCR-SSOCT. This technique maintains the existing advantages of HCCR-SSOCT in that it completely resolves the complex conjugate artifact and does not reduce imaging speed, while conferring the additional advantages of being low cost, maintaining system sensitivity and resolution, not requiring any additional signal processing, and working at all wavelengths and imaging speeds. The D-ODL also allows for hardware correction of unbalanced dispersion in the reference and sample arm, adding further flexibility to system design. We demonstrate the technique using an SSOCT system operating at 100kHz with a central wavelength of 1040nm. Falloff measurements performed using a standard OCT configuration and the proposed D-ODL demonstrate a doubling of the effective imaging range with no sensitivity or resolution penalty. Feasibility of the technique for in vivo imaging was demonstrated by imaging the ocular anterior segments of healthy human volunteers.


Transcription coactivator PBP/MED1-deficient hepatocytes are not susceptible to diethylnitrosamine-induced hepatocarcinogenesis in the mouse.
Nuclear receptor coactivator [peroxisome proliferator-activated receptor-binding protein (PBP)/mediator subunit 1 (MED1)] is a critical component of the mediator transcription complex. Disruption of this gene in the mouse results in embryonic lethality. Using the PBP/MED1 liver conditional null (PBP/MED1(DeltaLiv)) mice, we reported that PBP/MED1 is essential for liver regeneration and the peroxisome proliferator-activated receptor alpha ligand Wy-14,643-induced receptor-mediated hepatocarcinogenesis. We now examined the role of PBP/MED1 in genotoxic chemical carcinogen diethylnitrosamine (DEN)-induced and phenobarbital-promoted hepatocarcinogenesis. The carcinogenic process was initiated by a single intraperitoneal injection of DEN at 14 days of age and initiated cells were promoted with phenobarbital (PB) (0.05%) in drinking water. PBP/MED1(DeltaLiv) mice, killed at 1, 4 and 12 weeks, revealed a striking proliferative response of few residual PBP/MED1-positive hepatocytes that escaped Cre-mediated deletion of PBP/MED1 gene. No proliferative expansion of PBP/MED1 null hepatocytes was noted in the PBP/MED1(DeltaLiv) mouse livers. Multiple hepatocellular carcinomas (HCCs) developed in the DEN-initiated PBP/MED1(fl/fl) and PBP/MED1(DeltaLiv) mice, 1 year after the PB promotion. Of interest is that all HCC developing in PBP/MED1(DeltaLiv) mice were PBP/MED1 positive. None of the tumors was PBP/MED1 negative implying that hepatocytes deficient in PBP/MED1 are not susceptible to neoplastic conversion. HCC that developed in PBP/MED1(DeltaLiv) mouse livers were transplantable in athymic nude mice and these maintained PBP/MED1(fl/fl) genotype. PBP/MED1(fl/fl) HCC cell line derived from these tumors expressed PBP/MED1 and deletion of PBP/MED1(fl/fl) allele by adeno-Cre injection into tumors caused necrosis of tumor cells. These results indicate that PBP/MED1 is essential for the development of HCC in the mouse.


Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database.
Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.


Benefits of spine stabilization with biodegradable scaffolds in spinal cord injured rats.
Spine stabilization upon spinal cord injury (SCI) is a standard procedure in clinical practice, but rarely employed in experimental models. Moreover, the application of biodegradable biomaterials for this would come as an advantage as it would eliminate the presence of a nondegradable prosthesis within the vertebral bone. Therefore, in the present work, we propose the use of a new biodegradable device specifically developed for spine stabilization in a rat model of SCI. A 3D scaffold based on a blend of starch with polycaprolactone was implanted, replacing delaminated vertebra, in male Wistar rats with a T8-T9 spinal hemisection. The impact of spinal stabilization on the locomotor behavior was then evaluated for a period of 12 weeks. Locomotor evaluation--assessed by Basso, Beatie, and Bresnahan test; rotarod; and open field analysis--revealed that injured rats subjected to spine stabilization significantly improved their motor performance, including higher coordination and rearing activity when compared with SCI rats without stabilization. Histological analysis further revealed that the presence of the scaffolds not only stabilized the area, but also simultaneously prevented the infiltration of the injury site by connective tissue. Overall, these results reveal that SCI stabilization using a biodegradable scaffold at the vertebral bone level leads to an improvement of the motor deficits and is a relevant element for the successful treatment of SCI.


Sphingolipids and atherosclerosis.
The atherosclerotic lesion contains a high amount of sphingolipids, a large group of structurally diverse lipids that regulate distinct biological functions beyond their role as structural membrane components. Assessment of their role in atherogenesis has been enabled after genes that regulate their metabolism had been identified and facilitated by the more wide availability of mass spectrometry. Here we discuss recent mechanistic insights obtained in animal and epidemiological studies that have greatly enhanced our understanding of mechanisms how sphingolipids affect the atherosclerotic process.


