Oxidation of a cysteine-derived nucleophilic reagent by dimethyl sulfoxide in the amino acid derivative reactivity assay.
The amino acid derivative reactivity assay (ADRA), which is an in chemico alternative to the use of animals in testing for skin sensitization potential, offers significant advantages over the direct peptide reactivity assay (DPRA) in that it utilizes nucleophilic reagents that are sensitive enough to be used with test chemical solutions prepared to concentrations of 1 mm, which is one-hundredth that of DPRA. ADRA testing of hydrophobic or other poorly soluble compounds requires that they be dissolved in a solvent consisting of dimethyl sulfoxide (DMSO) and acetonitrile. DMSO is known to promote dimerization by oxidizing thiols, which then form disulfide bonds. We investigated the extent to which DMSO oxidizes the cysteine-derived nucleophilic reagents used in both DPRA and ADRA and found that oxidation of both N-(2-(1-naphthyl)acetyl)-l-cysteine (NAC) and cysteine peptide increases as the concentration of DMSO increases, thereby lowering the concentration of the nucleophilic reagent. We also found that use of a solvent consisting of 5% DMSO in acetonitrile consistently lowered NAC concentrations by about 0.4 μm relative to the use of solvents containing no DMSO. We also tested nine sensitizers and four nonsensitizers having different sensitization potencies to compare NAC depletion with and without 5% DMSO and found that reactivity was about the same with either solvent. Based on the above, we conclude that the use of a solvent containing 5% DMSO has no effect on the accuracy of ADRA test results. We plan to review and propose revisions to OECD Test Guideline 442C based on the above investigation.


The significance of plasmid DNA preparations contaminated with bacterial genomic DNA on inflammatory responses following delivery of lipoplexes to the murine lung.
Non-viral gene transfer using plasmid DNA (pDNA) is generally acknowledged as safe and non-immunogenic compared with the use of viral vectors. However, pre-clinical and clinical studies have shown that non-viral (lipoplex) gene transfer to the lung can provoke a mild, acute inflammatory response, which is thought to be, partly, due to unmethylated CG dinucleotides (CpGs) present in the pDNA sequence. Using a murine model of lung gene transfer, bronchoalveolar lavage fluid was collected following plasmid delivery and a range of inflammatory markers was analysed. The results showed that a Th1-related inflammatory cytokine response was present that was substantially reduced, though not abolished, by using CpG-free pDNA. The remaining minor level of inflammation was dependent on the quality of the pDNA preparation, specifically the quantity of contaminating bacterial genomic DNA, also a source of CpGs. Successful modification of a scalable plasmid manufacturing process, suitable for the production of clinical grade pDNA, produced highly pure plasmid preparations with reduced genomic DNA contamination. These studies help define the acceptable limit of genomic DNA contamination that will impact FDA/EMEA regulatory guidelines defining clinical grade purity of plasmid DNA for human use in gene therapy and vaccination studies.


Understanding the Barriers to Hiring and Promoting Women in Surgical Subspecialties.
The objective of this study was to characterize potential disparities in academic output, NIH-funding, and academic rank between male and female surgical faculty and identify subspecialties in which these differences may be more pronounced. Eighty metrics for 4,015 faculty members at the top-55 NIH-funded departments of surgery were collected. Demographic characteristics, NIH funding details, and scholarly output were analyzed. A new metric, academic velocity (V), reflecting recent citations is defined. Overall, 21.5% of surgical faculty are women. The percentage of female faculty is highest in science/research (41%) and surgical oncology (34%), and lowest in cardiothoracic surgery (9%). Female faculty are less likely to be full professors (22.7% vs 41.2%) and division chiefs (6.2% vs 13.6%). The fraction of women who are full professors is lowest in cardiothoracic surgery. Overall median numbers of publications/citations are lower for female faculty compared with male surgical faculty (21 of 364 vs 43 of 723, p < 0.001), and these differences are more pronounced for assistant professors. Current/previous NIH funding (21.3% vs 24%, p = NS) rates are similar between women and men, and surgical departments with more female full professors have higher NIH funding ranking (R(2) = 0.14, p < 0.05). In certain subspecialties, female associate and full professors outperform male counterparts. Overall, female authors have higher numbers of more recent citations. Subspecialty involvement and academic performance differences by sex vary greatly by subspecialty type and are most pronounced at the assistant professor level. Identification of potential barriers for entry of women into certain subspecialties, causes for the observed lower number of publications/citations among female assistant professors, and obstacles for attaining leadership roles need to be determined. We propose a new metric for assessment of publications/citations that can offset the effects of seniority differences between male and female faculty members.


A Machine Learning Approach for Tracing Tumor Original Sites With Gene Expression Profiles.
Some carcinomas show that one or more metastatic sites appear with unknown origins. The identification of primary or metastatic tumor tissues is crucial for physicians to develop precise treatment plans for patients. With unknown primary origin sites, it is challenging to design specific plans for patients. Usually, those patients receive broad-spectrum chemotherapy, while still having poor prognosis though. Machine learning has been widely used and already achieved significant advantages in clinical practices. In this study, we classify and predict a large number of tumor samples with uncertain origins by applying the random forest and Naive Bayesian algorithms. We use the precision, recall, and other measurements to evaluate the performance of our approach. The results have showed that the prediction accuracy of this method was 90.4 for 7,713 samples. The accuracy was 80% for 20 metastatic tumors samples. In addition, the 10-fold cross-validation is used to evaluate the accuracy of classification, which reaches 91%.


SAMHD1-dependent retroviral control and escape in mice.
SAMHD1 is a host restriction factor for human immunodeficiency virus 1 (HIV-1) in cultured human cells. SAMHD1 mutations cause autoimmune Aicardi-Goutières syndrome and are found in cancers including chronic lymphocytic leukaemia. SAMHD1 is a triphosphohydrolase that depletes the cellular pool of deoxynucleoside triphosphates, thereby preventing reverse transcription of retroviral genomes. However, in vivo evidence for SAMHD1's antiviral activity has been lacking. We generated Samhd1 null mice that do not develop autoimmune disease despite displaying a type I interferon signature in spleen, macrophages and fibroblasts. Samhd1(-/-) cells have elevated deoxynucleoside triphosphate (dNTP) levels but, surprisingly, SAMHD1 deficiency did not lead to increased infection with VSV-G-pseudotyped HIV-1 vectors. The lack of restriction is likely attributable to the fact that dNTP concentrations in SAMHD1-sufficient mouse cells are higher than the KM of HIV-1 reverse transcriptase (RT). Consistent with this notion, an HIV-1 vector mutant bearing an RT with lower affinity for dNTPs was sensitive to SAMHD1-dependent restriction in cultured cells and in mice. This shows that SAMHD1 can restrict lentiviruses in vivo and that nucleotide starvation is an evolutionarily conserved antiviral mechanism.


Orientation congruency effects for familiar objects: coordinate transformations in object recognition.
How do observers recognize objects after spatial transformations? Recent neurocomputational models have proposed that object recognition is based on coordinate transformations that align memory and stimulus representations. If the recognition of a misoriented object is achieved by adjusting a coordinate system (or reference frame), then recognition should be facilitated when the object is preceded by a different object in the same orientation. In the two experiments reported here, two objects were presented in brief masked displays that were in close temporal contiguity; the objects were in either congruent or incongruent picture-plane orientations. Results showed that naming accuracy was higher for congruent than for incongruent orientations. The congruency effect was independent of superordinate category membership (Experiment 1) and was found for objects with different main axes of elongation (Experiment 2). The results indicate congruency effects for common familiar objects even when they have dissimilar shapes. These findings are compatible with models in which object recognition is achieved by an adjustment of a perceptual coordinate system.


Self-management of fatal familial insomnia. Part 2: case report.
Fatal familial insomnia (FFI) is a genetically transmitted neurodegenerative prion disease that incurs great suffering and has neither a treatment nor cure. The clinical literature is devoid of management plans (other than palliative). Part 1 of this article reviews the sparse literature about FFI, including case descriptions. Part 2 describes the efforts of one patient (with the rapid-course Met-Met subtype) who contended with his devastating symptoms and improved the quality of his life. Interventions were based on the premise that some symptoms may be secondary to insomnia and not a direct result of the disease itself. Strategies (derived by trial and error) were devised to induce sleep and increase alertness. Interventions included vitamin supplementation, narcoleptics, anesthesia, stimulants, sensory deprivation, exercise, light entrainment, growth hormone, and electroconvulsive therapy (ECT). The patient exceeded the average survival time by nearly 1 year, and during this time (when most patients are totally incapacitated), he was able to write a book and to successfully drive hundreds of miles. Methods to induce sleep may extend and enhance life during the disease course, although they do not prevent death. It is hoped that some of his methods will inspire further clinical studies.


Phase I-II study on isolation antiblastic fotemustine perfusion after dacarbazine chemosensitization for advanced melanoma of the extremities.
Isolation limb perfusion (ILP) is the treatment of choice for locally advanced limb melanoma. With melphalan, the referral drug, complete response (CR) is achieved in about 50% of patients, but significant local toxicity occurs in up to 30%. The aim of the present phase I-II study was to challenge fotemustine (F) in ILP after systemic chemosensitization with dacarbazine (DTIC), given its lower toxicity and greater efficacy, as reported in a previous pilot study. Eleven patients with locally advanced limb melanoma were subdivided into triplets, and given F ILP at escalating doses (starting from 25 mg/l) after intravenous administration of 500 mg/m2 DTIC. Acute and chronic locoregional and systemic toxicity, tumour response and clinical outcome were evaluated. Two patients in the first triplet had G3-G4 local toxicity, so that the scheduled F dosage was halved. At drug levels of 12.5, 15.6 and 18.2 mg/l, local toxicity decreased, but only one of eight patients showed CR. The trial was then interrupted due to the low tolerability and poor efficacy of this perfusion regimen. At present, F ILP after DTIC chemosensitization should not be recommended for the treatment of locally advanced limb melanoma.


