Total improvement after surgery for obstructive sleep apnea syndrome in a patient with concurrent malignant idiopathic intracranial hypertension.
The association between idiopathic intracranial hypertension (IIH) and obstructive sleep apnea syndrome (OSAS) constitutes an interesting point of discussion regarding clinical approaches as well as the underlying pathophysiological mechanisms. Here, the case of a 42-year-old female with malignant IIH and OSAS is illustrated. Initially, the patient was treated with lumboperitoneal shunt surgery. However, OSAS surgery provided total recovery from the recurrent symptoms developing secondary to lumboperitoneal shunt malfunction. The authors point out the importance of identifying OSAS as a crucial causative agent in some IIH subtypes. Future studies are warranted to clarify this underestimated association.


Sex ratios.
Sex ratio theory attempts to explain variation at all levels (species, population, individual, brood) in the proportion of offspring that are male (the sex ratio). In many cases this work has been extremely successful, providing qualitative and even quantitative explanations of sex ratio variation. However, this is not always the situation, and one of the greatest remaining problems is explaining broad taxonomic patterns. Specifically, why do different organisms show so much variation in the amount and precision with which they adjust their offspring sex ratios?


[Factors associated with health promoting behaviors among Chilean adolescents].
Health-promoting behaviors are important to prevent diseases and prolong life in the population. People develop these behaviors throughout life. However, better benefits for health are obtained with an early development. To determine the prevalence of health-promoting behaviors among early adolescents and its associated factors. Cross-sectional survey performed in 1,465 students of high, medium and low socio-economic status, attending fifth to eighth grades of schools located in a small Chilean city. Participants answered a questionnaire that gathered information about frequency of health-promoting behaviors such as health responsibility and nutrition, physical exercise and stress management, life appreciation, social support and different personal, school and familial factors. A higher frequency of health-promoting behaviors was associated with better academic achievement, better school commitment, and higher perception of school membership. It also was associated with a better perception of health status and a higher conformity with physical appearance. Health promoting behaviors in these children are related to a better academic achievement and a higher integration with school environment.


The assessment of resting tongue posture in different sagittal skeletal patterns.
Resting tongue posture affects the surrounding structures and, theoretically, may result in altered arch form and jaw relationship. The objective of the present study was to investigate the association between resting tongue posture as observed in lateral cephalometric radiograph, sagittal jaw relationship and arch form. The study was conducted on pretreatment lateral cephalograms and dental casts of 90 subjects. Subjects were equally divided into three groups, based on sagittal jaw relationship (Class I, II and III). Tongue posture was determined in terms of tongue-to-palate distances at six different points (distances 1 to 6) using ViewPro-X software, according to the method described by Graber et al in 1997. The arch widths (intercanine and intermolar widths) were evaluated on pretreatment dental casts. Tongue-to-palate distances were found to be comparable among different study groups. Significant differences were found in intercanine and intermolar widths at the cuspal and gingival levels among the study groups, except for intercanine width at cuspal level in maxilla and intermolar width at cuspal level in mandible. Moderate positive correlation was found between arch widths ratios at distances 3 and 4 in skeletal Class III group. Effect size was found to be moderate to large in different sagittal skeletal patterns and arch widths. The results of the current study showed no significant differences in the resting tongue posture among the groups, and moderate to weak correlation between tongue posture and dental arch widths.


RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility.
p90 ribosomal S6 kinase (RSK1) is an effector of both Ras/MEK/MAPK and PI3K/PDK1 pathways. We present evidence that RSK1 drives p27 phosphorylation at T198 to increase RhoA-p27 binding and cell motility. RSK1 activation and p27pT198 both increase in early G(1). As for many kinase-substrate pairs, cellular RSK1 coprecipitates with p27. siRNA to RSK1 and RSK1 inhibition both rapidly reduce cellular p27pT198. RSK1 overexpression increases p27pT198, p27-cyclin D1-Cdk4 complexes, and p27 stability. Moreover, RSK1 transfectants show mislocalization of p27 to cytoplasm, increased motility, and reduced RhoA-GTP, phospho-cofilin, and actin stress fibers, all of which were reversed by shRNA to p27. Phosphorylation by RSK1 increased p27pT198 binding to RhoA in vitro, whereas p27T157A/T198A bound poorly to RhoA compared with WTp27 in cells. Coprecipitation of cellular p27-RhoA was increased in cells with constitutive PI3K activation and increased in early G(1). Thus T198 phosphorylation not only stabilizes p27 and mislocalizes p27 to the cytoplasm but also promotes RhoA-p27 interaction and RhoA pathway inhibition. These data link p27 phosphorylation at T198 and cell motility. As for other PI3K effectors, RSK1 phosphorylates p27 at T198. Because RSK1 is also activated by MAPK, the increased cell motility and metastatic potential of cancer cells with PI3K and/or MAPK pathway activation may result in part from RSK1 activation, leading to accumulation of p27T198 in the cytoplasm, p27:RhoA binding, inhibition of RhoA/Rock pathway activation, and loss of actomyosin stability.


Intermittent fasting combined with supplementation with Ayurvedic herbs reduces anxiety in middle aged female rats by anti-inflammatory pathways.
Intermittent fasting-dietary restriction (IF-DR) is an increasingly popular intervention to promote healthy aging and delay age associated decline in brain functions. Also, the use of herbal interventions is gaining attention due to their non-pharmacological approach to treat several abnormalities and promote general health with least side effects. The present study was aimed to investigate the synergistic effects of IF-DR regimen with herbal supplementation on anxiety-like behavior and neuroinflammation in middle aged female rats. We used dried leaf powder of Withania somnifera and dried stem powder of Tinospora cordifolia for our study. The rats were divided into three groups: (1) Control group fed ad libitum (AL); (2) rats deprived of food for full day and fed ad libitum on every alternate day (IF-DR); and (3) IF-DR and herbal extract (DRH) group in which rats were fed ad libitum with herbal extract supplemented diet, every alternate day. Post regimen, the rats were tested for anxiety-like behavior and further used for study of key inflammatory molecules (NFκB, Iba1, TNFα, IL-1β, IL-6) and glial marker (GFAP) in hippocampus and piriform cortex regions of brain. The study was further extended to explore the effect of DRH regimen on stress response protein (HSP70) and calcium dependent regulators of synaptic plasticity (CaMKIIα, Calcineurin). Our data demonstrated that DRH regimen reduced anxiety-like behavior in middle age female rats and associated neuroinflammation by ameliorating key inflammatory cytokines and modulated stress response. The present data may provide scientific validation for anxiolytic and anti-inflammatory potential of herbal intervention combined with short term IF-DR regimen.


Tobacco control policies and perinatal health: a national quasi-experimental study.
We investigated whether changes in perinatal outcomes occurred following introduction of key tobacco control policies in the Netherlands: smoke-free legislation in workplaces plus a tobacco tax increase and mass media campaign (January-February 2004); and extension of the smoke-free law to the hospitality industry, accompanied by another tax increase and mass media campaign (July 2008). This was a national quasi-experimental study using Netherlands Perinatal Registry data (2000-2011; registration: ClinicalTrials.gov NCT02189265). Primary outcome measures were: perinatal mortality, preterm birth, and being small-for-gestational age (SGA). The association with timing of the tobacco control policies was investigated using interrupted time series logistic regression analyses with adjustment for confounders. Among 2,069,695 singleton births, there were 13,027 (0.6%) perinatal deaths, 116,043 (5.6%) preterm live-births and 187,966 (9.1%) SGA live-births. The 2004 policies were not associated with significant changes in the odds of developing any of the primary outcomes. After the 2008 policy change, a -4.4% (95% CI -2.4; -6.4, p < 0.001) decrease in odds of being SGA was observed. A reduction in SGA births, but not preterm birth or perinatal mortality, was observed in the Netherlands after extension of the smoke-free workplace law to bars and restaurants in conjunction with a tax increase and mass media campaign.


The effect of referral for cardiac rehabilitation on survival following acute myocardial infarction: a comparison survival in two cohorts collected in 1995 and 2003.
International guidelines recommend referral for cardiac rehabilitation (CR) after acute myocardial infarction (AMI). However, the impact on long-term survival after CR referral has not been adjusted by time-variance. We compared the effects of CR referral after hospitalization for AMI in two consecutive decades. A total of 2196 and 2055 patients were recruited in the prospective observational studies of the Evaluation of the Methods and Management of Acute Coronary Events (EMMACE) -1 and 2 in 1995 and 2003, (1995: median age 72 years, 39% women, 74% referred vs 2003: median age 71 years, 36% women, 64% referred) and followed up through September 2010. Survival functions showed CR referral to be an independent predictor for survival in 2003, but not in 1995 (hazard ratio (HR), 0.90; 95% confidence interval [CI]; 0.70 to 1.17, p = 0.44 in 1995 vs HR, 0.80; 95% CI, 0.66 to 0.96, p = 0.02 in 2003) when patients entered the model at three months after discharge and had a common exit at 90 months. Significant positive and negative predictors for CR referral were beta-blocker prescription (+), reperfusion (+) and age (-) in 1995, and reperfusion (+), revascularization (+), heart failure (HF) (+), antiplatelets (+), angiotensin-converting-enzyme inhibitor (ACE-I) (+), statins (+), diabetes (-), and the modified Global Registry of Acute Cardiac Events (GRACE) risk score (-) in 2003. CR referral was associated with improved survival in 2003, but not in 1995 in patients admitted with acute MI.


Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma.
The major cause of death in aggressive lymphoma is relapse or nonresponse to initial therapy. Lenalidomide has activity in a variety of hematologic malignancies, including non-Hodgkin's lymphoma (NHL). We report the results of a phase II, single-arm, multicenter trial evaluating the safety and efficacy of lenalidomide oral monotherapy in patients with relapsed or refractory aggressive NHL. Patients were treated with oral lenalidomide 25 mg once daily on days 1 to 21, every 28 days, for 52 weeks, until disease progression or intolerance. The primary end point was response; secondary end points included duration of response, progression-free survival (PFS), and safety. Forty-nine patients with a median age of 65 years received lenalidomide in this study. The most common histology was diffuse large B-cell lymphoma (53%), and patients had received a median of four prior treatment regimens for NHL. An objective response rate of 35% was observed in 49 treated patients, including a 12% rate of complete response/unconfirmed complete response. Responses were observed in each aggressive histologic subtype tested (diffuse large B-cell, follicular center grade 3, mantle cell, and transformed lymphomas). Of patients with stable disease or partial response at first assessment, 25% improved with continued treatment. Estimated median duration of response was 6.2 months, and median PFS was 4.0 months. The most common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), and thrombocytopenia (12.2%). Oral lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable side effects.


True and false gharials: a nuclear gene phylogeny of crocodylia.
The phylogeny of Crocodylia offers an unusual twist on the usual molecules versus morphology story. The true gharial (Gavialis gangeticus) and the false gharial (Tomistoma schlegelii), as their common names imply, have appeared in all cladistic morphological analyses as distantly related species, convergent upon a similar morphology. In contrast, all previous molecular studies have shown them to be sister taxa. We present the first phylogenetic study of Crocodylia using a nuclear gene. We cloned and sequenced the c-myc proto-oncogene from Alligator mississippiensis to facilitate primer design and then sequenced an 1,100-base pair fragment that includes both coding and noncoding regions and informative indels for one species in each extant crocodylian genus and six avian outgroups. Phylogenetic analyses using parsimony, maximum likelihood, and Bayesian inference all strongly agreed on the same tree, which is identical to the tree found in previous molecular analyses: Gavialis and Tomistoma are sister taxa and together are the sister group of Crocodylidae. Kishino-Hasegawa tests rejected the morphological tree in favor of the molecular tree. We excluded long-branch attraction and variation in base composition among taxa as explanations for this topology. To explore the causes of discrepancy between molecular and morphological estimates of crocodylian phylogeny, we examined puzzling features of the morphological data using a priori partitions of the data based on anatomical regions and investigated the effects of different coding schemes for two obvious morphological similarities of the two gharials.


Antidiabetic potential of two medicinal plants used in Gabonese folk medicine.
Diabetes mellitus is a metabolic disorder which is rising globally in rich and developing countries. In the African region this rate is the highest, with 20 million diagnosed diabetics. Despite a noticeable progress in the treatment of diabetes mellitus by synthetic drugs, the search for new natural anti-diabetic agents is going on. Nauclea diderrichii (De Wild.) Merr. (ND) and Sarcocephalus pobeguinii Hua ex Pellegr. (SP) are used as traditional medicines in Gabon for the treatment of different diseases, especially in the case of diabetes. The aim of this study was to evaluate the antidiabetic potential of these two medicinal plants traditionally used in Gabon. Pharmacological (inhibitory action on α and β-glucosidases) and toxicological (effect on human T cell proliferation) studies were conducted on aqueous extracts of ND (leaves and bark) and SP (bark) collected in Gabon. All raw extracts were analyzed by HPTLC and their content in phenolic compounds was determined by using standard method. The most active extracts were submitted to preparative HPLC in order to evidence the most efficient subfractions by biological evaluation. The results showed that two extracts from ND were potent α-glucosidase inhibitors, the leaf extract being more active that the bark extract: the first one was more than 60 fold more active than Acarbose, which is an oral medication used to treat type 2 diabetes; the extract from SP bark was less efficient. The HPLC subfractions of the extracts of ND leaves and SP bark were tested in the same experimental conditions. In each case, the most active subfractions still show very potent inhibitory effect on α-glucosidase (80-90% inhibition at 0.1 mg/mL). The most efficient extract, from ND leaves, was also characterized by the highest percentage of phenolic compounds, which suggests a relationship between its inhibitory potential on α-glucosidase and its content in phenolic compounds. Conversely, only a moderate inhibitory activity of the three extracts was observed on β-glucosidase. These results clearly indicated that active compounds present in N. diderrichii and S. pobeguinii leaves or/and bark were selective and highly potent inhibitors of α-glucosidase and validate their popular use for the treatment of diabetes.


LEUCOPROTEASE AND ANTI-LEUCOPROTEASE OF MAMMALS AND OF BIRDS.
The inhibiting action of the blood serum upon the enzyme of the polynuclear leucocytes, leucoprotease, is exerted by the albumin fraction of the serum. The albumin fraction contains no proteolytic enzymes. The globulin fraction of the serum contains no anti-enzyme for leucoprotease; it contains, on the contrary, an enzyme which digests proteids in a neutral or alkaline medium. This enzyme resembles leucoprotease which is present in the polynuclear leucocytes of an inflammatory exudate and in the bone marrow from which these cells are derived, and is doubtless identical with the similar enzyme occurring in smaller quantity in the spleen. This enzyme which is present in the blood serum is held in check by its anti-enzyme, but the latter is in such excess that the serum as a whole is capable of checking the action of leucoprotease when added in considerable quantity. Leucoprotease of one mammalian species is inhibited by sera of other mammalian species, but the anti-enzymotic activity of various sera differs; the anti-enzyme of the rabbit's serum is stronger than that of dog's serum, when tested either with dog's or with rabbit's leucoprotease. The co-existence in the rabbit of leucoprotease with feeble strength and anti-body of great activity may explain the absence in these animals of typical suppuration with liquefaction of tissues. The serum of birds which have been tested, namely, pigeon and hen, almost completely fails to inhibit mammalian leucoprotease (of dog). The polynuclear leucocytes, the bone marrow and the spleen of the hen do not contain an enzyme resembling leucoprotease of mammals. The absence of anti-enzyme in the serum is associated with absence of a corresponding enzyme in the leucocytes.


Impact of Immunosuppressive Agents on Clinical Manifestations and Outcome of Staphylococcus aureus Bloodstream Infection: A Propensity Score-Matched Analysis in 2 Large, Prospectively Evaluated Cohorts.
Staphylococcus aureus bloodstream infection (SAB) is a common, life-threatening infection. The impact of immunosuppressive agents on the outcome of patients with SAB is incompletely understood. Data from 2 large prospective, international, multicenter cohort studies (Invasive Staphylococcus aureus Infections Cohort [INSTINCT] and International Staphylococcus aureus Collaboration [ISAC]) between 2006 and 2015 were analyzed. Patients receiving immunosuppressive agents were identified and a 1:1 propensity score-matched analysis was performed to adjust for baseline characteristics of patients. Overall survival and time to SAB-related late complications (SAB relapse, infective endocarditis, osteomyelitis, or other deep-seated manifestations) were analyzed by Cox regression and competing risk analyses, respectively. This approach was then repeated for specific immunosuppressive agents (corticosteroid monotherapy and immunosuppressive agents other than steroids [IMOTS]). Of 3188 analyzed patients, 309 were receiving immunosuppressive treatment according to our definitions and were matched to 309 nonimmunosuppressed patients. After propensity score matching, baseline characteristics were well balanced. In the Cox regression analysis, we observed no significant difference in survival between the 2 groups (death during follow-up: 105/309 [33.9%] immunosuppressed vs 94/309 [30.4%] nonimmunosuppressed; hazard ratio [HR], 1.20 [95% confidence interval {CI}, .84-1.71]). Competing risk analysis showed a cause-specific HR of 1.81 (95% CI, .85-3.87) for SAB-related late complications in patients receiving immunosuppressive agents. The cause-specific HR was higher in patients taking IMOTS (3.69 [95% CI, 1.41-9.68]). Immunosuppressive agents were not associated with an overall higher mortality. The risk for SAB-related late complications in patients receiving specific immunosuppressive agents such as IMOTS warrants further investigations.


A multiphase CMAQ version 5.0 adjoint.
We present the development of a multiphase adjoint for the Community Multiscale Air Quality (CMAQ) model, a widely used chemical transport model. The adjoint model provides location- and time-specific gradients that can be used in various applications such as backward sensitivity analysis, source attribution, optimal pollution control, data assimilation, and inverse modeling. The science processes of the CMAQ model include gas-phase chemistry, aerosol dynamics and thermodynamics, cloud chemistry and dynamics, diffusion, and advection. Discrete adjoints are implemented for all the science processes, with an additional continuous adjoint for advection. The development of discrete adjoints is assisted with algorithmic differentiation (AD) tools. Particularly, the Kinetic PreProcessor (KPP) is implemented for gas-phase and aqueous chemistry, and two different automatic differentiation tools are used for other processes such as clouds, aerosols, diffusion, and advection. The continuous adjoint of advection is developed manually. For adjoint validation, the brute-force or finite-difference method (FDM) is implemented process by process with box- or column-model simulations. Due to the inherent limitations of the FDM caused by numerical round-off errors, the complex variable method (CVM) is adopted where necessary. The adjoint model often shows better agreement with the CVM than with the FDM. The adjoints of all science processes compare favorably with the FDM and CVM. In an example application of the full multiphase adjoint model, we provide the first estimates of how emissions of particulate matter (PM2.5) affect public health across the US.


Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a "cocktail" study design.
Nifedipine (NF), sparteine (SP), mephenytoin (MP) and antipyrine (AP) were administered simultaneously ("cocktail" design) to 15 healthy subjects, including 4 poor metabolizers (PM) of SP and 4 PMs of MP, on three different occasions: without pretreatment, after pentobarbital (PB) pretreatment and together with cimetidine (cim). Concentrations of AP, NF, its pyridine metabolite 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-methylester (M-O), SP, dehydrosparteine (DHS) were determined in plasma; 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-monomethyle ster (which is ester hydrolyzed M-O), SP, DHS, 4-hydroxymephenytoin, AP and metabolites 3-hydroxymethylantipyrine, norantipyrine and 4-hydroxyantipyrine were measured in urine. Clearance of NF had increased 270% after PB and decreased 32% with cim. Area under the plasma-concentration time curve of M-O and urinary excretion of 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-monoethyles ter had also decreased after PB. Neither extensive metabolizers nor PMs of SP and MP were sensitive to PB treatment, but sparteine clearance was reduced 55% by cim in extensive metabolizers and 59% in PMs. Ratio SP/DHS in urine was hardly influenced by cim. AP oxidation was significantly induced and inhibited by PB and cim, respectively. The cocktail study design seems to be suitable to assess induction and inhibition of the metabolism of the applied model substrates, which are metabolized by at least partly independent isozymes of the cytochrome P-450 system, simultaneously.


Golden moth-inspired structures with a synergistic effect of interference, absorption and scattering.
We describe a new type of photonic material inspired by a Diachrysia chrysitis moth, whose nano-structured wings exhibit a prominent golden color. This is a layered photonic structure with a large refractive index contrast, whose alternating layers are rough at the nanoscale level. Theoretical analysis shows that the scattering and interference interact to enhance the local field within the layers and increase the absorption of the material, particularly in the UV-blue part of the spectrum. Theory is experimentally verified using holographically manufactured Bragg gratings in the dichromated-pullulan (DCP). Alternating air-pullulan layers are produced and held in place by sparsely separated nano-pillars. Air voids are filled with 20-100 nm diameter spherical nanoparticles which act as scatterers. Such materials, with a high refractive index contrast and nano-scale scatterers, are important for achieving large reflectance and a broad spectrum, with scattering as an additional mechanism for spectral control.


Facial expression of pain: an evolutionary account.
This paper proposes that human expression of pain in the presence or absence of caregivers, and the detection of pain by observers, arises from evolved propensities. The function of pain is to demand attention and prioritise escape, recovery, and healing; where others can help achieve these goals, effective communication of pain is required. Evidence is reviewed of a distinct and specific facial expression of pain from infancy to old age, consistent across stimuli, and recognizable as pain by observers. Voluntary control over amplitude is incomplete, and observers can better detect pain that the individual attempts to suppress rather than amplify or simulate. In many clinical and experimental settings, the facial expression of pain is incorporated with verbal and nonverbal vocal activity, posture, and movement in an overall category of pain behaviour. This is assumed by clinicians to be under operant control of social contingencies such as sympathy, caregiving, and practical help; thus, strong facial expression is presumed to constitute and attempt to manipulate these contingencies by amplification of the normal expression. Operant formulations support skepticism about the presence or extent of pain, judgments of malingering, and sometimes the withholding of caregiving and help. To the extent that pain expression is influenced by environmental contingencies, however, "amplification" could equally plausibly constitute the release of suppression according to evolved contingent propensities that guide behaviour. Pain has been largely neglected in the evolutionary literature and the literature on expression of emotion, but an evolutionary account can generate improved assessment of pain and reactions to it.


The degree of image degradation and the depth of amblyopia.
To determine whether the depth of monocular form-deprivation amblyopia is dependent on the degree of retinal image degradation. Chronic monocular form deprivation was produced in nine infant rhesus monkeys by securing one of three different strengths of diffuser spectacle lenses in front of the treated eye and a clear zero-powered lens in front of the fellow eye. Three infant monkeys reared with plano lenses in front of both eyes provided control data. The treatment lenses were worn continuously from approximately 3 weeks of age for periods ranging between 11 and 19 weeks. When the monkeys were approximately 18 months of age, psychophysical procedures were used to measure the effects of the rearing procedures on the spatial contrast sensitivity function for each eye. The treated eyes of all nine diffuser-reared monkeys showed contrast sensitivity deficits that were indicative of amblyopia. On average, the interocular grating acuity difference increased systematically from 0.6 octaves for the weakest diffuser lens to 2.3 +/- 0.7 and 3.5 +/- 0.8 octaves for the intermediate and strongest diffuser lenses, respectively. There was a close correspondence between the magnitude of the amblyopic deficits and the reduction in retinal image contrast produced by the diffuser lenses. The results demonstrate that the depth of monocular, nonstrabismic amblyopia is strongly influenced by the degree of retinal image degradation experienced early in life.


Obesity reveals an association between blood pressure and the G-protein beta3-subunit gene: a study of female dizygotic twins.
The 825C>T polymorphism of the G-protein beta3-subunit gene (GNB3) has been associated with hypertension, although results are not entirely consistent. In a sample of 282 female Caucasian dizygotic twins aged 21-80 years, we aimed to investigate the associations between blood pressure and five single nucleotide polymorphisms (SNPs) including the 825C>T and haplotypes of the GNB3 gene. The polymorphisms (-350A>G, 657A>T, 814G>A, 825C>T and 1429C>T) were genotyped by polymerase chain reaction-restriction enzyme assays. Regular association tests did not show a significant effect on blood pressure for any of the five SNPs. However, strongly significant interactions between the -350A>G, 825C>T and 1429C>T loci and adiposity (both body mass index and waist circumference) were observed for systolic blood pressure (Ps < 0.01) as well as diastolic blood pressure (Ps < 0.05), suggesting increases in adiposity amplify the effects of the SNPs on blood pressure. Haplotype analyses confirmed the effects of the GNB3 gene-obesity interaction on hypertension risk. Additionally, sib-transmission disequilibrium tests (sib-TDTs) showed significant associations with blood pressure for the 825C>T and 1429C>T loci. In summary, the presence of obesity reveals an association between blood pressure and the GNB3 gene in White females. Our data suggest that adiposity is a final pathway through which gene-lifestyle interactions may exert their effects on the development of hypertension. Our results from the combined SNP, haplotype and sib-TDT analyses also support the hypothesis that the 825C>T is a susceptibility locus for hypertension, whereas effects of other loci on blood pressure may result from their strong linkage disequilibrium with the 825C>T locus.


First Described Case of Anterior and Posterior Segment Crystals in Phacolytic Glaucoma.
Phacolytic glaucoma is an open-angle glaucoma that occurs when lens proteins from hypermature cataracts seep through an intact anterior capsule and induce obstruction of the trabecular meshwork by inflammatory cells. We review the case of a 66-year-old man who presented with acute pain, a hypermature cataract, prominent anterior chamber crystals, and elevated intraocular pressure. After cataract surgery was performed, iridescent crystals were noted in the posterior chamber. Anterior chamber crystals have been associated with phacolytic glaucoma, but this is the first case demonstrating crystals in the posterior chamber as well.


International fieldwork placements and occupational therapy: lived experiences of the major stakeholders.
Occupational therapy students obtain a great deal of their professional preparation and experience through fieldwork placements. Although many occupational therapy students have taken part in international fieldwork placements, there is little research on this topic. As fieldwork placements are an integral part of the education of occupational therapy students, literature on the subject of international fieldwork placements is necessary. Accordingly, the aim of this study was to examine the personal and professional experiences of occupational therapy students, supervisors, and on-site staff who have taken part in an international fieldwork placement. Qualitative interviews for this phenomenological study were administered with 14 participants who had taken part in an international fieldwork placement in Trinidad and Tobago. Data were analysed using thematic analysis. Three themes emerged: collaborative learning, cultural negotiations and thinking on my own. Considering fieldwork is a critical component in the occupational therapy curriculum, it is reassuring to uncover that international placements can be of benefit to all stakeholders while achieving its primary goal of preparing students to become competent therapists. All participants developed a greater cultural awareness and appreciation, which is necessary as occupational therapists are increasingly working in diverse settings with diverse client groups. This information can also be used to enhance international fieldwork education as students continue to travel abroad to complete their mandatory fieldwork hours.


Chemical Characterization of Dew Water Collected in Different Geographic Regions of Poland.
The results of a dew monitoring program performed in Poland with the aim to outline the chemical composition of dew water in meteorological context are presented. Dew samples were collected from eight measurement stations from August 2004 to November 2006. Taking into account the type of land use and characteristics of pollutant emission, sampling sites were divided into the following categories: rural, coastal urban and inland urban stations. Selected anions and cations as well as formaldehyde and sum of phenols were determined. The average TIC (Total Inorganic Ionic Content) values in dew samples ranged from 0.83 to 3.93 between individual stations with 10.9 meq/L as the highest daily value of TIC measured. The average TIC values observed in dew at all stations were at a similar level (2.46 meq/L) when compared with hoarfrost (2.86 meq/L). However, these values were much higher in comparison with other kinds of atmospheric water like precipitation (wet only; 0.37 meq/L) or fog/cloud (1.01 meq/L). The pH values of dew water ranged from 5.22 to 7.35 for urban coastal stations, from 5.67 to 8.02 for urban inland stations and from 4.16 to 8.76 for dew samples collected in the rural area. HCHO was found in 97 % of dew samples, with concentrations ranging from 0.010 to 5.40 meq/L. Excluding stations near the seashore, where the contribution of Na⁺ and Cl- increased, the most important ions were sulphates. A very low contribution of NO3- and noticeable increase of Ca2+ which were not observed in the case of precipitation and fog water, were typical in all stations. The contribution of ammonium ion was two times higher at rural stations as a result of agricultural ammonia emissions. The strongest correlations were noticed between the sum of acidifying anions SO₄2- + NO3- and Ca2+ ion for all urban and rural stations. A very strong correlation was also observed for Na+ and Cl⁻ ions in urban coastal stations, as a natural consequence of the location of these stations close to the sea. It was proved that thermal stratification, direction of circulation and local breeze circulation control the atmospheric chemistry at ground level, where dew is formed. The highest TIC values at urban stations were associated with anticyclonic weather, while at rural sites with cyclonic weather situations. The chemistry of dew water in urban coastal stations was closely related to local breeze circulation in the warm season, mainly in the form of diurnal breeze causing a significant increase of the concentration of Na⁺ and Cl⁻ions. Thus, dew can be a good indicator of the atmospheric pollution level at a given site. Taking into account both high TIC values and the annual water equivalent estimated at around 50 mm, dew is a considerable factor of wet deposition, responsible for an additional 60 % of pollutant input into the ground when compared with precipitation.