Protein B61 as a new growth factor: expression of B61 and up-regulation of its receptor epithelial cell kinase during melanoma progression.
Epithelial cell kinase (ECK) is a receptor protein tyrosine kinase, the role of which in melanoma biology is unclear. Here we studied the role of ECK during melanoma progression. ECK mRNA was overexpressed in virtually all melanoma lines tested, and levels were significantly higher in cell lines from distant metastases than primary melanomas; melanocytes were negative. Gene amplification was not detected in melanomas. Levels of ECK protein corresponded well with mRNA levels. B61 or LERK-1, recently identified as an ECK ligand, stimulated the growth of ECK-expressing melanoma cell lines, its first identified biological activity. Melanoma chemotaxis and chemoinvasion were not affected by B61. Growth of normal melanocytes was not affected. mRNA for B61 was detected in both melanoma cell lines and normal melanocytes. B61 was also identified by Western blotting and ECK binding activity with the use of a BIAcore binding assay in melanoma cell-conditioned media. These results suggest that B61 is an autocrine growth factor for melanomas but not normal melanocytes.


Spatial variability and temporal trends in water-use efficiency of European forests.
The increasing carbon dioxide (CO2 ) concentration in the atmosphere in combination with climatic changes throughout the last century are likely to have had a profound effect on the physiology of trees: altering the carbon and water fluxes passing through the stomatal pores. However, the magnitude and spatial patterns of such changes in natural forests remain highly uncertain. Here, stable carbon isotope ratios from a network of 35 tree-ring sites located across Europe are investigated to determine the intrinsic water-use efficiency (iWUE), the ratio of photosynthesis to stomatal conductance from 1901 to 2000. The results were compared with simulations of a dynamic vegetation model (LPX-Bern 1.0) that integrates numerous ecosystem and land-atmosphere exchange processes in a theoretical framework. The spatial pattern of tree-ring derived iWUE of the investigated coniferous and deciduous species and the model results agreed significantly with a clear south-to-north gradient, as well as a general increase in iWUE over the 20th century. The magnitude of the iWUE increase was not spatially uniform, with the strongest increase observed and modelled for temperate forests in Central Europe, a region where summer soil-water availability decreased over the last century. We were able to demonstrate that the combined effects of increasing CO2 and climate change leading to soil drying have resulted in an accelerated increase in iWUE. These findings will help to reduce uncertainties in the land surface schemes of global climate models, where vegetation-climate feedbacks are currently still poorly constrained by observational data.


Renal expression of hypoxia inducible factor-1α in patients with chronic kidney disease: a clinicopathologic study from nephrectomized kidneys.
Hypoxia inducible factor-1α (HIF-1α) has been shown to play a role in the pathogenesis of renal interstitial fibrosis. However, the relationship of HIF-1α expression intensity in human renal tissue with the degree of renal function or renal fibrosis has not been investigated. We therefore, undertook this study to assess the relationship between HIF-1α expression and degree of renal impairment and renal fibrosis using renal tissue from nephrectomized kidneys from patients with chronic kidney disease. This retrospective study was performed with 70 patients undergoing unilateral or bilateral nephrectomy because of renal cell carcinoma, urothelial cell carcinoma, or renal abscess. Immunohistochemical analysis of HIF-1α expression in non-tumourous or non-abscess renal parenchyma was performed. The patients were divided into two groups: group 1 (n=37) with low intensity HIF-1α expression and group 2 (n=33) with high intensity HIF-1α expression. The intensity of renal HIF-1α expression was significantly associated with serum creatinine level (P =0.005), estimated glomerular filtration rate (P=0.02), fibrosis score of the interstitium (P=0.004) and glomerular sclerosis (P=0.013). A high intensity of HIF-1α expression tended to be associated with lower serum creatinine, higher estimated glomerular filtration rate, low interstitial fibrosis score and low glomerular sclerosis. In addition, multivariate analysis by step-wise logistic regression demonstrated that interstitial fibrosis was the only independent factor associated with the intensity of renal HIF-1α expression (OR 4.107, CI 1.535-11.313, P=0.005). This study demonstrated a correlation between intensity of HIF-1α expression and degree of renal interstitial fibrosis. The association demonstrated an elevated HIF-1α expression in less severe kidney disease. The intensity of HIF-1α renal expression plays a role in the pathogenesis of chronic kidney disease.