Polymorphisms of HLA microsatellite marker in Tunisian pemphigus foliaceus.
Pemphigus foliaceus (PF) is an autoimmune blistering skin disease that partly results from genetic factors, especially from human leucocyte antigen (HLA) class II genes. Several data have reported the involvement of microsatellite (STR) markers across different regions of the HLA in many auto-immune diseases. To test the hypothesis of the existence of a major HLA haplotype predisposing to PF, we analyzed six polymorphisms of microsatellite loci at 6p21.3-21.4 spanning HLA: D6S291, D6S273, TNFa, MICA, D6S265 and D6S276 in 81 PF patients compared to 123 healthy individuals recruited from the south of Tunisia. In this study, after Bonferroni's correction, 3 STR alleles from the TNFa locus were associated with the disease: the allele TNFa(∗)2 (p(c) = 4.2×10(-6)) and, at a lower level, the TNFa(∗)5 (p(c) = 0.014) as susceptibility alleles and TNFa(∗)6 (p(c) = 0.014) as protective ones. Furthermore, the expression of the TNFa(∗)2/TNFa(∗)5 genotype seem to confer susceptibility to PF (p = 0.00001, OR = 11.25). Interestingly, no significant LD was found between TNFa2/TNFa5 alleles and DRB1(∗)03/DRB1(∗)04 alleles. However, the multivariant regression analysis indicates that both the HLA class II and the TNFa alleles remained significant (p < 0.001). Although, these findings rejected our hypothesis on the existence of HLA susceptibility haplotype, they assessed the role of TNFa loci. Accordingly, TNFa seem to contribute to the aethiopathogenesis of Tunisian endemic PF may be by the induction of a high TNFα production which is known to enhance the autoimmune cascade of the disease.


Deer movement and resource selection during Hurricane Irma: implications for extreme climatic events and wildlife.
Extreme climatic events (ECEs) are increasing in frequency and intensity and this necessitates understanding their influence on organisms. Animal behaviour may mitigate the effects of ECEs, but field studies are rare because ECEs are infrequent and unpredictable. Hurricane Irma made landfall in southwestern Florida where we were monitoring white-tailed deer (Odocoileus virginianus seminolus) with GPS collars. We report on an opportunistic case study of behavioural responses exhibited by a large mammal during an ECE, mitigation strategies for reducing the severity of the ECE effects, and the demographic effect of the ECE based on known-fate of individual animals. Deer altered resource selection by selecting higher elevation pine and hardwood forests and avoiding marshes. Most deer left their home ranges during Hurricane Irma, and the probability of leaving was inversely related to home range area. Movement rates increased the day of the storm, and no mortality was attributed to Hurricane Irma. We suggest deer mobility and refuge habitat allowed deer to behaviourally mitigate the negative effects of the storm, and ultimately, aid in survival. Our work contributes to the small but growing body of literature linking behavioural responses exhibited during ECEs to survival, which cumulatively will provide insight for predictions of a species resilience to ECEs and improve our understanding of how behavioural traits offset the negative impacts of global climate change.


Investigating the role of cholesterol in the formation of non-ionic surfactant based bilayer vesicles: thermal analysis and molecular dynamics.
The aim of this research was to investigate the molecular interactions occurring in the formulation of non-ionic surfactant based vesicles composed monopalmitoyl glycerol (MPG), cholesterol (Chol) and dicetyl phosphate (DCP). In the formulation of these vesicles, the thermodynamic attributes and surfactant interactions based on molecular dynamics, Langmuir monolayer studies, differential scanning calorimetry (DSC), hot stage microscopy and thermogravimetric analysis (TGA) were investigated. Initially the melting points of the components individually, and combined at a 5:4:1 MPG:Chol:DCP weight ratio, were investigated; the results show that lower (90 °C) than previously reported (120-140 °C) temperatures could be adopted to produce molten surfactants for the production of niosomes. This was advantageous for surfactant stability; whilst TGA studies show that the individual components were stable to above 200 °C, the 5:4:1 MPG:Chol:DCP mixture show ∼2% surfactant degradation at 140 °C, compared to 0.01% was measured at 90 °C. Niosomes formed at this lower temperature offered comparable characteristics to vesicles prepared using higher temperatures commonly reported in literature. In the formation of niosome vesicles, cholesterol also played a key role. Langmuir monolayer studies demonstrated that intercalation of cholesterol in the monolayer did not occur in the MPG:Chol:DCP (5:4:1 weight ratio) mixture. This suggests cholesterol may support bilayer assembly, with molecular simulation studies also demonstrating that vesicles cannot be built without the addition of cholesterol, with higher concentrations of cholesterol (5:4:1 vs 5:2:1, MPG:Chol:DCP) decreasing the time required for niosome assembly.


Cortisol is not associated with telomere shortening or chromosomal instability in human lymphocytes cultured under low and high folate conditions.
Chronic psychological stress and nutritional deficiencies are factors that impact negatively on human health and disease risk. Chronic stress has been associated with accelerated leukocyte telomere shortening in numerous cohorts, however, a mechanistic link has proven elusive. This study tested the hypotheses that chronic exposure to the stress hormone, cortisol, causes telomere shortening and chromosome instability (CIN) in vitro, and that these effects would be further exacerbated by folate (vitamin B9) deficiency. Primary human lymphocytes were maintained in vitro for 12 days in medium containing either 25 nM folic acid (FA(low)) or 100 nM FA (FA(high)), together with either 0, 400, 1000 or 3500 nM cortisol. The interactive effects of cortisol and FA were examined by comparing telomere length (TL), biomarkers of DNA damage, and cytostasis. At day 12 TL was 5-17% longer in lymphocytes cultured in FA(low) conditions (mean ± SD;10.2% ± 1.6), compared with those in FA(high) medium (9.1% ± 1, p = 0.02). Refuting the hypothesis, TL was consistently greater in the presence of cortisol. The effect of FA deficiency on the frequency of DNA damage was significant for nucleoplasmic bridges, circular nuclei, micronuclei and nuclear buds, (p < 0.0001-0.001). The effect of cortisol, however, was negligible, only reaching statistical significance for the frequency of fused nuclei (p = 0.04). Cortisol was significantly associated with reduced cell division and growth and had an apparent protective effect on cell viability in the FA(low) conditions. Conclusions: Both chronic cortisol exposure, and folate deficiency, resulted in telomere elongation, however, the effect of cortisol was marginal relative to that of folate. Cortisol was not associated with increased chromosomal instability, but caused a significant reduction in cell division and growth. Together these results indicate that cortisol is not directly genotoxic and that the telomere shortening associated with increased psychological stress in vivo may not be explained by a direct effect of cortisol.


A critical assessment of some biomarker approaches linked with dietary intake.
In this review many examples are given of the complexities involved in using some biomarkers in relation to assessing the effects of dietary exposure, when there is frequently a need to determine changes following long-term low level exposure to dietary components. These range from understanding why the biomarker might be valuable and how best it can be measured, to the pitfalls which can occur in the interpretation of data. Analytical technique is considered in relation to folate and selenium, and flavonoid and carotenoid species are used to illustrate how the metabolism of a compound may alter the validity or adequacy of a marker. Vitamin A is discussed in relation to the difficulties which can arise when there are several biomarkers that may be available to assess exposure to one nutrient. Vitamin B12 is discussed in relation to the dietary choices made by individuals. Possible interactions and the role of measuring total antioxidant capacity is considered in some detail. In contrast to most nutrients, there is a marked lack of biomarkers of either exposure or effect for most non-nutrients. The role of biological effect monitoring is considered for dietary contaminants, fumonisins and polyhalogenated aromatic hydrocarbons. Aflatoxins are discussed to exemplify food contaminants for which the biomarker approach has been extensively studied. Finally some compounds which are deliberately added to foods and some which appear as processing contaminants are each considered briefly in relation to the requirement for a biomarker of exposure to be developed.