Maternal Deprivation of Lewis Rat Pups Increases the Severity of Experi-mental Periodontitis in Adulthood.
Early life adverse events may influence susceptibility/resistance to chronic inflammatory diseases later in life by permanently dysregulating brain-controlled immune-regulatory systems. We have investigated the impact of infant-mother separation during early postnatal life on the severity of experimental periodontitis, as well as systemic stress and immune responses, in adulthood. Pups of periodontitis resistant Lewis rats were separated from their mothers for 3 h daily during postnatal days 2-14 (termed maternal deprivation; MD), separated for 15 min daily during the same time period (termed handling; HD), or left undisturbed. As adults, their behaviour was tested in a novel stressful situation, and ligature-induced periodontitis applied for 21 days. Two h before sacrifice all rats were exposed to a gram-negative bacterial lipopolysaccharide (LPS) challenge to induce a robust immune and stress response. Compared to undisturbed controls, MD rats developed significantly more periodontal bone loss as adults, whereas HD rats showed a tendency to less disease. MD and HD rats exhibited depression-like behaviour in a novel open field test, while MD rats showed higher glucocorticoid receptor (Gr) expression in the hippocampus, and HD rats had altered methylation of genes involved in the expression of hippocampal Gr. LPS provoked a significantly lower increase in circulating levels of the cytokine TGF-1β in MD and HD rats, but there were no significant differences in levels of the stress hormone corticosterone. Stressful environmental exposures in very early life may alter immune responses in a manner that influences susceptibility/resistance to periodontitis.


Thermal tissue damage caused by ultrasonic cement removal from the humerus.
Ultrasound devices can selectively remove cement during revision arthroplasty. These instruments initially were designed for the hip and knee but also have been applied to the upper extremity. We describe a patient in whom a radial nerve palsy and a pathologic humeral fracture developed after ultrasonic cement removal was performed because of an infection at the site of a total elbow arthroplasty. Biopsies of the humerus, the triceps muscle, and the radial nerve showed widespread necrosis consistent with thermal injury. A study involving six human cadaveric specimens was conducted to measure temperature elevations in bone and adjacent soft tissue during cement removal with use of an ultrasound device with and without irrigation. While temperature increased only minimally during cement polymerization, ultrasonic melting and removal of cement with use of constant energy delivery led to markedly elevated temperatures in the humeral cortex, the triceps muscle, and the radial nerve. These temperatures were above the known thresholds for thermal injury and necrosis. Subsequently, strategies designed to allow for safe ultrasonic cement removal from the humerus were applied, including intermittent delivery of energy and the use of cold irrigation between probe passes. These strategies resulted in markedly lower maximum temperatures in all tissues tested. Temperatures in the humerus, triceps, and, most importantly, the radial nerve can reach potentially dangerous levels when ultrasound technology is used to remove cement from the humerus. We suggest intermittent cold irrigation of the humeral canal, no tourniquet use, education of surgeons with regard to proper techniques designed to limit heat generation, and consideration of exposure and protection of the radial nerve when ultrasound devices are used.


Aerobic power and lean mass are indicators of competitive sprint performance among elite female cross-country skiers.
The purpose of this study was to establish the optimal allometric models to predict International Ski Federation's ski-ranking points for sprint competitions (FISsprint) among elite female cross-country skiers based on maximal oxygen uptake ( [Formula: see text]) and lean mass (LM). Ten elite female cross-country skiers (age: 24.5±2.8 years [mean ± SD]) completed a treadmill roller-skiing test to determine [Formula: see text] (ie, aerobic power) using the diagonal stride technique, whereas LM (ie, a surrogate indicator of anaerobic capacity) was determined by dual-emission X-ray anthropometry. The subjects' FISsprint were used as competitive performance measures. Power function modeling was used to predict the skiers' FISsprint based on [Formula: see text], LM, and body mass. The subjects' test and performance data were as follows: [Formula: see text], 4.0±0.3 L min-1; LM, 48.9±4.4 kg; body mass, 64.0±5.2 kg; and FISsprint, 116.4±59.6 points. The following power function models were established for the prediction of FISsprint: [Formula: see text] and 6.95 × 1010 · LM-5.25; these models explained 66% (P=0.0043) and 52% (P=0.019), respectively, of the variance in the FISsprint. Body mass failed to contribute to both models; hence, the models are based on [Formula: see text] and LM expressed absolutely. The results demonstrate that the physiological variables that reflect aerobic power and anaerobic capacity are important indicators of competitive sprint performance among elite female skiers. To accurately indicate performance capability among elite female skiers, the presented power function models should be used. Skiers whose [Formula: see text] differs by 1% will differ in their FISsprint by 5.8%, whereas the corresponding 1% difference in LM is related to an FISsprint difference of 5.1%, where both differences are in favor of the skier with higher [Formula: see text] or LM. It is recommended that coaches use the absolute expression of these variables to monitor skiers' performance-related training adaptations linked to changes in aerobic power and anaerobic capacity.


40Ar-39Ar Dating of the Manson Impact Structure: A Cretaceous-Tertiary Boundary Crater Candidate.
The mineralogy of shocked mineral and lithic grains in the Cretaceous-Tertiary (K-T) boundary claystone worldwide is most consistent with a bolide impact on a continent. Both the concentrations and sizes of these shocked grains are greatest in the western interior of North America. These data suggest that the Manson impact structure in north-central Iowa is a viable candidate for the K-T boundary impact event. Argon-40-argon-39 age spectrum dating of shocked microcline from the crystalline central uplift of the Manson impact structure indicates that there was severe argon-40 loss at 65.7 +/- 1.0 million years ago, an age that is indistinguishable from that of the K-T boundary, within the limits of analytical precision.


Diffuse pollution monitoring and modelling of small urban watershed in Brazil Cerrado.
The stormwater runoff carries different pollutants that can reduce the quality of receiving waters due to diffuse pollutant loads. This research was aimed at evaluating the concentration of pollutants in stormwater and the application of SWMM (Storm Water Management Model) to an urban catchment in Lake Paranoá watershed to carry out the simulation of flow discharge with the hydraulic model, and subsequently to estimate the loads conveyed to the lake in ordinary events of precipitation. This study was carried out based on rainfall and runoff monitoring during events. It was confirmed that this model's results fit well in simulation of this type of watershed, leading to high value of the Nash-Sutcliffe coefficient after calibration but, as expected, precipitation distribution is a very important factor for calibration. Concerning water quality, it was observed that the event mean concentration values of suspended solids and chemical oxygen demand were high, indicating that the diffuse pollution is an important source of pollution of the receiving waters. The monitoring and modelling of stormwater are essential to identify diffuse pollution discharge, in searching for a sustainable solution.


Multifunctional hetero-nanostructures of hydroxyl-rich polycation wrapped cellulose-gold hybrids for combined cancer therapy.
The development of new hetero-nanostructures for multifunctional applications in cancer therapy has attracted widespread attention. In this work, we put forward a facile approach to synthesize multifunctional hetero-nanostructures of cellulose nanocrystal (CNC)-gold nanoparticle hybrids wrapped with low-toxic hydroxyl-rich polycations to integrate versatile functions for effective cancer therapy. Biocompatible CNCs with the superior rod-like morphology for high cellular uptake were employed as substrates to flexibly load spherical gold nanoparticles (Au NPs) or gold nanorods (Au NRs) through gold-thiolate bonds, producing hetero-layered nanohybrids of CNC-Au NPs or CNC-Au NRs. Profound hydroxyl-rich cationic gene carrier, CD-PGEA (comprising β-cyclodextrin cores and ethanolamine-functionalized poly(glycidyl methacrylate) arms), was then assembled onto the surface of CNC-Au nanohybrids through host-guest interaction and gold-thiolate bonds, where PEG was employed as the intermediate and spacer. The resultant CNC-Au-PGEA hetero-nanostructures exhibited excellent performances as gene carriers. Furthermore, CNC-Au NR-PGEA comprising Au NRs demonstrated favorable optical absorption properties and were validated for photoacoustic imaging and combined photothermal/gene therapy with considerable antitumor effects. The present work provided a flexible strategy for the construction of new multifunctional hetero-nanostructures with high antitumor efficacy.


Fundamental trade-offs between information flow in single cells and cellular populations.
Signal transduction networks allow eukaryotic cells to make decisions based on information about intracellular state and the environment. Biochemical noise significantly diminishes the fidelity of signaling: networks examined to date seem to transmit less than 1 bit of information. It is unclear how networks that control critical cell-fate decisions (e.g., cell division and apoptosis) can function with such low levels of information transfer. Here, we use theory, experiments, and numerical analysis to demonstrate an inherent trade-off between the information transferred in individual cells and the information available to control population-level responses. Noise in receptor-mediated apoptosis reduces information transfer to approximately 1 bit at the single-cell level but allows 3-4 bits of information to be transmitted at the population level. For processes such as eukaryotic chemotaxis, in which single cells are the functional unit, we find high levels of information transmission at a single-cell level. Thus, low levels of information transfer are unlikely to represent a physical limit. Instead, we propose that signaling networks exploit noise at the single-cell level to increase population-level information transfer, allowing extracellular ligands, whose levels are also subject to noise, to incrementally regulate phenotypic changes. This is particularly critical for discrete changes in fate (e.g., life vs. death) for which the key variable is the fraction of cells engaged. Our findings provide a framework for rationalizing the high levels of noise in metazoan signaling networks and have implications for the development of drugs that target these networks in the treatment of cancer and other diseases.