Surface state and composition of a disperse Pd catalyst after its exposure to ethylene.
Pd black was exposed to ethylene alone or in its mixture with hydrogen at 300 and 573 K. The samples were investigated by X-ray photoelectron spectroscopy (XPS) and ultraviolet photoelectron spectroscopy (UPS). Room temperature introduction of C(2)H(4) (also in the presence of H(2)) induced a binding-energy (BE) shift in the Pd 3d doublet and changed its full width at half-maximum (fwhm). The UPS features indicate shifting of electrons from the Pd d-band to Pd-H, Pd-C, and even Pd-OH species. Vinylidene (BE approximately 284.1 eV) may be the most abundant individual surface species on disperse Pd black, along with carbon in various stages of polymerization: "disordered C" (BE approximately 284 eV), graphite (approximately 284.6 eV), and ethylene polymer (approximately 286 eV), and also some "atomic" C (BE approximately 283.5 eV). Introduction of H(2) followed by ethylene brought about stronger changes in the state of Pd than exposure in the reverse sequence. This may indicate that the presence of some surface C may hinder the decomposition of bulk PdH. Formation of Pd hydride was blocked when ethylene was introduced prior to H(2). The C 1s intensity increased, the low-binding-energy C components disappeared, and graphitic carbon (BE approximately equal to 284.6 eV) prevailed after ethylene treatment at 573 K. The loss of the Pd surface state and "PdH" signal were observed in the corresponding valence band and UPS spectra. Hydrogen treatment at 540 K was not able to decrease the concentration of surface carbon and re-establish the near-surface H-rich state. UPS showed overlayer-type C in these samples. The interaction of Pd with components from the feed gas modified its electronic structure that is consistent with lattice strain induced by dissolution of carbon and hydrogen into Pd, as indicated by the d-band shift and the dilution of the electron density at E(F).


A multispecies polyadenylation site model.
Polyadenylation is present in all three domains of life, making it the most conserved post-transcriptional process compared with splicing and 5'-capping. Even though most mammalian poly(A) sites contain a highly conserved hexanucleotide in the upstream region and a far less conserved U/GU-rich sequence in the downstream region, there are many exceptions. Furthermore, poly(A) sites in other species, such as plants and invertebrates, exhibit high deviation from this genomic structure, making the construction of a general poly(A) site recognition model challenging. We surveyed nine poly(A) site prediction methods published between 1999 and 2011. All methods exploit the skewed nucleotide profile across the poly(A) sites, and the highly conserved poly(A) signal as the primary features for recognition. These methods typically use a large number of features, which increases the dimensionality of the models to crippling degrees, and typically are not validated against many kinds of genomes. We propose a poly(A) site model that employs minimal features to capture the essence of poly(A) sites, and yet, produces better prediction accuracy across diverse species. Our model consists of three dior-trinucleotide profiles identified through principle component analysis, and the predicted nucleosome occupancy flanking the poly(A) sites. We validated our model using two machine learning methods: logistic regression and linear discriminant analysis. Results show that models achieve 85-92% sensitivity and 85-96% specificity in seven animals and plants. When we applied one model from one species to predict poly(A) sites from other species, the sensitivity scores correlate with phylogenetic distances. A four-feature model geared towards small motifs was sufficient to accurately learn and predict poly(A) sites across eukaryotes.


A Nationwide Virtual Research Education Program for Medical Students in Pakistan: Methodological Framework, Feasibility Testing, and Outcomes.
Introduction: Equipping young medical trainees with fundamental research skills can be a promising strategy to address the need for professionals who can understand and responsibly communicate evolving scientific evidence during a pandemic. Despite an ardent interest to partake in research, most educational institutions in Pakistan and other low-middle income countries have not yet adopted a comprehensive strategy for research skills education. The authors aimed to design and assess the feasibility of implementing the first nation-wide virtual research workshop for medical students in Pakistan. Methods: The course "Beginners Guide to Research," designed as a nation-wide virtual research workshop series, was conducted for medical students across Pakistan in June 2020. Four interactive live workshops took place online on alternate days from June 22nd, 2020, to June 27th, 2020, each lasting 1-2 h. Outcomes included: (i) reach, (ii) efficacy as indexed by pre-post change in score pertaining to knowledge and application of research and (iii) self-rated perceptions about understanding of research on a Likert scale. Results: 3,862 participants enrolled from 41 cities and 123 institutions. Enrolled participants belonged to the following provinces: Sindh (n = 1,852, 48.0%), Punjab (n = 1,767, 45.8%), Khyber Pakhtunkhwa (n = 109, 2.8%), Azad Jammu and Kashmir (n = 84, 2.2%) Balochistan (n = 42, 1.1%). We also saw a few registrations from international students (n = 8, 0.2%). Mean (SD) age of enrolled medical students was 21.1 (2.1) years, 2,453 (63.5%) participants were female and 2,394 (62.0%) were from private-sector medical colleges. Two thousand ninety-three participants participants filled out all four pre-test and post-test forms. The total median knowledge score improved from 39.7 to 60.3% with the highest improvements in concepts of research bioethics and literature search (p < 0.001) with greater change for females compared to males (+20.6 vs. +16.2%, p < 0.001) and private institutions compared to public ones (+16.2 vs. +22.1%, p < 0.001). Conclusion: The overwhelming enrollment and significant improvement in learning outcomes (>50% of baseline) indicate feasibility of a medical student-led research course during a pandemic, highlighting its role in catering to the research needs in the LMICs.