[Health-related quality of life assessment in depression after low-frequency transcranial magnetic stimulation].
Major depressive disorder remains one of the leading causes of disability in developed countries despite pharmacological and psychological treatments. Patients with major depression have poorer health-related quality of life than persons of the general population, or patients with chronic somatic illness. Improvement of health-related quality of life in depression is thus a pertinent treatment objective. Both high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex and low-frequency rTMS over the right dorsolateral prefrontal cortex have shown their effectiveness in medication-resistant depression. However, the Health-related Quality of Life questionnaire remains under-utilized to assess the effectiveness of rTMS in research or in a routine clinical setting. Our study aims to investigate in an open label trial the efficacy of low-frequency rTMS over the right dorsolateral prefrontal cortex on health-related quality of life and clinical outcomes in medication-resistant depression. In a naturalistic trial, 33 unipolar and bipolar patients with medication-resistant depression were treated with daily low-frequency rTMS over the right dorsolateral prefrontal cortex for 4 weeks. Health-related quality of life was assessed using the SF-36 questionnaire. The SF-36 is a generic, self-administered, and worldwide-used questionnaire, consisting of 36 items describing eight health dimensions: physical functioning, social functioning, role-physical problems, role-emotional problems, mental health, vitality, bodily pain, and general health. Physical component summary and mental component summary scores were then obtained. Depression severity was assessed using the 21-item self-report Beck Depression Inventory. Anxiety severity was assessed using the State-Trait Anxiety Inventory. The SF-36, the Beck Depression Inventory and the State-Trait Anxiety Inventory were assessed before and after low-frequency rTMS. The effect of rTMS treatment on the SF-36 and the clinical outcome was evaluated for significance with the Wilcoxon two-tailed signed-rank test. The reliable change index (RCI) was calculated to determine clinically significant change in the eight dimension and composite scores of the SF-36 from pre-intervention to post-intervention, at the level of individual patients. Effect size (r) was then calculated, r values from 0.1 to 0.29, 0.3 to 0.49 and from 0.5 were considered as indicating small, medium and large effect sizes, respectively. Correlations between improvement in Health-related Quality of Life and improvement in the other rating scale scores were calculated using Spearman's correlation test. There were significant improvements of 37.6% in the mental health (P=0.018), 130 % in the role-emotional problem (P=0.045), 15.5% in the physical functioning (P=0.008), 110.6% in the role-physical problem (P=0.002), 22.4% in the bodily pain (P=0.013) dimensions, 6.1% in the Physical Component Score (P=0.043), and 22,5 % in the Beck Depression Inventory (P=0.002). Eighteen patients (54%) showed clinically significant improvement in one of the two composite scores after RCI calculation. Seven out of the eight SF-36 dimension scores and the two composite scores showed effect sizes ranging from 0.12 to 0.38, indicating small to moderate effect. Significant correlations were found between improvement in the Beck Depression Inventory and improvement in the Mental Component Score, the social functioning, the mental health, the general health, the vitality and the physical functioning dimensions. Small sample size and non-controlled design. Low-frequency rTMS over the right dorsolateral prefrontal cortex improves Health-related Quality of Life in unipolar and bipolar patients with medication-resistant depression. Improvement in mental health-related quality of life is significantly correlated with improvement in depressive symptoms. However, further studies with larger samples and controlled designs are needed to clarify our findings.


Dietary supplementation with the tribomechanically activated zeolite clinoptilolite in immunodeficiency: effects on the immune system.
Natural zeolites are crystalline aluminosilicates with unique adsorption, cation-exchange, and catalytic properties that have multiple uses in industry and agriculture. TMAZ, a natural zeolite clinoptilolite with enhanced physicochemical properties, is the basis of the dietary supplements Megamin and Lycopenomin, which have demonstrated antioxidant activity in humans. The aim of this prospective, open, and controlled parallel-group study was to investigate the effects of supplementation with TMAZ on the cellular immune system in patients undergoing treatment for immunodeficiency disorder. A total of 61 patients were administered daily TMAZ doses of 1.2 g (Lycopenomin) and 3.6 g (Megamin) for 6 to 8 weeks, during which the patients' primary medical therapy was continued unchanged. Blood and lymphocyte counts were performed at baseline and at the end of the study. Blood count parameters were not relevantly affected in either of the two treatment groups. Megamin administration resulted in significantly increased CD4+, CD19+, and HLA-DR+ lymphocyte counts and a significantly decreased CD56+ cell count. Lycopenomin was associated with an increased CD3+ cell count and a decreased CD56+ lymphocyte count. No adverse reactions to the treatments were observed.


Good clinical outcomes from a 7-year holistic programme of fistula repair in Guinea.
Female genital fistula remains a public health concern in developing countries. From January 2007 to September 2013, the Fistula Care project, managed by EngenderHealth in partnership with the Ministry of Health and supported by USAID, integrated fistula repair services in the maternity wards of general hospitals in Guinea. The objective of this article was to present and discuss the clinical outcomes of 7 years of work involving 2116 women repaired in three hospitals across the country. This was a retrospective cohort study using data abstracted from medical records for fistula repairs conducted from 2007 to 2013. The study data were reviewed during the period April to August 2014. The majority of the 2116 women who underwent surgical repair had vesicovaginal fistula (n = 2045, 97%) and 3% had rectovaginal fistula or a combination of both. Overall 1748 (83%) had a closed fistula and were continent of urine immediately after surgery. At discharge, 1795 women (85%) had a closed fistula and 1680 (79%) were dry, meaning they no longer leaked urine and/or faeces. One hundred and fifteen (5%) remained with residual incontinence despite fistula closure. Follow-up at 3 months was completed by 1663 (79%) women of whom 1405 (84.5%) had their fistula closed and 80% were continent. Twenty-one per cent were lost to follow-up. Routine programmatic repair for obstetric fistula in low resources settings can yield good outcomes. However, more efforts are needed to address loss to follow-up, sustain the results and prevent the occurrence and/or recurrence of fistula.


Effects of rasagiline on freezing of gait in Parkinson's disease - an open-label, multicenter study.
Freezing of gait is a disabling symptom in advanced Parkinson's disease. Positive effects have been suggested with MAO-B inhibitors. We report on an open label clinical study on the efficacy of rasagiline as add-on therapy on freezing of gait and quality of life in patients with Parkinson's disease. Forty two patients with freezing of gait were treated with 1 mg rasagiline daily as an add-on therapy. Patients were assessed at baseline and after 1, 2 and 3 months of treatment. Freezing of gait severity was assessed using the Freezing of Gait Questionnaire, motor impairment by the modified MDS UPDRS part III, and quality of life using the PDQ-39 questionnaire. Patients treated with rasagiline had a statistically significant decrease in FoG-Q score and modified MDS UPDRS score after 1, 2 and 3 months of therapy. A moderately strong (r = 0.686, P = 0.002) correlation between the effects on mobility and freezing of gait was found. We also observed a statistically significant improvement in global QoL and in the subscales mobility, ADL, stigma and bodily discomfort in patients after 3 months of rasagiline therapy. A significant correlation (r = 0.570, P = 0.02) between baseline FoG-Q score and the baseline score for the PDQ Mobility subscale was found. In our study rasagiline as add-on antiparkinsonian therapy significantly improved mobility, freezing of gait and quality of life. The positive effect on freezing of gait appears to be related to improvement of mobility.


Glycosyl disulfides: novel glycosylating reagents with flexible aglycon alteration.
[reaction: see text] Glycosyl disulfides have been shown for the first time to be effective glycosyl donors. Glucosylation and galactosylation of a panel of representative alcohol acceptors allowed the formation of 28 simple glycosides, disaccharides, and glycoamino acids in yields of up to 90%. As well as providing a novel class of effective glycosyl donors, the ability to easily alter the nature of the aglycon and the ability to differently activate donors that differ only in their aglycon simply through altering conditions lends glycosyl disulfide donors to their use in latent-active reactivity tuning strategies.


Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs.
Prophylactic use of antiepileptic drugs (AEDs) in patients admitted with aneurysmal subarachnoid hemorrhage (SAH) is common practice; however, the impact of this treatment strategy on in-hospital complications and outcome has not been systematically studied. The goal in this study was twofold: first, to describe the prescribing pattern for AEDs in an international study population; and second, to delineate the impact of AEDs on in-hospital complications and outcome in patients with SAH. The authors examined data collected in 3552 patients with SAH who were entered into four prospective, randomized, double-blind, placebo-controlled trials conducted in 162 neurosurgical centers and 21 countries between 1991 and 1997. The prevalence of AED use was assessed by study country and center. The impact of AEDs on in-hospital complications and outcome was evaluated using conditional logistic regressions comparing treated and untreated patients within the same study center. Antiepileptic drugs were used in 65.1% of patients and the prescribing pattern was mainly dependent on the treating physicians: the prevalence of AED use varied dramatically across study country and center (intraclass correlation coefficients 0.22 and 0.66, respectively [p < 0.001]). Other predictors included younger age, worse neurological grade, and lower systolic blood pressure on admission. After adjustment, patients treated with AEDs had odds ratios of 1.56 (95% confidence interval [CI] 1.16-2.10; p = 0.003) for worse outcome based on the Glasgow Outcome Scale; 1.87 (95% CI 1.43-2.44; p < 0.001) for cerebral vasospasm; 1.61 (95% CI 1.25-2.06; p < 0.001) for neurological deterioration; 1.33 (95% CI 1.01-1.74; p = 0.04) for cerebral infarction; and 1.36 (95% CI 1.03-1.80; p = 0.03) for elevated temperature during hospitalization. Prophylactic AED treatment in patients with aneurysmal SAH is common, follows an arbitrary prescribing pattern, and is associated with increased in-hospital complications and worse outcome.


Cholesterol synthesis in vivo and in vitro in the WHHL rabbit, an animal with defective low density lipoprotein receptors.
These studies were undertaken to measure rates of synthesis of digitonin-precipitable sterols in vivo and in vitro in control rabbits (New Zealand (NZ) control) and in homozygous Watanabe heritable hyperlipidemic rabbits (WHHL) that lack receptors for low density lipoproteins (LDL). The plasma cholesterol concentration in NZ control fetuses equaled 79 mg/dl, rose to 315 mg/dl 12 days after birth, and fell to 80 mg/dl in young adult animals. At these same ages, cholesterol concentrations in the WHHL animals equal 315, 625, and 715 mg/dl, respectively. The rate of whole animal sterol synthesis in vivo, expressed as the mumol of [3H]water incorporated into sterols per hr per kg of body weight, was lower in the WHHL animals than in the NZ controls both in the fetuses (108 vs 176) and in the adult animals (48 vs 66). In adult NZ controls the content of newly synthesized sterols (rate of sterol synthesis) per g of tissue was highest in the liver (538 nmol/g per hr), adrenal gland (438), small bowel (371), and ovary (225) while lower rates of synthesis were found in 15 other tissues. In the WHHL rabbits a higher content of [3H]sterols was found only in the adrenal gland (2,215) while synthesis was suppressed in the liver (310), colon, lung, and kidney, and was unchanged in the remaining organs. These findings were confirmed by measurements of rates of sterol synthesis in the same tissues in vitro. When whole organ weight was taken into consideration, the tissues that were the major contributors to whole body sterol synthesis in both types of rabbits were liver, small bowel, skin, and carcass. However, it was the lower rate of synthesis in the liver of the WHHL animals that alone accounted for the lower rate of whole animal sterol synthesis seen in these rabbits. These studies demonstrate that in WHHL animals that lack LDL receptors and that have very high levels of circulating LDL cholesterol, the rate of cholesterol synthesis in nearly all tissues is normal but in the liver is significantly suppressed. Only the adrenal gland manifested enhanced synthesis. Such findings suggest that in the WHHL rabbit where LDL receptor activity is reduced and plasma LDL levels rise, mechanisms other than receptor-mediated LDL uptake may act to deliver cholesterol to the cells of the various organs and to the liver.