Assessing the Costs and Benefits of Insuring Psychological Services as Part of Medicare for Depression in Canada.
The study estimated costs and effects associated with increasing access to publicly funded psychological services for depression in a public health care system. Discrete event simulation modeled clinical events (relapse, recovery, hospitalizations, suicide attempts, and suicide), health service use, and cost outcomes over 40 years in a population with incident depression. Parameters included epidemiologic and economic data from the literature and data from a secondary analysis of the 2012 Canadian Community Health Survey on mental health. Societal costs were measured with the human capital approach. Analyses estimated the incremental cost-effectiveness ratio associated with improved access to psychological services among individuals not receiving adequate mental health care and reporting an unmet need for such care compared with present use of health services for mental health reasons. Over 40 years, increased access to mental health services in a simulated population of adults with incident depression would lead to significantly lower lifetime prevalence of hospitalizations (27.9% versus 30.2% base case) and suicide attempts (14.1% versus 14.6%); fewer suicides (184 versus 250); a per-person gain of .17 quality-adjusted life years; and average societal cost savings of $2,590 CAD per person (range $1,266-$6,320). Publicly funding psychological services would translate to additional costs of $123,212,872 CAD ($67,709,860-$190,922,732) over 40 years. Savings to society would reach, on average, $246,997,940 CAD ($120,733,356-$602,713,120). In Canada, every $1 invested in covering psychological services would yield $2.00 ($1.78 to $3.15) in savings to society. Covering psychological services as part of Medicare for individuals with an unmet need for mental health care would pay for itself.


Microvascular invasion in hepatocellular carcinoma.
Microvascular invasion is a crucial histopathologic prognostic factor for hepatocellular carcinoma. We reviewed the literature and aimed to draw attention to clinicopathologic and imaging findings that may predict the presence of microvascular invasion in hepatocellular carcinoma. Imaging findings suggesting microvascular invasion are disruption of capsule, irregular tumor margin, peritumoral enhancement, multifocal tumor, increased tumor size, and increased glucose metabolism on positron emission tomography-computed tomography. In the presence of typical findings, microvascular invasion may be predicted.


Clinical pharmacokinetics of metformin.
Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine. Metformin is excreted unchanged in urine. The elimination half-life (t(½)) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CL(R)) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CL(R) and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CL(CR)). As the CL(R) and CL/F decrease approximately in proportion to CL(CR), the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CL(CR). The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin. Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5 mg/L in order to minimize the development of this adverse effect.


Impact of Acyl Chain Mismatch on the Formation and Properties of Sphingomyelin-Cholesterol Domains.
Lateral segregation and the formation of lateral domains are well-known phenomena in ternary lipid bilayers composed of an unsaturated (low gel-to-liquid phase transition temperature (Tm)) phospholipid, a saturated (high-Tm) phospholipid, and cholesterol. The formation of lateral domains has been shown to be influenced by differences in phospholipid acyl chain unsaturation and length. Recently, we also showed that differential interactions of cholesterol with low- and high-Tm phospholipids in the bilayer can facilitate phospholipid segregation. Now, we have investigated phospholipid-cholesterol interactions and their role in lateral segregation in ternary bilayers composed of different unsaturated phosphatidylcholines (PCs) with varying acyl chain lengths, N-palmitoyl-D-erythro-sphingomyelin (PSM), and cholesterol. Using deuterium NMR spectroscopy, we determined how PSM was influenced by the acyl chain composition in surrounding PC environments and correlated this with the affinity of cholestatrienol (a fluorescent cholesterol analog) for PSM in the different PC environments. Results from a combination of time-resolved fluorescence measurements of trans-parinaric acid and Förster resonance energy transfer experiments showed that the relative affinity of cholesterol for phospholipids determined the degree to which the sterol promoted domain formation. From Förster resonance energy transfer, deuterium NMR, and differential scanning calorimetry results, it was clear that cholesterol also influenced both the thermostability of the domains and the degree of order in and outside the PSM-rich domains. The results of this study have shown that the affinity of cholesterol for both low-Tm and high-Tm phospholipids and the effects of low- and high-Tm phospholipids on each other influence both lateral structure and domain properties in complex bilayers. We envision that similar effects also contribute to lateral heterogeneity in even more complex biological membranes.


Inactivation of the srtA gene in Listeria monocytogenes inhibits anchoring of surface proteins and affects virulence.
During infection of their hosts, Gram-positive bacteria express surface proteins that serve multiple biological functions. Surface proteins harbouring a C-terminal sorting signal with an LPXTG motif are covalently linked to the cell wall peptidoglycan by a transamidase named sortase. Two genes encoding putative sortases, termed srtA and srtB, were identified in the genome of the intracellular pathogenic bacterium Listeria monocytogenes. Inactivation of srtA abolishes anchoring of the invasion protein InlA to the bacterial surface. It also prevents the proper sorting of several other peptidoglycan-associated LPXTG proteins. Three were identified by a mass spectrometry approach. The DeltasrtA mutant strain is defective in entering epithelial cells, similar to a DeltainlA mutant. In contrast to a DeltainlA mutant, the DeltasrtA mutant is impaired for colonization of the liver and spleen after oral inoculation in mice. Thus, L. monocytogenes srtA is required for the cell wall anchoring of InlA and, presumably, for the anchoring of other LPXTG-containing proteins that are involved in listerial infections.


Development of a Non-Invasive Blink Reflexometer.
Qualitative assessments of the blink reflex are used clinically to assess neurological status in critical care, operating room, and rehabilitative settings. Despite decades of literature supporting the use of quantitative measurements of the blink reflex in the evaluation of multiple neurological disorders, clinical adoption has failed. Thus, there remains an unmet clinical need for an objective, portable, non-invasive metric of neurological health that can be used in a variety of settings. We have developed a high-speed videography-based device to trigger, record, and analyze a blink reflex. A pilot study was performed to compare the device's measurements to the published literature of electromyographic measurements, currently the gold standard. The study results indicate that the device is a viable tool to obtain fast, objective, and quantitative metrics of a blink reflex, and has promise as a non-invasive diagnostic assessment of neurological health.


Psychological determinants of physical activity in Japanese female employees.
To understand how psychological characteristics influence adoption and maintenance of physical activity/exercise, we conducted a cross-sectional study among Japanese employees based upon the idea of stages of behavior modification. The study population consisted of 719 employees (male, 396, female, 323) from five medium-sized manufacturing companies (50-200 employees) in Okayama Prefecture, Japan. The female response rate was 67.5% (n=218), among which 201 eligible female subjects (62.2%) were analyzed. The study questionnaire included demographic characteristics, physical activity/exercise measures, self-efficacy measures, and perceived benefit and barriers scales. Participants were asked to select the items that best described their current physical activity/exercise level from an 8-item questionnaire, and we converted their answers to the 5 stages of change according to a transtheoretical model of behavior change. Perceived benefit and barrier scales were classified into 7 factors (4 benefits and 3 barriers) by factor analyses. The relationship between psychological determinants and the stage of physical activity/exercise was examined by one-way analysis of variance. Only 10% of the subjects had moderate physical activity (in the action and maintenance stages) regularly. We found that self-efficacy, "weight control benefit", "physical barrier" and "time barrier" were psychological determinants of physical activity/exercise stages in female employees, and especially there was a consistent relationship between self-efficacy and the stage of physical activity/exercise. Our data suggest that health education for Japanese female employees requires that health professionals should provide support for strengthening self-efficacy, show practical ways to increase physical activity in daily life, and provide broad and accurate information showing that physical activity/exercise have a good effect on health.


Conventional versus LigaSure hemorrhoidectomy for patients with symptomatic Hemorrhoids.
Hemorrhoidectomy is a frequently performed surgical procedure and associated with postprocedural pain. The use of the Ligasure could result in a decreased incidence of pain as coagulation with high frequency currency and active feedback control over the power output has minimal thermal spread and limited tissue charring. To compare patient tolerance focussing on pain following Ligasure and conventional hemorrhoidectomy in patients with symptomatic hemorrhoids. A multi-database (MEDLINE, EMBASE, CENTRAL and CINAHL) systematic search was conducted. Key journals were handsearched. There was no restriction on language. Randomized controlled trials comparing hemorroidectomy using the Ligasure-technique with conventional diathermy techniques for symptomatic hemorrhoids in adult patients were included. Two reviewers independently extracted data, assessed trial quality and resolved discrepancies together with a third party. Odd Ratios were generated for dichotomous variables. Weight Mean Differences were used for analysing continuous variables. Only random effects models were used. Heterogeneity was explored by sensitvity analysis. Twelve studies with 1142 patients met the inclusion criteria. The pain score at the first day following surgery was significantly less in the Ligasure group (10 studies, 835 patients, WMD -2.07 CI -2.77 to -1.38). Most outcomes concerning analgesics used (7 studies) and pain scores up to 7 days (5 studies) favoured the Ligasure-technique. The benefit was diminished at day 14 (VAS pain score, 4 studies, 183 patients, WMD -0.12 CI -0.37 to 0.12). The conventional technique took significantly longer to complete (11 trials, 9.15 minutes, CI 3.21 to 15.09). There was no relevant difference in postoperative complications, symptoms of recurrent bleeding or incontinence at final follow-up. Hospital stay was similar for both groups (6 reports, 525 patients, WMD -0.19 CI -0.63 to 0.24). Patients treated with the Ligasure-technique returned to work significantly earlier (4 studies, 451 patients, 4.88 days, CI 2.18 to 7.59). Sensitivity analysis on high quality studies, fixed effects models, open or closed conventional techniques revealed no clinical relevant different results. Since the usage of the Ligasure technique results in significantly less immediate postoperative pain after hemoroidectomy without any adverse effect on postoperative complications, convalescence and incontinence-rate, this technique is superior in terms of patient tolerance. Although there was a tendency for equal efficacy, more evaluation of the long-term risk of recurrent hemorrhoidal disease is required.