The role of an active site Mg(2+) in HDV ribozyme self-cleavage: insights from QM/MM calculations.
The hepatitis delta virus (HDV) ribozyme is a catalytic RNA motif embedded in the human pathogenic HDV RNA. It catalyzes self-cleavage of its sugar-phosphate backbone with direct participation of the active site cytosine C75. Biochemical and structural data support a general acid role of C75. Here, we used hybrid quantum mechanical/molecular mechanical (QM/MM) calculations to probe the reaction mechanism and changes in Gibbs energy along the ribozyme's reaction pathway with an N3-protonated C75H(+) in the active site, which acts as the general acid, and a partially hydrated Mg(2+) ion with one deprotonated, inner-shell coordinated water molecule that acts as the general base. We followed eight reaction paths with a distinct position and coordination of the catalytically important active site Mg(2+) ion. For six of them, we observed feasible activation barriers ranging from 14.2 to 21.9 kcal mol(-1), indicating that the specific position of the Mg(2+) ion in the active site is predicted to strongly affect the kinetics of self-cleavage. The deprotonation of the U-1(2'-OH) nucleophile and the nucleophilic attack of the resulting U-1(2'-O(-)) on the scissile phosphodiester are found to be separate steps, as deprotonation precedes the nucleophilic attack. This sequential mechanism of the HDV ribozyme differs from the concerted nucleophilic activation and attack suggested for the hairpin ribozyme. We estimate the pKa of the U-1(2'-OH) group to range from 8.8 to 11.2, suggesting that it is lowered by several units from that of a free ribose, comparable to and most likely smaller than the pKa of the solvated active site Mg(2+) ion. Our results thus support the notion that the structure of the HDV ribozyme, and particularly the positioning of the active site Mg(2+) ion, facilitate deprotonation and activation of the 2'-OH nucleophile.


Molecular Targets of Cannabidiol in Neurological Disorders.
Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD's effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD's therapeutic mechanism of action.


Lymphoscintigraphy and intraoperative lymphatic mapping of sentinel lymph nodes in melanoma patients.
Identification of sentinel lymph nodes (SLNs) using lymphoscintigraphy, the blue dye technique and intraoperative lymphatic mapping with a gamma-detecting probe has become the standard of care in diagnosing and treating melanoma. Numerous clinical studies have proven the reliability of predicting the histology of remaining lymph nodes in the lymphatic basin from the histologic evaluation of the SLNs. Technical and clinical factors presented in this paper have been shown to increase the accuracy of localization of SLNs. The nuclear medicine technologist shares a vital role in the radiopharmaceutical preparation and administration for preoperative lymphoscintigraphy and intraoperative lymphatic mapping in patients with melanoma.


Antidepressant-like effect of Hypericum perforatum (St John's wort) on the sleep polysomnogram.
We studied the effect of two doses (0.9 mg and 1.8 mg) of Hypericum perforatum (St John's wort) on the sleep polysomnogram of healthy subjects using a placebo-controlled, cross-over design. Both doses of hypericum significantly increased the latency to rapid eye movement (REM) sleep without producing any other effect on sleep architecture. Our data are consistent with the proposed clinical antidepressant efficacy of hypericum, and raise the possibility that its pharmacological mechanism of action may be similar to that of conventional antidepressant medication.


Feasibility and outcome of community-based screening for cardiovascular disease risk factors in a remote rural area of South India: The Chunampet rural-Cardiovascular health assessment and management program.
As committed by India in Global Action Plan, Sustainable Development Goals and National Health Policy 2017, India has the responsibility to provide accessible, affordable noncommunicable disease care to the people. Our study aimed to find out the burden of cardiovascular risk factors among hypertension and diabetic patients, through a community-based screening, in a remote rural area of South India. A special program named "Chunampet Rural-Cardiovascular Health Assessment and Management Program" (CR-CHAMP) was launched in August and September 2017 in a Rural Health Training Center (RHTC), functioning under a private medical college in South India. In this program, participants with hypertension (HT) and diabetes (DM) were line listed from 10 remote villages, and then history, initial biochemical, hormonal, and hematological screenings were done to assess the cardiovascular diseases (CVDs) risk factors among these patients, following which special consultation was offered in RHTC. Out of 415 eligible patients with HT and DM, 389 were approached; among them, 328 were willing to participate and were screened initially; among them, 235 were attended special consultation. Higher CVD risk was found in 21%. Prevalence of chronic kidney disease was 14%, deranged lipid profile was more than 50%, metabolic syndrome was 49%, anemia was 68%, abnormal waist-hip ratio was 56%, abdominal obesity was 59%, and overweight and obesity using body mass index (BMI) was 59%. Females' participation was more in our community-based screening procedure (66%) than male participation (34%). CR-CHAMP demonstrated feasibility and value of implementing a screening program for high-risk individuals with HT and DM for CVD risk through existing primary care in a remote rural area of South India. This will help the National Program and policymakers to plan for interventions in the remote rural area in future.


Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder.
Early environmental risk factors associated with attention-deficit/hyperactivity disorder (ADHD) have been increasingly suggested. Our study investigates the maternal, pregnancy, and newborn risk factors by gender for children prescribed stimulant medication for treatment of ADHD in Western Australia. This is a population-based, record linkage case-control study. The records of all non-Aboriginal children and adolescents born in Western Australia and aged <25 years who were diagnosed with ADHD and prescribed stimulant medication (cases = 12,991) were linked to the Midwives Notification System (MNS) to obtain maternal, pregnancy, and birth information. The control population of 30,071 children was randomly selected from the MNS. Mothers of children with ADHD were significantly more likely to be younger, be single, have smoked in pregnancy, have labor induced, and experience threatened preterm labor, preeclampsia, urinary tract infection in pregnancy, or early term delivery irrespective of the gender of the child, compared with the control group. In the fully adjusted model, a novel finding was of a possible protective effect of oxytocin augmentation in girls. Low birth weight, postterm pregnancy, small for gestational age infant, fetal distress, and low Apgar scores were not identified as risk factors. Smoking in pregnancy, maternal urinary tract infection, being induced, and experiencing threatened preterm labor increase the risk of ADHD, with little gender difference, although oxytocin augmentation of labor appears protective for girls. Early term deliveries marginally increased the risk of ADHD. Studies designed to disentangle possible mechanisms, confounders, or moderators of these risk factors are warranted.


Cutaneous sensibility and peripheral nerve function in patients with unmedicated essential hypertension.
Sensorimotor deficits in patients with essential hypertension may be due to impaired nerve function. Cutaneous sensory thresholds, median nerve sensory and motor conduction velocities, and median nerve sensory action potential amplitudes were assessed in 30 patients with unmedicated essential hypertension and 29 normotensives. Cutaneous sensory thresholds were higher and sensory action potential amplitudes smaller in hypertensives than normotensives whereas sensory and motor nerve conduction velocities did not differ between groups. These data suggest that hypertension may reduce the number of active sensory nerve fibers without affecting myelination. Sensory action potential amplitudes were inversely related to cutaneous sensory thresholds, suggesting that subclinical axonal neuropathy of sensory afferents may help account for perceptual deficits that characterize hypertension.


Alzheimer's disease and mild cognitive impairment are associated with elevated levels of isoaspartyl residues in blood plasma proteins.
Increased levels of isoaspartyl residues (isoAsp) have previously been found in proteins of Alzheimer's disease (AD) brains and in blood proteins of patients suffering from uremia, the disease sharing common pathological features with AD. One can hypothesize that higher levels of isoAsp should be present in blood proteins of AD patients. Also, because of higher AD prevalence in females, they can be expected to have higher level of isoAsp than males. Here we modified our recently developed proteome-wide isoAsp analysis approach for testing these hypotheses. Eight blood plasma samples pooled from 218 individuals suffering from either mild cognitive impairment (MCI) or AD were analyzed by tandem mass spectrometry using electron transfer dissociation. Based on specific fragmentation pattern of isoAsp, the healthy controls were found to contain lower level of isoAsp compared with age-matched MCI and AD patients (p = 0.03). This result was further validated (p = 0.05) by 96 individual sample analyses, giving the combined value of p ≈ 0.01. Female pooled samples were found to contain higher level of isoAsp than male in both pooled and individual samples, with overall p ≈ 0.01. These findings verify the above hypotheses, and provide protein candidates for further investigation of the link between isoAsp and AD.


Binding between G Quadruplexes at the Homodimer Interface of the Corn RNA Aptamer Strongly Activates Thioflavin T Fluorescence.
Thioflavin T (ThT) is widely used for the detection of amyloids. Many unrelated DNAs and RNAs that contain G-quadruplex motifs also bind ThT and strongly activate its fluorescence. To elucidate the structural basis of ThT binding to G quadruplexes and its fluorescence turn-on, we determined its co-crystal structure with the homodimeric RNA Corn, which contains two G quadruplexes. We found that two ThT molecules bind in the dimer interface, constrained by a G quartet from each protomer into a maximally fluorescent planar conformation. The unliganded Corn homodimer crystal structure reveals a collapsed fluorophore-binding site. In solution, Corn must fluctuate between this and an open, binding-competent conformation. A co-crystal structure with another benzothiazole derivate, thiazole orange (TO), also shows binding at the Corn homodimer interface. As the bound ThT and TO make no interactions with the RNA backbone, their Corn co-crystal structures likely explain their fluorescence activation upon sequence-independent DNA and RNA G-quadruplex binding.


PreTCR and TCRγδ signal initiation in thymocyte progenitors does not require domains implicated in receptor oligomerization.
Whether thymocytes adopt an αβ or a γδ T cell fate in the thymus is determined at the β selection checkpoint by the relatively weak or strong signals that are delivered by either the pre-T cell receptor (preTCR) or the γδ TCR, respectively. Signal initiation at the β selection checkpoint is thought to be independent of ligand engagement of these receptors. Some reports have suggested that receptor oligomerization, which is thought to be mediated by either the immunoglobulin (Ig)-like domain of the preTCRα (pTα) chain or the variable domain of TCRδ, is a unifying mechanism that initiates signaling in early CD4(-)CD8(-) double-negative (DN) thymocyte progenitors. Here, we demonstrate that the extracellular regions of pTα and TCRδ that are implicated in mediating receptor oligomerization were not required for signal initiation from the preTCR or TCRγδ. Indeed, a truncated TCRγδ that lacked all of its extracellular Ig-like domains still formed a signaling-competent TCR that drove cells through the β selection checkpoint. These observations suggest that signal initiation in DN thymocytes is simply a consequence of the surface-pairing of TCR chains, with signal strength being a function of the abundances of surface TCRs. Thus, processes that regulate the surface abundances of TCR complexes in DN cells, such as oligomerization-induced endocytosis, would be predicted to have a major influence in determining whether cells adopt an αβ versus γδ T cell fate.


A radiation-induced adaptive response prolongs the survival of prion-infected mice.
Previously, it has been demonstrated that an "adaptive response" that includes the prevention, repair, and removal of oxidative damage can be evoked by radiation at dose rates substantially lower than those at which risks have been observed. The exact pathogenic mechanism of prion diseases is unknown, but circumstantial evidence suggests that oxidative stress plays a central role. Exposure of prion-infected mice to four 500 mGy/fraction doses of (60)Co γ-radiation administered every other day at a low dose rate (0.5 mGy/min) starting at 2 days before infection, 7 days postinfection (dpi), or 50 dpi significantly prolonged the survival of infected mice. The 500-mGy radiation treatments started at 50 dpi also significantly prolonged the symptom-free period of the disease and caused a significant delay in the rise of the 8-hydroxydeoxyguanosine concentration observed in the urine of nonirradiated infected mice at 98 dpi. The duration of the reduction in oxidative stress achieved by the radiation treatments was similar in length to the prolonged survival of the irradiated mice. This suggests that the adaptive response induced by low-dose whole-body radiation treatments prolongs the survival of prion-infected mice by reducing oxidative stress.


"Endothelial progenitor cells" as a therapeutic strategy in cardiovascular disease.
Cardiovascular atherosclerotic and ischemic diseases constitute the leading cause of morbidity and mortality throughout middle- and high-income countries. More efficient preventive and regenerative therapeutic strategies are therefore urgently needed. The repeated finding that putative "endothelial progenitor cells" (EPCs) can efficiently promote angiogenesis and restore perfusion of ischemic tissues has provoked a wealth of studies evaluating and developing their therapeutic potential. In the present review, we discuss the growing knowledge about various distinct cell populations which have been collectively termed "EPCs", including myeloid cells and progenitor cells of different origin. We also present clinical studies aiming to examine their therapeutic potential for cardiovascular disease. In addition, we will discuss recent insights into mechanisms leading to dysfunction of "EPCs" in cardiovascular disease. Those findings may help to optimize autologous cell-based treatment approaches, as well as to establish cellular dysfunction itself as an interesting novel therapeutic target.


40 Gb/s silicon photonics modulator for TE and TM polarisations.
A key device in future high speed short reach interconnect technology will be the optical modulator. These devices, in silicon, have experienced dramatic improvements over the last 6 years and the modulation bandwidth has increased from a few tens of MHz to over 30 GHz. However, the demands of optical interconnects are significant. Here we describe an approach based on a self-aligned wrap around p-n junction structure embedded in a silicon waveguide that can produce high-speed optical phase modulation, whilst at the same time, capable of a high extinction ratio. An all-silicon optical modulator using a CMOS compatible fabrication process with a data rate of 40 Gb/s and extinction ratio up to approximately 6.5 dB for TE and TM polarisations is demonstrated. This technology is not only compatible with conventional complementary MOS (CMOS) processing, but is also intended to simplify and improve the reliability of, the fabrication process.


Ages at menarche- and menopause-related genetic variants in relation to terminal duct lobular unit involution in normal breast tissue.
Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single-nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. Fourteen percent of evaluated SNPs (eight SNPs) were associated with TDLU counts at p < 0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50 % that were either significantly or nonsignificantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among ten SNPs that were statistically significantly associated with at least one TDLU involution measure (p < 0.05), seven SNPs (rs466639: RXRG; rs2243803: SLC14A2; rs2292573: GAB2; rs6438424: 3q13.32; rs7606918: METAP1D; rs11668344: TMEM150B; rs1635501: EXO1) were associated in the consistent directions. Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results.


Spatial mapping of metals in tissue-sections using combination of mass-spectrometry and histology through image registration.
We describe a new procedure for the parallel mapping of selected metals in histologically characterized tissue samples. Mapping is achieved via image registration of digital data obtained from two neighbouring cryosections by scanning the first as a histological sample and subjecting the second to laser ablation inductively coupled plasma mass spectrometry. This computer supported procedure enables determination of the distribution and content of metals of interest directly in the chosen histological zones and represents a substantial improvement over the standard approach, which determines these values in tissue homogenates or whole tissue sections. The potential of the described procedure was demonstrated in a pilot study that analysed Zn and Cu levels in successive development stages of pig melanoma tissue using MeLiM (Melanoma-bearing-Libechov-Minipig) model. We anticipate that the procedure could be useful for a complex understanding of the role that the spatial distribution of metals plays within tissues affected by pathological states including cancer.


Primary non-transecting bulbar urethroplasty long-term success rates are similar to transecting urethroplasty.
To review the long-term outcomes of transecting versus non-transecting urethroplasty to repair bulbar urethral strictures. A retrospective review was conducted of 342 patients who underwent anterior urethroplasty performed by a single surgeon from 2003 to 2014. Patients were excluded from further analysis if there had been prior urethroplasty, stricture location outside the bulbous urethra, or age <18 years. In the transecting group, surgical techniques used included excision and primary anastomosis and augmented anastomotic urethroplasty. In the non-transecting group, surgical techniques used included non-transecting anastomotic urethroplasty and dorsal and/or ventral buccal grafting. The primary endpoint was stricture resolution in transecting vs. non-transecting bulbar urethroplasty. Success was defined as freedom from secondary procedures including dilation, urethrotomy, or repeat urethroplasty. One hundred and fifty-two patients met inclusion criteria. At a mean follow-up of 65 months (range: 10-138 months), stricture-free recurrence in the transecting and non-transecting groups was similar, 83% (n = 85/102) and 82% (n = 41/50), respectively (p = 0.84). Surgical technique (p = 0.91), stricture length (p = 0.8), and etiology (p = 0.6) did not affect stricture recurrence rate on multivariate analysis. There was no difference detected in time to stricture recurrence (p = 0.21). In this retrospective series, transecting and non-transecting primary bulbar urethroplasty resulted in similar long-term stricture resolution rate. Prospective studies are needed to determine what differences may present in outcomes related to sexual function and long-term success.


Macrophage migration inhibitory factor regulates interleukin-6 production by facilitating nuclear factor-kappa B activation during Vibrio vulnificus infection.
Patients infected with Vibrio vulnificus (V. vulnificus) show severe inflammatory responses characterised by the upregulation of proinflammatory cytokines. Macrophage migration inhibitory factor (MIF), an upstream proinflammatory regulator, increases the inflammation caused by sepsis. Whether MIF regulates responses to V. vulnificus infection and the actual mechanism by which V. vulnificus initiates these MIF-modulated proinflammatory cytokines remain unclear. MIF increased inflammation during V. vulnificus infection in vivo. In V. vulnificus-infected mice, MIF was produced earlier than tumour necrosis factor (TNF)-α and interleukin (IL)-6 and was expressed in a time-dependent manner. ISO-1 ((S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester), a small-molecule inhibitor of MIF, significantly decreased IL-6, IL-8, and TNF-α production in a time- and dose-dependent manner in human peripheral blood cells infected with V. vulnificus. The induction of IL-6, IL-8, and TNF-α production by V. vulnificus infection was mediated via the NF-κB- and p38 MAPK-regulated pathways but not via the Akt pathway. ISO-1-treated human peripheral blood cells showed lower V. vulnificus-induced NF-κB activation, IL-6 mRNA expression, and IκB phosphorylation, but they did not show lower p38 MAPK activation. We conclude that MIF regulates V. vulnificus-induced IL-6 production via NF-κB activation and that p38 MAPK activation in V. vulnificus infection is not MIF dependent.