Effects of dietary fat intervention on mental health in women.
Several studies have identified potential detrimental sequelae of cholesterol and fat-lowering interventions in randomized trial. Little research has been published to document changes in mental health in women as a result of fat and cholesterol lowering interventions to prevent chronic disease. This paper examines the relationships among changes in dietary fat consumption and mental health in the Women's Health Trial, a randomized, controlled trial to determine whether lowering fat consumption to 20% of daily calories could reduce the incidence of breast cancer in women ages 45-69 years. Assessments were made at baseline and at the 12-month follow-up of several aspects of quality of life, including negative and positive affect and past, present, and future perceptions of health. Mental health variables were measured by the Mental Health Inventory, a standardized scale used in the Medical Outcomes study. Dietary intake was assessed for all subjects with the use of semiquantitative food frequency questionnaires. The change in mental health values (follow-up minus baseline) was significantly different between intervention and control groups for three of the four psychological variables: (a) anxiety; (b) depression; and (c) vigor. In all three cases, the direction of the change for intervention women was positive. Neither randomization assignment nor percent of calories from fat at the follow-up visit were significant predictors of mental health at the 1-year follow-up. Cholesterol changes were not related to levels of mental health variables in a sample of the women. These data indicate that lowering fat in the diets of healthy women does not produce overall lowering of any mental health variables.(ABSTRACT TRUNCATED AT 250 WORDS)


Patchiness and duodenal-jejunal variation of the mucosal abnormality in coeliac disease and dermatitis herpetiformis.
The incidence and degree of patchiness of mucosal abnormality in both coeliac disease (CD) and dermatitis herpetiformis (DH) is documented. As judged by both stereomicroscopy and subjective histology, patchiness occurred frequently in both CDand DH patients. In most cases the difference of abnormality was of only one grade, but in approximately 25% as assessed by stereomicroscopy and 10% as assessed by histology the difference was of two or more grades. In control subjects with normal small bowel mucosa the variation of the mucosal appearance between the duodenum and proximal jejunum was studied. Contrary to popular belief, no significant difference of villous and crypt measurements or of apparent villous "bridging" and "branching" between these two sites was found, if only well-orientated sections were studied. The stereomicroscopic appearances were also similar at these two sites, although villi tended to be broader in the duodenal biopsies. The duodenal-jejunal variation was also studied in CD and DH patients and although by both stereomicroscopy and subjective histology the appearances were similar in most patients, in approximately 33% the duodenal abnormality was the most severe and, surprisingly, the jejunal abnormality was more severe in approximately 15%. It is concluded that multiple, precisely located biopsies of both the duodenum and proximal jejunum are invaluable in the investigation of small bowel disease and in assessing response to treatment.


Towards Cost-Effective Operational Monitoring Systems for Complex Waters: Analyzing Small-Scale Coastal Processes with Optical Transmissometry.
The detection and prediction of changes in coastal ecosystems require a better understanding of the complex physical, chemical and biological interactions, which involves that observations should be performed continuously. For this reason, there is an increasing demand for small, simple and cost-effective in situ sensors to analyze complex coastal waters at a broad range of scales. In this context, this study seeks to explore the potential of beam attenuation spectra, c(λ), measured in situ with an advanced-technology optical transmissometer, for assessing temporal and spatial patterns in the complex estuarine waters of Alfacs Bay (NW Mediterranean) as a test site. In particular, the information contained in the spectral beam attenuation coefficient was assessed and linked with different biogeochemical variables. The attenuation at λ = 710 nm was used as a proxy for particle concentration, TSM, whereas a novel parameter was adopted as an optical indicator for chlorophyll a (Chl-a) concentration, based on the local maximum of c(λ) observed at the long-wavelength side of the red band Chl-a absorption peak. In addition, since coloured dissolved organic matter (CDOM) has an important influence on the beam attenuation spectral shape and complementary measurements of particle size distribution were available, the beam attenuation spectral slope was used to analyze the CDOM content. Results were successfully compared with optical and biogeochemical variables from laboratory analysis of collocated water samples, and statistically significant correlations were found between the attenuation proxies and the biogeochemical variables TSM, Chl-a and CDOM. This outcome depicted the potential of high-frequency beam attenuation measurements as a simple, continuous and cost-effective approach for rapid detection of changes and patterns in biogeochemical properties in complex coastal environments.


Chimpanzee reservoirs of pandemic and nonpandemic HIV-1.
Human immunodeficiency virus type 1 (HIV-1), the cause of human acquired immunodeficiency syndrome (AIDS), is a zoonotic infection of staggering proportions and social impact. Yet uncertainty persists regarding its natural reservoir. The virus most closely related to HIV-1 is a simian immunodeficiency virus (SIV) thus far identified only in captive members of the chimpanzee subspecies Pan troglodytes troglodytes. Here we report the detection of SIVcpz antibodies and nucleic acids in fecal samples from wild-living P. t. troglodytes apes in southern Cameroon, where prevalence rates in some communities reached 29 to 35%. By sequence analysis of endemic SIVcpz strains, we could trace the origins of pandemic (group M) and nonpandemic (group N) HIV-1 to distinct, geographically isolated chimpanzee communities. These findings establish P. t. troglodytes as a natural reservoir of HIV-1.


An atlas of the speed of copy number changes in animal gene families and its implications.
The notion that gene duplications generating new genes and functions is commonly accepted in evolutionary biology. However, this assumption is more speculative from theory rather than well proven in genome-wide studies. Here, we generated an atlas of the rate of copy number changes (CNCs) in all the gene families of ten animal genomes. We grouped the gene families with similar CNC dynamics into rate pattern groups (RPGs) and annotated their function using a novel bottom-up approach. By comparing CNC rate patterns, we showed that most of the species-specific CNC rates groups are formed by gene duplication rather than gene loss, and most of the changes in rates of CNCs may be the result of adaptive evolution. We also found that the functions of many RPGs match their biological significance well. Our work confirmed the role of gene duplication in generating novel phenotypes, and the results can serve as a guide for researchers to connect the phenotypic features to certain gene duplications.


A human case of otoacariasis involving a histiostomatid mite (Acari: Histiostomatidae).
A 31-year-old Saudi man was seen at an ear, nose, and throat clinic at Riyadh, Saudi Arabia, with bilateral itching in the external auditory canal. On otoscopic examination, the skin lining the ear canal was thickened with whitish sheets of sloughed cells and thick discharge. Large numbers of mites of an undescribed species closely related to members of the genus Loxanoetus (Histiostomatidae) were present. The patient underwent successive washings of the ear canal with saline and 70% ethanol at intervals of 2-3 months and was treated with antibiotics. Treatment with Eurax (crotamiton) ear drops for one week cleared the mite infestation. This represents the first reported case of human otoacariasis involving a histiostomatid mite. Based on the known biology of histiostomatid mites and the associated hosts of Loxanoetus and related genera, there is reason to speculate that the patient acquired the infestation while swimming in a lake or pond where this mite was present.


Impact of Drug Induced Long QT Syndrome: A Systematic Review.
Drug induced long QT syndrome is quite common in daily clinical practice but its impact is unknown. PubMed and EMBASE databases (until May 2, 2017) were searched to identify studies reporting drug induced long QT syndrome and followed the PRISMA guidelines. The main outcomes measured in these studies were QTc prolongation, ventricular arrhythmias, torsade de pointes (TdP) and death. Out of 176 non-duplicate reports, 36 studies satisfied inclusion criteria and provided data on patients exposed to drugs that can potentially cause long QT. Totally, 14,756 patients were exposed and 930 patients (6.3%) were found to have QTc prolongation. The number of males was 6,400 and females were 5,723 patients. The mean age of the patients was 43.8 ± 9.36 years. Ventricular arrhythmias were found in 379 patients (2.6%), 26 patients were found to have premature atrial contractions (PACs) and premature ventricular contractions (PVCs). TdP was found in 49 patients (0.33 %), sudden cardiac death (SCD) was found in five patients and 586 patients were found to have all-cause mortality. Around 6% of patients have risk of QT prolongation when exposed but only 0.3% developed TdP and 2.6% developed ventricular arrhythmias. Risk of developing arrhythmias is higher with concomitant use of multiple QT prolonging drugs.


Constant relative rate of protein evolution and detection of functional diversification among bacterial, archaeal and eukaryotic proteins.
Detection of changes in a protein's evolutionary rate may reveal cases of change in that protein's function. We developed and implemented a simple relative rates test in an attempt to assess the rate constancy of protein evolution and to detect cases of functional diversification between orthologous proteins. The test was performed on clusters of orthologous protein sequences from complete bacterial genomes (Chlamydia trachomatis, C. muridarum and Chlamydophila pneumoniae), complete archaeal genomes (Pyrococcus horikoshii, P. abyssi and P. furiosus) and partially sequenced mammalian genomes (human, mouse and rat). Amino-acid sequence evolution rates are significantly correlated on different branches of phylogenetic trees representing the great majority of analyzed orthologous protein sets from all three domains of life. However, approximately 1% of the proteins from each group of species deviates from this pattern and instead shows variation that is consistent with an acceleration of the rate of amino-acid substitution, which may be due to functional diversification. Most of the putative functionally diversified proteins from all three species groups are predicted to function at the periphery of the cells and mediate their interaction with the environment. Relative rates of protein evolution are remarkably constant for the three species groups analyzed here. Deviations from this rate constancy are probably due to changes in selective constraints associated with diversification between orthologs. Functional diversification between orthologs is thought to be a relatively rare event. However, the resolution afforded by the test designed specifically for genomic-scale datasets allowed us to identify numerous cases of possible functional diversification between orthologous proteins.


Spx mediates oxidative stress regulation of the methionine sulfoxide reductases operon in Bacillus subtilis.
All aerobically grown living cells are exposed to oxidative damage by reactive oxygen species (ROS). A major damage by ROS to proteins is caused by covalent modifications of methionine residues giving methionine sulfoxide (Met-SO). Methionine sulfoxide reductases are enzymes able to regenerate methionine and restore protein function after oxidative damage. We characterized the methionine sulfoxide reductase genes msrA and msrB in Bacillus subtilis, forming an operon transcribed from a single sigma A-dependent promoter. The msrAB operon was specifically induced by oxidative stress caused by paraquat (PQ) but not by H2O2. Spx, a global oxidative stress regulator in B. subtilis, is primarily responsible for this PQ-specific induction of msrAB expression. In support of this finding, an spx deletion mutant is extremely sensitive to PQ, and increased expression of msrA was identified in a clpX mutant in which Spx accumulated. However, the Spx effect was also visible under conditions where the protein did not accumulate (PQ treatment), suggesting a specific molecular effect at the level of the Spx protein. Indeed, the CXXC motif of Spx was found essential for its function in the PQ-specific induction of msrAB expression. PQ caused a modification of Spx requiring at least one of the cysteines of the CXXC motif of Spx. The PQ modified form of Spx showed a dynamic change in vivo. The Spx mediated PQ-specific regulation pathway of the msrAB operon in B. subtilis is reported. Our results suggest that PQ induced the expression of msrAB partially through an oxidation on Spx via modification of its CXXC motif.


Threat-related selective attention predicts treatment success in childhood anxiety disorders.
The present study examined whether threat-related selective attention was predictive of treatment success in children with anxiety disorders and whether age moderated this association. Specific components of selective attention were examined in treatment responders and nonresponders. Participants consisted of 131 children with anxiety disorders (aged 8-16 years), who received standardized cognitive-behavioral therapy. At pretreatment, a pictorial dot-probe task was administered to assess selective attention. Both at pretreatment and posttreatment, diagnostic status of the children was evaluated with a semistructured clinical interview (the Anxiety Disorders Interview Schedule for Children). Selective attention for severely threatening pictures at pretreatment assessment was predictive of treatment success. Examination of the specific components of selective attention revealed that nonresponders showed difficulties to disengage their attention away from severe threat. Treatment responders showed a tendency not to engage their attention toward severe threat. Age was not associated with selective attention and treatment success. Threat-related selective attention is a significant predictor of treatment success in children with anxiety disorders. Clinically anxious children with difficulties disengaging their attention away from severe threat profit less from cognitive-behavioral therapy. For these children, additional training focused on learning to disengage attention away from anxiety-arousing stimuli may be beneficial.


Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity.
There is considerable variation in the level of toxicity patients experience for a given dose of radiotherapy, which is associated with differences in underlying individual normal tissue radiosensitivity. A number of syndromes have a large effect on clinical radiosensitivity, but these are rare. Among non-syndromic patients, variation is less extreme, but equivalent to a ±20% variation in dose. Thus, if individual normal tissue radiosensitivity could be measured, it should be possible to optimise schedules for individual patients. Early investigations of in vitro cellular radiosensitivity supported a link with tissue response, but individual studies were equivocal. A lymphocyte apoptosis assay has potential, and is currently under prospective validation. The investigation of underlying genetic variation also has potential. Although early candidate gene studies were inconclusive, more recent genome-wide association studies are revealing definite associations between genotype and toxicity and highlighting the potential for future genetic testing. Genetic testing and individualised dose prescriptions could reduce toxicity in radiosensitive patients, and permit isotoxic dose escalation to increase local control in radioresistant individuals. The approach could improve outcomes for half the patients requiring radical radiotherapy. As a number of patient- and treatment-related factors also affect the risk of toxicity for a given dose, genetic testing data will need to be incorporated into models that combine patient, treatment and genetic data.


SLIM: an improved generalized Born implicit membrane model.
In most implicit continuum models, membranes are represented as heterogeneous dielectric environments, but their treatment within computationally efficient generalized Born (GB) models is challenging. Despite several previous attempts, an adequate description of multiple dielectric regions in implicit GB-based membrane models that reproduce the qualitative and quantitative features of Poisson-Boltzmann (PB) electrostatics remains an unmet prerequisite of qualitatively correct implicit membrane models. A novel scheme (SLIM) to decompose one environment consisting of multiple dielectric regions into a sum of multiple environments consisting only of two dielectric regions each is proposed to solve this issue. These simpler environments can be treated with established GB methods. This approach captures qualitative features of PB electrostatic that are not present in previous models. Simulations of three membrane proteins demonstrate that this model correctly reproduces known properties of these proteins in agreement with experimental or other computational studies.


Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the Radiation Therapy Oncology Group 0129 trial: long-term report of efficacy and toxicity.
We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost (AFX-C) versus standard fractionation (SFX) in locally advanced head and neck carcinoma (LA-HNC). Patients had stage III to IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks (SFX) or 72 Gy in 42 fractions over 6 weeks (AFX-C). Cisplatin doses were 100 mg/m(2) once every 3 weeks for two (AFX-C) or three (SFX) cycles. Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. Overall survival (OS) and progression-free survival (PFS) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test. Locoregional failure (LRF) and distant metastasis (DM) rates were estimated by using the cumulative incidence method and Gray's test. In all, 721 of 743 patients were analyzable (361, SFX; 360, AFX-C). At a median follow-up of 7.9 years (range, 0.3 to 10.1 years) for 355 surviving patients, no differences were observed in OS (hazard ratio [HR], 0.96; 95% CI, 0.79 to 1.18; P = .37; 8-year survival, 48% v 48%), PFS (HR, 1.02; 95% CI, 0.84 to 1.24; P = .52; 8-year estimate, 42% v 41%), LRF (HR, 1.08; 95% CI, 0.84 to 1.38; P = .78; 8-year estimate, 37% v 39%), or DM (HR, 0.83; 95% CI, 0.56 to 1.24; P = .16; 8-year estimate, 15% v 13%). For oropharyngeal cancer, p16-positive patients had better OS than p16-negative patients (HR, 0.30; 95% CI, 0.21 to 0.42; P < .001; 8-year survival, 70.9% v 30.2%). There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status. When combined with cisplatin, AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC. Long-term high survival rates in p16-positive patients with oropharyngeal cancer support the ongoing efforts to explore deintensification.


Self-sorting molecular clips.
We report the synthesis and characterization of 12 C-shaped methylene-bridged glycoluril dimers (1-12) bearing H-bonding groups on their aromatic rings. Compounds 1, 2, (+/-)-4a, (+/-)-5, (+/-)-7, and 8 form tightly associated homodimers in CDCl3, due to the combined driving force of pi-pi and H-bonding interactions. Compounds 2, (+/-)-5, and 8, having disparate spatial distribution of their H-bonding groups, display the ability to efficiently distinguish between self and nonself even within three-component mixtures in CDCl3. When the spatial distributions of the H-bonding groups of the molecular clips are similar (e.g., 1 and 2), a mixture of homodimers and heterodimers is formed. The effect of various structural modifications (e.g., chirality, side chain steric bulk, number and pattern of H-bonds) on the strength of self-assembly and the fidelity of self-sorting are presented. On the basis of these results we prepared self-sorting systems comprising three (e.g., 1, (+/-)-5, and (+/-)-7) and even four ( 2, (+/-)-5, 9, and 10) components. The potential of molecular clips 1-12 as robust, functionalizable, self-sorting modules to control the noncovalent interaction network in systems chemistry studies is described.


Gut Dysbiosis Dysregulates Central and Systemic Homeostasis via Suboptimal Mitochondrial Function: Assessment, Treatment and Classification Implications.
The gut and mitochondria have emerged as two important hubs at the cutting edge of research across a diverse array of medical conditions, including most psychiatric conditions. This article highlights the interaction of the gut and mitochondria over the course of development, with an emphasis on the consequences for transdiagnostic processes across psychiatry, but with relevance to wider medical conditions. As well as raised levels of circulating lipopolysaccharide (LPS) arising from increased gut permeability, the loss of the short-chain fatty acid, butyrate, is an important mediator of how gut dysbiosis modulates mitochondrial function. Reactive cells, central glia and systemic immune cells are also modulated by the gut, in part via impacts on mitochondrial function in these cells. Gut-driven alterations in the activity of reactive cells over the course of development are proposed to be an important determinant of the transdiagnostic influence of glia and the immune system. Stress, including prenatal stress, also acts via the gut. The suppression of butyrate, coupled to raised LPS, drives oxidative and nitrosative stress signalling that culminates in the activation of acidic sphingomyelinase-induced ceramide. Raised ceramide levels negatively regulate mitochondrial function, both directly and via its negative impact on daytime, arousal-promoting orexin and night-time sleep-promoting pineal gland-derived melatonin. Both orexin and melatonin positively regulate mitochondria oxidative phosphorylation. Consequently, gut-mediated increases in ceramide have impacts on the circadian rhythm and the circadian regulation of mitochondrial function. Butyrate, orexin and melatonin can positively regulate mitochondria via the disinhibition of the pyruvate dehydrogenase complex, leading to increased conversion of pyruvate to acetyl- CoA. Acetyl-CoA is a necessary co-substrate for the initiation of the melatonergic pathway in mitochondria and therefore the beneficial effects of mitochondria melatonin synthesis on mitochondrial function. This has a number of treatment implications across psychiatric and wider medical conditions, including the utilization of sodium butyrate and melatonin. Overall, gut dysbiosis and increased gut permeability have significant impacts on central and systemic homeostasis via the regulation of mitochondrial function, especially in central glia and systemic immune cells.