The Potential in Preparing Community Health Workers to Address Hearing Loss.
In underserved areas, it is crucial to investigate ways of increasing access to hearing health care. The community health worker (CHW) is a model that has been applied to increase access in various health arenas. This article proposes further investigation into the application of this model to audiology. To assess the feasibility of training CHWs about hearing loss as a possible approach to increase accessibility of hearing health support services in an underserved area. A specialized three-phase training process for CHWs was developed, implemented, and evaluated by audiologists and public health researchers. The training process included (1) focus groups with CHWs and residents from the community to raise awareness of hearing loss among CHWs and the community; (2) a 3-hr workshop training to introduce basic topics to prepare CHWs to identify signs of hearing loss among community members and use effective communication strategies; and (3) a 24-hr multisession, interactive training >6 weeks for CHWs who would become facilitators of educational and peer-support groups for individuals with hearing loss and family members. Twelve Spanish-speaking local CHWs employed by a federally qualified health center participated in a focus group, twelve received the general training, and four individuals with prior experience as health educators received further in-person training as facilitators of peer-education groups on hearing loss and communication. Data was collected from each step of the three-phase training process. Thematic analysis was completed for the focus group data. Pre- and posttraining assessments and case study discussions were used to analyze results for the general workshop and the in-depth training sessions. CHWs increased their knowledge base and confidence in effective communication strategies and developed skills in facilitating hearing education and peer-support groups. Through case study practice, CHWs demonstrated competencies and applied their learning to specific situations related to effective communication with hearing loss, family support, availability of assistive technology, use of hearing protection, and making referrals for hearing health care. Needs were identified for ongoing training in the area of use of assistive technology and addressing situations of more severe hearing loss and its effects. Initial results suggest it is feasible to train CHWs to engage community members regarding hearing loss and facilitate culturally relevant peer-health education and peer-support groups for individuals with hearing loss and their family members. In efforts to increase access to audiological services in rural or underserved communities, application of the CHW model with a partnership of audiologists deserves further consideration as a viable approach.


Phenology in a warming world: differences between native and non-native plant species.
Phenology is a harbinger of climate change, with many species advancing flowering in response to rising temperatures. However, there is tremendous variation among species in phenological response to warming, and any phenological differences between native and non-native species may influence invasion outcomes under global warming. We simulated global warming in the field and found that non-native species flowered earlier and were more phenologically plastic to temperature than natives, which did not accelerate flowering in response to warming. Non-native species' flowering also became more synchronous with other community members under warming. Earlier flowering was associated with greater geographic spread of non-native species, implicating phenology as a potential trait associated with the successful establishment of non-native species across large geographic regions. Such phenological differences in both timing and plasticity between native and non-natives are hypothesised to promote invasion success and population persistence, potentially benefiting non-native over native species under climate change.


Suppression of Wnt1-induced mammary tumor growth and lower serum insulin in offspring exposed to maternal blueberry diet suggest early dietary influence on developmental programming.
Despite the well-accepted notion that early maternal influences persist beyond fetal life and may underlie many adult diseases, the risks imposed by the maternal environment on breast cancer development and underlying biological mechanisms remain poorly understood. In this study, we investigated whether early exposure to blueberry (BB) via maternal diet alters oncogene Wnt1-induced mammary tumorigenesis in offspring. Wnt1-transgenic female mice were exposed to maternal Casein (CAS, control) or blueberry-supplemented (CAS + 3%BB) diets throughout pregnancy and lactation. Offspring were weaned to CAS and mammary tumor development was followed until age 8 months. Tumor incidence and latency were similar for both groups; however, tumor weight at killing and tumor volume within 2 weeks of initial detection were lower (by 50 and 60%, respectively) in offspring of BB- versus control-fed dams. Dietary BB exposure beginning at weaning did not alter mammary tumor parameters. Tumors from maternal BB-exposed offspring showed higher tumor suppressor (Pten and Cdh1) and lower proproliferative (Ccnd1), anti-apoptotic (Bcl2) and proangiogenic (Figf, Flt1 and Ephb4) transcript levels, and displayed attenuated microvessel density. Expression of Pten and Cdh1 genes was also higher in mammary tissues of maternal BB-exposed offspring. Mammary tissues and tumors of maternal BB-exposed offspring showed increased chromatin-modifying enzyme Dnmt1 and Ezh2 transcript levels. Body weight, serum insulin and serum leptin/adiponectin ratio were lower for maternal BB-exposed than control tumor-bearing offspring. Tumor weights and serum insulin were positively correlated. Results suggest that dietary influences on the maternal environment contribute to key developmental programs in the mammary gland to modify breast cancer outcome in adult progeny.


Prdm1 (Blimp-1) and the expression of fast and slow myosin heavy chain isoforms during avian myogenesis in vitro.
Multiple types of fast and slow skeletal muscle fibers form during early embryogenesis in vertebrates. In zebrafish, formation of the earliest slow myofibers in fin muscles requires expression of the zinc-finger transcriptional repressor Prdm1 (also known as Blimp1). To further understand how the role of Prdm1 in early myogenesis may vary through evolution and during development, we have now analyzed Prdm1 expression in the diverse types of myotubes that form in culture from somitic, embryonic, and fetal chicken myoblasts. In cultures of somitic, embryonic limb, and fetal limb chicken cells, we found that Prdm1 was expressed in all of the differentiated muscle cells that formed, including those that expressed only fast myosin heavy chain isoforms, as well as those that co-expressed both fast and slow myosin heavy chain isoforms. Prdm1 was also expressed in Pax7-positive myoblasts, as well as in non-myogenic cells in the cultures. Furthermore, though all differentiated cells in control somite cultures co-expressed fast and slow myosin heavy chains, antisense knockdown of Prdm1 expression inhibited the formation of these co-expressing cells in somite cultures. In chicken myogenic cell cultures, Prdm1 was expressed in most Pax7-positive myoblasts and in all differentiated muscle cells, irrespective of the developmental stage of cell donor or the pattern of fast and slow myosin heavy chains expressed in the differentiated cells that were formed. Thus, Prdm1 was expressed in myogenic cells prior to terminal differentiation; and, after differentiation, Prdm1 expression was not limited to cells that expressed slow myosin heavy chain isoforms. In addition, Prdm1 appeared to be required for differentiation of the somitic myocytes, which are the earliest myocytes to form in the avian embryo.


Tick paralysis with atypical presentation: isolated, reversible involvement of the upper trunk of brachial plexus.
Tick paralysis is a disease that occurs worldwide. It is a relatively rare but potentially fatal condition. The only way to establish the diagnosis is to carefully search for the tick paralysis. It is caused by a neurotoxin secreted by engorged female ticks. Tick paralysis generally begins in the lower extremities and ascends symmetrically to involve the trunk, upper extremities and head within a few hours. Although early-onset prominent bulbar palsy and isolated facial weakness without generalised paralysis are rare, there is no report in the English literature concerning isolated, reversible involvement of the upper trunk of brachial plexus caused by tick bite. We report a case of isolated, reversible involvement of the upper trunk of brachial plexus as a variant of tick paralysis. Diagnosis was confirmed with needle electromyography and nerve conduction examination. Within 2 weeks, the patient was fully recovered. The purpose of presenting this case is to remind clinicians that tick paralysis should be considered even in cases with atypical neurological findings admitted to the emergency department.


Complications Following Therapeutic Bronchoscopy for Malignant Central Airway Obstruction: Results of the AQuIRE Registry.
There are significant variations in how therapeutic bronchoscopy for malignant airway obstruction is performed. Relatively few studies have compared how these approaches affect the incidence of complications. We used the American College of Chest Physicians (CHEST) Quality Improvement Registry, Evaluation, and Education (AQuIRE) program registry to conduct a multicenter study of patients undergoing therapeutic bronchoscopy for malignant central airway obstruction. The primary outcome was the incidence of complications. Secondary outcomes were incidence of bleeding, hypoxemia, respiratory failure, adverse events, escalation in level of care, and 30-day mortality. Fifteen centers performed 1,115 procedures on 947 patients. There were significant differences among centers in the type of anesthesia (moderate vs deep or general anesthesia, P < .001), use of rigid bronchoscopy (P < .001), type of ventilation (jet vs volume cycled, P < .001), and frequency of stent use (P < .001). The overall complication rate was 3.9%, but significant variation was found among centers (range, 0.9%-11.7%; P = .002). Risk factors for complications were urgent and emergent procedures, American Society of Anesthesiologists (ASA) score > 3, redo therapeutic bronchoscopy, and moderate sedation. The 30-day mortality was 14.8%; mortality varied among centers (range, 7.7%-20.2%, P = .02). Risk factors for 30-day mortality included Zubrod score > 1, ASA score > 3, intrinsic or mixed obstruction, and stent placement. Use of moderate sedation and stents varies significantly among centers. These factors are associated with increased complications and 30-day mortality, respectively.


Naltrexone implants can completely prevent early (1-month) relapse after opiate detoxification: a pilot study of two cohorts totalling 101 patients with a note on naltrexone blood levels.
Early relapse is common after opiate withdrawal and deprives addicts of important opportunities to develop new, opiate-free cognitive-behavioural habits. The oral opiate antagonist naltrexone (NTX) significantly reduces relapse only when rigorously supervised and/or probation-linked. Simple but effective NTX implants, containing 1G NTX and giving an average blockade of 6 - 7 weeks, have been available since 1997. We present outcome data for two cohorts. Group 1 were the first 55 consecutive implanted British patients (76% male, 51% unemployed, 64% in social classes III - V). Group 2 were a second consecutive group of 46. Implants were inserted subcutaneously mainly during rapid opiate detoxification under general anaesthesia or sedation. The follow-up rate for group 1 was 100%. At 12 weeks after first implantation, 21% of group 1 patients and 26% of group 2 patients had apparently resumed opiate use. Thirty per cent of patients tested-out the blockade in the first week. None reported any opiate effects at less than 5 weeks after insertion. In other patients, typical blood NTX levels 4 - 5 weeks post-insertion were in the range 3 - 5 ng/ml, which is evidently enough to block 500 mg of pure diamorphine. NTX implants provide considerable protection against early relapse and may increase the likelihood of therapeutically useful periods of abstinence after opiate withdrawal. Troublesome tissue reactions were infrequent. Improvements in implant technology and duration are already occurring. We stress that implants strengthen rather than replace the therapeutic alliance.


Primary Care Screening Methods and Outcomes for Asylum Seekers in New York City.
Effective screening in primary care among asylum-seekers in the US is critical as this population grows. This study aimed to evaluate disease prevalence and screening methods in this high-risk group. Two hundred ten new clients from 51 countries, plus Tibet, who were accepted into a program for asylum seekers from 2012 to 2014 were included. Screening rates and outcomes for infectious, non-communicable, and mental illnesses were evaluated. Screening rates were highest for PTSD, depression, hepatitis B, and latent tuberculosis. Seventy-one percent of clients screened positive for depression and 55 % for PTSD, followed by latent tuberculosis (41 %), hypertension (10 %), hepatitis B (9.4 %), and HIV (0.8 %). Overall screening rates were high. Point of care testing was more effective than testing that required a repeat visit. A large psychiatric and infectious disease burden was identified. These findings can inform future primary care screening efforts for asylum seekers in the US.


Characterization of a 60Co unit at a secondary standard dosimetry laboratory: Monte Carlo simulations compared to measurements and results from the literature.
To compare a Monte Carlo (MC) characterization of a 60Co unit at the Swedish Secondary Standard Dosimetry Laboratory (SSDL) with the results of both measurements and literature with the aims of (1) resolving a change in the ratio of air-kerma free in air Kair and absorbed dose to water Dw in a water phantom noted experimentally after a source exchange in the laboratory and (2) reviewing results from the literature on similar MC simulations. Although their use in radiotherapy is decreasing, the characteristics of 60Co beams are of interest since 60Co beams are utilized in calibrating ionization chambers for the absolute dosimetry of radiotherapy beams and as reference radiation quality in evaluating the energy dependence of radiation detectors and in studies on radiobiological effectiveness. The BEAMnrc MC code was used with a detailed geometrical model of the treatment head and two models of the 60Co source representing the sources used before and after source exchange, respectively. The active diameters of the 60Co sources were 1.5 cm in pellet form and 2.0 cm in sintered form. Measurements were performed on the actual unit at the Swedish SSDL. Agreement was obtained between the MC and the measured results within the estimated uncertainties for beam profiles, water depth-dose curve, relative air-kerma output factors, and for the ratios of Kair/Dw before and after source exchange. The on-axis energy distribution of the photon fluence free in air for the unit loaded with its present (1.5 cm in diameter) source agreed closely with the results from the literature in which a source of the same make and active diameter, inside a different treatment head, was simulated. The spectrum for the larger (2.0 cm in diameter) source was in close agreement with another published spectrum, also modeling a 60Co source with an active diameter of 2.0 cm inside a different treatment head. The reduction in the value of Kair/Dw following source exchange was explained by the spectral differences between the two sources that were larger in the free in-air geometry used for Kair calibrations than at 5 g/cm2 depth in the water phantom used for Dw calibrations. Literature review revealed differences between published in-air 60Co spectra derived for sources of different active diameters, and investigators in need of an accurately determined 60Co in-air spectrum should be aware of differences due to source active diameter.


Enhancing clot properties through fibrin-specific self-cross-linked PEG side-chain microgels.
Excessive bleeding and resulting complications are a major cause of death in both trauma and surgical settings. Recently, there have been a number of investigations into the design of synthetic hemostatic agents with platelet-mimicking activity to effectively treat patients suffering from severe hemorrhage. We developed platelet-like particles from microgels composed of polymers carrying polyethylene glycol (PEG) side-chains and fibrin-targeting single domain variable fragment antibodies (PEG-PLPs). Comparable to natural platelets, PEG-PLPs were found to enhance the fibrin network formation in vitro through strong adhesion to the emerging fibrin clot and physical, non-covalent cross-linking of nascent fibrin fibers. Furthermore, the mechanical reinforcement of the fibrin mesh through the incorporation of particles into the network leads to a ∼three-fold decrease of the overall clot permeability as compared to control clots. However, transport of biomolecules through the fibrin clots, such as peptides and larger proteins is not hindered by the presence of PEG-PLPs and the altered microstructure. Compared to control clots with an elastic modulus of 460+/-260 Pa, PEG-PLP-reinforced fibrin clots exhibit higher degrees of stiffness as demonstrated by the significantly increased average Younǵs modulus of 1770 +/±720 Pa, as measured by AFM force spectroscopy. Furthermore, in vitro degradation studies with plasmin demonstrate that fibrin clots formed in presence of PEG-PLPs withstand hydrolysis for 24 h, indicating enhanced stabilization against exogenous fibrinolysis. The entire set of data suggests that the designed platelet-like particles have high potential for use as hemostatic agents in emergency medicine and surgical settings.


Paratesticular fibrous hamartoma in an infant.
Fibrous hamartoma of infancy is a rare benign tumour with local infiltration. The lesion is usually found in the upper torso and rarely occurs in the genital region. Diagnosis before surgery is rare, and complete excision is essential to prevent recurrence. We present a case in which fibrous hamartoma of infancy involving the spermatic cord was found. A pre-operative clinical diagnosis could not be made. On inguinal exploration, the tumour could not be dissected away from the testicular vessels, which necessitated an orchidectomy for complete removal. The case is presented due to its rarity and successful management.


Location of release sites and calcium-activated chloride channels relative to calcium channels at the photoreceptor ribbon synapse.
Vesicle release from photoreceptor ribbon synapses is regulated by L-type Ca(2+) channels, which are in turn regulated by Cl(-) moving through calcium-activated chloride [Cl(Ca)] channels. We assessed the proximity of Ca(2+) channels to release sites and Cl(Ca) channels in synaptic terminals of salamander photoreceptors by comparing fast (BAPTA) and slow (EGTA) intracellular Ca(2+) buffers. BAPTA did not fully block synaptic release, indicating some release sites are <100 nm from Ca(2+) channels. Comparing Cl(Ca) currents with predicted Ca(2+) diffusion profiles suggested that Cl(Ca) and Ca(2+) channels average a few hundred nanometers apart, but the inability of BAPTA to block Cl(Ca) currents completely suggested some channels are much closer together. Diffuse immunolabeling of terminals with an antibody to the putative Cl(Ca) channel TMEM16A supports the idea that Cl(Ca) channels are dispersed throughout the presynaptic terminal, in contrast with clustering of Ca(2+) channels near ribbons. Cl(Ca) currents evoked by intracellular calcium ion concentration ([Ca(2+)](i)) elevation through flash photolysis of DM-nitrophen exhibited EC(50) values of 556 and 377 nM with Hill slopes of 1.8 and 2.4 in rods and cones, respectively. These relationships were used to estimate average submembrane [Ca(2+)](i) in photoreceptor terminals. Consistent with control of exocytosis by [Ca(2+)] nanodomains near Ca(2+) channels, average submembrane [Ca(2+)](i) remained below the vesicle release threshold (∼ 400 nM) over much of the physiological voltage range for cones. Positioning Ca(2+) channels near release sites may improve fidelity in converting voltage changes to synaptic release. A diffuse distribution of Cl(Ca) channels may allow Ca(2+) influx at one site to influence relatively distant Ca(2+) channels.


Selective retrograde transsynaptic transfer of a protein, tetanus toxin, subsequent to its retrograde axonal transport.
The fate of tetanus toxin (mol wt 150,000) subsequent to its retrograde axonal transport in peripheral sympathetic neurons of the rat was studied by both electron microscope autoradiography and cytochemistry using toxin-horseradish peroxidase (HRP) coupling products, and compared to that of nerve growth factor (NGF), cholera toxin, and the lectins wheat germ agglutinin (WGA), phytohaemagglutinin (PHA), and ricin. All these macromolecules are taken up by adrenergic nerve terminals and transported retrogradely in a selective, highly efficient manner. This selective uptake and transport is a consequence of the binding of these macromolecules to specific receptive sites on the nerve terminal membrane. All these ligands are transported in the axons within smooth vesicles, cisternae, and tubules. In the cell bodies these membrane compartments fuse and most of the transported macromolecules are finally incorporated into lysosomes. The cell nuclei, the parallel golgi cisternae, and the extracellular space always remain unlabeled. In case the tetanus toxin, however, a substantial fraction of the labeled material appears in presynaptic cholinergic nerve terminals which innervate the labeled ganglion cells. In these terminals tetanus toxin-HRP is localized in 500-1,000 A diam vesicles. In contrast, such a retrograde transsynaptic transfer is not at all or only very rarely detectable after retrograde transport of cholera toxin, NGF, WGA, PHA, or ricin. An atoxic fragment of the tetanus toxin, which contains the ganglioside-binding site, behaves like intact toxin. With all these macromolecules, the extracellular space and the glial cells in the ganglion remain unlabeled. We conclude that the selectivity of this transsynaptic transfer of tetanus toxin is due to a selective release of the toxin from the postsynaptic dendrites. This release is immediately followed by an uptake into the presynaptic terminals.


Unique and shared functions of nuclear lamina LEM domain proteins in Drosophila.
The nuclear lamina is an extensive protein network that contributes to nuclear structure and function. LEM domain (LAP2, emerin, MAN1 domain, LEM-D) proteins are components of the nuclear lamina, identified by a shared ∼45-amino-acid motif that binds Barrier-to-autointegration factor (BAF), a chromatin-interacting protein. Drosophila melanogaster has three nuclear lamina LEM-D proteins, named Otefin (Ote), Bocksbeutel (Bocks), and dMAN1. Although these LEM-D proteins are globally expressed, loss of either Ote or dMAN1 causes tissue-specific defects in adult flies that differ from each other. The reason for such distinct tissue-restricted defects is unknown. Here, we generated null alleles of bocks, finding that loss of Bocks causes no overt adult phenotypes. Next, we defined phenotypes associated with lem-d double mutants. Although the absence of individual LEM-D proteins does not affect viability, loss of any two proteins causes lethality. Mutant phenotypes displayed by lem-d double mutants differ from baf mutants, suggesting that BAF function is retained in animals with a single nuclear lamina LEM-D protein. Interestingly, lem-d double mutants displayed distinct developmental and cellular mutant phenotypes, suggesting that Drosophila LEM-D proteins have developmental functions that are differentially shared with other LEM-D family members. This conclusion is supported by studies showing that ectopically produced LEM-D proteins have distinct capacities to rescue the tissue-specific phenotypes found in single lem-d mutants. Our findings predict that cell-specific mutant phenotypes caused by loss of LEM-D proteins reflect both the constellation of LEM-D proteins within the nuclear lamina and the capacity of functional compensation of the remaining LEM-D proteins.


Mice with cardiac-restricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death.
To investigate the local effects of angiotensin II on the heart, we created a mouse model with 100-fold normal cardiac angiotensin-converting enzyme (ACE), but no ACE expression in kidney or vascular endothelium. This was achieved by placing the endogenous ACE gene under the control of the alpha-myosin heavy chain promoter using targeted homologous recombination. These mice, called ACE 8/8, have cardiac angiotensin II levels that are 4.3-fold those of wild-type mice. Despite near normal blood pressure and a normal renal function, ACE 8/8 mice have a high incidence of sudden death. Both histological analysis and in vivo catheterization of the heart showed normal ventricular size and function. In contrast, both the left and right atria were three times normal size. ECG analysis showed atrial fibrillation and cardiac block. In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death.


Glucocorticoid receptor number predicts increase in amygdala activity after severe stress.
Individuals who are exposed to a traumatic event are at increased risk of developing psychiatric disorders such as posttraumatic stress disorder (PTSD). Studies have shown that increased amygdala activity is frequently found in patients with PTSD. In addition, pre-trauma glucocorticoid receptor (GR) number in peripheral blood mononuclear cells (PBMCs) has been found to be a significant predictor for the development of PTSD symptoms. Research in rodents has shown that the response of basolateral amygdala neurons to corticosterone is mediated by GR. However, to the best of our knowledge, no previous study has investigated GR number in PBMCs and amygdala function in humans. To investigate whether peripheral GR number is related to amygdala functioning, we assessed GR number in PBMCs of healthy soldiers before their deployment to Afghanistan. Amygdala functioning was assessed with fMRI before and after deployment. We found that pre-deployment GR number was significantly negatively correlated to pre-deployment amygdala activity. More importantly, pre-deployment GR number predicted the increase in amygdala activity by deployment. Our results demonstrate that peripheral GR number is associated with amygdala functioning and predicts the increase in amygdala activity following military deployment in healthy individuals who did not develop PTSD. It is uncertain how this relationship is mediated mechanistically, but future studies should examine the relation of GR and amygdala activity to determine whether this is part of a common pathway leading to increased vulnerability to stress-related disorders.


Self-pumped phase-conjugation properties of cerium-doped BaTiO(3) crystals in the near infrared.
Studies of a new Ce-doped BaTiO(3) crystal as an efficient self-pumped phase conjugator in the near infrared are presented. The internal beam production during the establishment of self-pumped phase conjugation (SPPC) is closely observed, and the corresponding mechanisms of SPPC are identified accordingly. When the incident beam is in an a-face-incidence geometric arrangement, it is observed for the first time that SPPC mechanism has a transition from stimulated photorefractive backscattering and four-wave mixing to total internal reflection when λ is varied from 706 to 733 nm. Variations of the SPPC reflectivity with the λ, incident angle, and position of the input beam have been investigated, and a high reflectivity of approximately 80% has been obtained. In addition, SPPC reflectivity of approximately 40% is obtained when the incident beam enters the crystal by the +c face, and a variation with λ of optical beam patterns in the crystal has also been observed. Qualitative explanations of the phenomenon of SPP mechanism transition with λ that will be very useful in practical applications are given.


Electric versus manual tooth brushing among neuroscience ICU patients: is it safe?
Poor oral hygiene has been associated with ventilator-acquired pneumonia. Yet providing oral care for intubated patients is problematic. Furthermore, concerns that oral care could raise intracranial pressure (ICP) may cause nurses to use foam swabs to provide oral hygiene rather than tooth brushing as recommended by the American Association of Critical-Care Nurses. Evidence is needed to support the safety of toothbrushing during oral care. We therefore evaluated ICP and cerebral perfusion pressure (CPP) during oral care with a manual or electric toothbrush in intubated patients in a neuroscience intensive care unit (ICU). As part of a larger 2-year, prospective, randomized clinical trial, 47 adult neuroscience ICU patients with an ICP monitor received oral care with a manual or electric toothbrush. ICP and CPP were recorded before, during, and after oral care over the first 72 h of admission. Groups did not differ significantly in age, gender, or severity of injury. Of 807 ICP and CPP measurements obtained before, during, and after oral care, there were no significant differences in ICP (P = 0.72) or CPP (P = 0.68) between toothbrush methods. Analysis of pooled data from both groups revealed a significant difference across the three time points (Wilks' lambda, 12.56; P < 0.001; partial η(2), 0.36). ICP increased significantly (mean difference, 1.7 mm Hg) from before to during oral care (P = 0.001) and decreased significantly (mean difference, 2.1 mm Hg) from during to after oral care (P < 0.001). In the absence of preexisting intracranial hypertension during oral care, tooth brushing, regardless of method, was safely performed in intubated neuroscience ICU patients.


On-Surface Cross Coupling Methods for the Construction of Modified Electrode Assemblies with Tailored Morphologies.
Controlling the molecular topology of electrode-catalyst interfaces is a critical factor in engineering devices with specific electron transport kinetics and catalytic efficiencies. As such, the development of rational methods for the modular construction of tailorable electrode surfaces with robust molecular wires (MWs) exhibiting well-defined molecular topologies, conductivities and morphologies is critical to the evolution and implementation of electrochemical arrays for sensing and catalysis. In response to this need, we have established modular on-surface Sonogashira and Glaser cross-coupling processes to synthetically install arrays of ferrocene-capped MWs onto electrochemically functionalized surfaces. These methods are of comparable convenience and efficiency to more commonly employed Huisgen methods. Furthermore, unlike the Huisgen reaction, this new surface functionalization chemistry generates modified electrodes that do not contain unwanted ancillary metal binding sites, while allowing the bridge between the ferrocenyl moiety and electrode surface to be synthetically tailored. Electrochemical and surface analytical characterization of these platforms demonstrate that the linker topology and connectivity influences the ferrocene redox potential and the kinetics of charge transport at the interface.


The GAG database: a new resource to gather genomic annotation cross-references.
Several institutions provide genomic annotation data, and therefore these data show a significant segmentation and redundancy. Public databases allow access, through their own methods, to genomic and proteomic sequences and related annotation. Although some cross-reference tables are available, they don't cover the complete datasets provided by these databases. The Genomic Annotation Gathering project intends to unify annotation data provided by GenBank and Ensembl. We introduce an intra-species, cross-bank method. Generated results provide an enriched set of cross- references. This method allows for identifying an average of 30% of new cross-references that can be integrated to other utilities dedicated to analyzing related annotation data. By using only sequence comparison, we are able to unify two datasets that previously didn't share any stable cross-bank accession method. The whole process is hosted by the GenOuest platform to provide public access to newly generated cross-references and to allow for regular updates (http://gag.genouest.org).


Renal cell carcinoma with renal vein and inferior vena caval involvement: clinicopathological features, surgical techniques and outcomes.
We present a contemporary review of patients with renal cell carcinoma (RCC) in whom renal vein/inferior vena caval thrombus was treated with radical nephrectomy and thrombectomy. A total of 220 patients underwent radical nephrectomy for RCC at our institution from 1998 to 2002. Of them 49 patients with renal vein/inferior vena caval involvement (T3b/c) were selected for review. We evaluated demographics, presenting symptoms, imaging modalities, clinical staging, pathological features, adjuvant treatment and clinical outcomes. We also evaluated surgical incisions, liver mobilization procedures, blood loss, transfusion requirements and perioperative mortality/morbidity. Gross hematuria was the most common presenting symptom, seen in 22 patients (45%), followed by constitutional symptoms in 8 (16%). Stage T3b/c was clinically diagnosed in 44 patients, while 2 had T2 and 2 had T4 disease. A subcostal incision was made in 30 patients, a chevron incision was made in 18, and a sternotomy and flank incision were made in 1. Liver mobilization was necessary in 13 patients and 2 required a Pringle maneuver. Cardiopulmonary bypass was performed in a single patient. Lymph node involvement was seen in 4 patients (8%) and distant metastases were present in 10 (20%). Median tumor size was 10 cm. Clear cell carcinoma was most common, as seen in 42 patients. Early (30-day) mortality in this series was 8%. At a median followup of 15 months 21 patients (43%) were without evidence of disease, 14 (29%) had disease, 8 (16%) had died of disease and 2 (4%) had died of other causes. None of the patients with lymph node involvement survived beyond 8 months after surgery. Tumor grade and T stage were found to be significant negative predictors of survival on univariate analysis. Most patients with RCC and tumor thrombus are symptomatic at presentation and metastatic disease at presentation is not uncommon. These results support the role of aggressive surgical treatment as the best initial management of these tumors. The majority of tumors can be approached and safely controlled without the need for a thoracoabdominal incision. While surgery provides modest disease-free survival, most patients should be offered immunotherapy, particularly those with advanced stage, grade, nodal involvement or metastases.