Body Odor and Sex: Do Cuticular Hydrocarbons Facilitate Sexual Attraction in the Small Hairy Maggot Blowfly?
Cuticular hydrocarbons (CHCs) play an important role as contact pheromones in insects, particularly in flies. However, for many fly taxa our understanding of the importance of CHCs in sexual communication is limited. Within the family Calliphoridae (blowflies), sex-specific differences in CHCs have been reported for several species, but there is no evidence that CHCs facilitate sexual behavior. In order to elucidate the function of CHCs in Calliphoridae, studies combining behavioral and chemical analyses are required. The present study used gas chromatography/mass spectrometry, along with behavioral assays, to assess whether CHCs facilitate sexual attraction in the small hairy maggot blowfly, Chrysomya varipes. The specific aims were to: 1) determine if CHCs differ between the sexes and 2) assess whether flies exhibit positive chemotaxis to CHCs of the opposite sex. Fifty-two hydrocarbons common to both sexes were identified, and quantitative differences for numerous CHCs were observed between the sexes. However, behavioral assays provided no evidence that flies were attracted to CHCs of the opposite sex, challenging the hypothesis that CHCs facilitate sexual attraction in Ch. varipes. In contrast to other blowflies, Ch. varipes males invest heavily in courtship displays and ornamentation, so we speculate that visual communication in this species may have relaxed sexual selection for chemical communication. More broadly, our findings support suggestions that CHCs may not always facilitate insect sexual communication.


Ascl1b and Neurod1, instead of Neurog3, control pancreatic endocrine cell fate in zebrafish.
NEUROG3 is a key regulator of pancreatic endocrine cell differentiation in mouse, essential for the generation of all mature hormone producing cells. It is repressed by Notch signaling that prevents pancreatic cell differentiation by maintaining precursors in an undifferentiated state. We show that, in zebrafish, neurog3 is not expressed in the pancreas and null neurog3 mutant embryos do not display any apparent endocrine defects. The control of endocrine cell fate is instead fulfilled by two basic helix-loop-helix factors, Ascl1b and Neurod1, that are both repressed by Notch signaling. ascl1b is transiently expressed in the mid-trunk endoderm just after gastrulation and is required for the generation of the first pancreatic endocrine precursor cells. Neurod1 is expressed afterwards in the pancreatic anlagen and pursues the endocrine cell differentiation program initiated by Ascl1b. Their complementary role in endocrine differentiation of the dorsal bud is demonstrated by the loss of all hormone-secreting cells following their simultaneous inactivation. This defect is due to a blockage of the initiation of endocrine cell differentiation. This study demonstrates that NEUROG3 is not the unique pancreatic endocrine cell fate determinant in vertebrates. A general survey of endocrine cell fate determinants in the whole digestive system among vertebrates indicates that they all belong to the ARP/ASCL family but not necessarily to the Neurog3 subfamily. The identity of the ARP/ASCL factor involved depends not only on the organ but also on the species. One could, therefore, consider differentiating stem cells into insulin-producing cells without the involvement of NEUROG3 but via another ARP/ASCL factor.


Accuracy of quantitative MR vessel wall imaging applying a semi-automated gradient detection algorithm--a validation study.
Magnetic resonance imaging (MRI) is uniquely suited to study the pathophysiology of arteriosclerosis. So far, magnetic resonance (MR) measurements of vessel dimensions have mainly been done by manual tracing of vessel wall contours. However, such data postprocessing is very time-consuming and has limited accuracy due to difficulties in precise tracing of the thin vessel wall. To assess the accuracy and reproducibility of quantitative vascular MR imaging applying a data analysis method based on (1) vessel wall unwrapping, followed by (2) a gradient detection algorithm for MR data postprocessing. Vascular MR imaging studies were done both in vessel phantoms and in healthy volunteers (n=29) on a clinical 1.5 T MR scanner. A dark blood double-inversion turbo spin echo sequence with fat suppression was applied, with proton-density-weighted and breath-hold acquisition for aortic imaging and T2-weighted acquisition for carotid imaging. Intraobserver and interobserver variability were systematically evaluated by two independent observers. A repeat study within 10 days of the first MRI was performed in 10 of these subjects for assessment of interstudy reproducibility. The semiautomated edge detection software revealed a clear view of the inner and outer vessel wall boundaries both in the phantoms and in the volunteers studied. There was close agreement between MR-derived measurements and phantom dimensions (mean difference of 1.1+/-16.9 mm2, 8.0+/-19.9 mm2, 9.0+/-12.1 mm2 for vessel wall cross-sectional area, inner vessel area, and total vessel area, respectively). Quantification of vessel dimensions was feasible in all 29 healthy volunteers studied. Semiautomated quantification of cross-sectional vessel wall area (mean+/-SD, 253.6+/-208.4 mm2) revealed close correlation for repeated measurements by one or two observers (r=0.99 each). Both intraobserver and interobserver variability of vessel wall area MR measurements were low (mean difference 7.5+/-16.7 mm2 and 14.4+/-24.6 mm2 , respectively). In the repeat study of 10 volunteers, MRI with semiautomated postprocessing quantitation revealed a high correlation and agreement of vessel dimensions between the two scans (r=0.994, mean difference 2.6+/-25.1 mm2). Semiautomated analysis methods can provide approaches that benefit from the human understanding of the image and the computer's ability to measure precisely and rapidly. Thus, by combining the latest MRI methods and semiautomated image analysis methods, we are now able to reproducibly determine the geometric parameters of blood vessels.


Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery.
Peripheral arterial disease (PAD) may cause occlusions (blockages) in the main arteries of lower limbs. One treatment option is bypass surgery using autologous (the patient's own tissue) vein graft or artificial graft. A number of factors influence occlusion rates, including the material used. To prevent graft occlusion patients are usually treated with antiplatelet, antithrombotic drugs, or a combination of both. To evaluate whether antiplatelet treatment in patients with symptomatic PAD undergoing infrainguinal bypass surgery improves graft patency, limb salvage and survival. The authors searched the Cochrane Peripheral Vascular Diseases Group Specialised Register (January 2008) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 4). Additional trials were sought through reference lists of papers and proceedings from the vascular surgical society meetings. For this update the methodological quality of each original trial was assessed independently by review authors (JB, HM, AW) with emphasis on concealment of allocation. Details of the selected studies were extracted independently by JB and HM for the update. The treatment and control groups were compared for important prognostic factors and differences described. If any data were unavailable, further information was sought from authors. Data were synthesised by comparing group results. Unit of analysis issues were addressed by subgroup analysis. The administration of a variety of platelet inhibitors resulted in improved venous and artificial graft patency when compared to no treatment. However, analysing patients for graft-type indicated that those patients receiving a prosthetic graft were more likely to benefit from administration of platelet inhibitors than patients treated with venous grafts. Antiplatelet therapy with aspirin had a slight beneficial effect on the patency of peripheral bypass grafts but seemed to have an inferior effect on venous graft patency compared with artificial grafts. The effect of aspirin on cardiovascular outcomes and survival was small and not statistically significant. This might be due to the fact that the majority of patients receiving a peripheral graft have an advanced stage of PAD with critical ischaemia. They are usually seriously ill as a result of cardiovascular disease and have high mortality rates, of 20% per year. Additionally, the number of patients included in this analysis might be too small to reach a statistically significant effect for mortality and cardiovascular morbidity.


Predictive capacity of pre-donation GFR and renal reserve capacity for donor renal function after living kidney donation.
Kidney transplantation from living donors is important to reduce organ shortage. Reliable pre-operative estimation of post-donation renal function is essential. We evaluated the predictive potential of pre-donation glomerular filtration rate (GFR) (iothalamate) and renal reserve capacity for post-donation GFR in kidney donors. GFR was measured in 125 consecutive donors (age 49 +/- 11 years; 36% male) 119 +/- 99 days before baseline GFR (GFRb) and 57 +/- 16 days after donation (GFRpost). Reserve capacity was assessed as GFR during stimulation by low-dose dopamine (GFRdopa), amino acids (GFRAA) and both (GFRmax). GFRb was 112 +/- 18, GFRdopa 124 +/- 22, GFRAA 127 +/- 19 and GFRmax 138 +/- 22 mL/min. After donation, GFR remained 64 +/- 7%. GFRpost was predicted by GFRb(R2 = 0.54), GFRdopa(R2 = 0.35), GFRAA(R2 = 0.56), GFRmax(R2 = 0.55)and age (R2 = -0.22; p < 0.001 for all). Linear regression provided the equation GFRpost = 20.01 + (0.46*GFRb). Multivariate analysis predicted GFRpost by GFRb, age and GFRmax(R2 = 0.61, p < 0.001). Post-donation renal function impairment (GFR < or = 60 mL/min/1.73 m2) occurred in 31 donors. On logistic regression, GFRb, body mass index (BMI) and age were independent predictors for renal function impairment, without added value of reserve capacity. GFR allows a relatively reliable prediction of post-donation GFR, improving by taking age and stimulated GFR into account. Long-term studies are needed to further assess the prognostic value of pre-donation characteristics and to prospectively identify subjects with higher risk for renal function loss.


Induction of broadly neutralizing H1N1 influenza antibodies by vaccination.
The rapid dissemination of the 2009 pandemic influenza virus underscores the need for universal influenza vaccines that elicit protective immunity to diverse viral strains. Here, we show that vaccination with plasmid DNA encoding H1N1 influenza hemagglutinin (HA) and boosting with seasonal vaccine or replication-defective adenovirus 5 vector encoding HA stimulated the production of broadly neutralizing influenza antibodies. This prime/boost combination increased the neutralization of diverse H1N1 strains dating from 1934 to 2007 as compared to either component alone and conferred protection against divergent H1N1 viruses in mice and ferrets. These antibodies were directed to the conserved stem region of HA and were also elicited in nonhuman primates. Cross-neutralization of H1N1 subtypes elicited by this approach provides a basis for the development of a universal influenza vaccine for humans.


Oxidative damage and neurodegeneration in manganese-induced neurotoxicity.
Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson's disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterations in biomarkers of oxidative damage, F2-isoprostanes (F2-IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 microM Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E2 (PGE2). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F2-IsoPs and PGE2 in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration.