Effect of chlorhexidine gluconate on the adherence of Candida species to denture acrylic.
The effect of pretreatment of denture acrylic with chlorhexidine gluconate on the subsequent adherence of Candida albicans GDH 2346 was measured in vitro. Adherence was significantly reduced by pretreatment with chlorhexidine; maximal inhibition was achieved by incubation at room temperature for 30 min in 2% chlorhexidine. Inhibition of adherence was greatest when the organisms were grown in conditions that enhanced adherence the most, i.e., growth to stationary phase in high concentrations of galactose and sucrose. Yeasts grown in high concentrations of galactose, which were the most adherent to acrylic, were also the most sensitive to the fungicidal action of chlorhexidine gluconate, whereas those grown in a low concentration of glucose were the least adherent and also the most resistant. Adherence to acrylic of seven strains of C. albicans isolated from active infections (I strains) and grown in medium containing 500 mM sucrose was significantly higher than that of four strains obtained from asymptomatic carriers (C strains). A spectrum of adherence values was obtained when various yeasts other than C. albicans were tested.


Intra-Site Variability in the Still Bay Fauna at Blombos Cave: Implications for Explanatory Models of the Middle Stone Age Cultural and Technological Evolution.
To explain cultural and technological innovations in the Middle Stone Age (MSA) of southern Africa, scholars invoke several factors. A major question in this research theme is whether MSA technocomplexes are adapted to a particular set of environmental conditions and subsistence strategies or, on the contrary, to a wide range of different foraging behaviours. While faunal studies provide key information for addressing these factors, most analyses do not assess intra-technocomplex variability of faunal exploitation (i.e. variability within MSA phases). In this study, we assess the spatial variability of the Still Bay fauna in one phase (M1) of the Blombos Cave sequence. Analyses of taxonomic composition, taphonomic alterations and combustion patterns reveal important faunal variability both across space (lateral variation in the post-depositional history of the deposits, spatial organisation of combustion features) and over time (fine-scale diachronic changes throughout a single phase). Our results show how grouping material prior to zooarchaeological interpretations (e.g. by layer or phase) can induce a loss of information. Finally, we discuss how multiple independent subdivisions of archaeological sequences can improve our understanding of both the timing of different changes (for example in technology, culture, subsistence, environment) and how they may be inter-related.


European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions.
The European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT-R) was set up with the aim of describing the clinical epidemiology and the 1-year outcomes of patients with heart failure (HF) with the added intention of comparing differences between participating countries. The ESC-HF-LT-R is a prospective, observational registry contributed to by 211 cardiology centres in 21 European and/or Mediterranean countries, all being member countries of the ESC. Between May 2011 and April 2013 it collected data on 12 440 patients, 40.5% of them hospitalized with acute HF (AHF) and 59.5% outpatients with chronic HF (CHF). The all-cause 1-year mortality rate was 23.6% for AHF and 6.4% for CHF. The combined endpoint of mortality or HF hospitalization within 1 year had a rate of 36% for AHF and 14.5% for CHF. All-cause mortality rates in the different regions ranged from 21.6% to 36.5% in patients with AHF, and from 6.9% to 15.6% in those with CHF. These differences in mortality between regions are thought reflect differences in the characteristics and/or management of these patients. The ESC-HF-LT-R shows that 1-year all-cause mortality of patients with AHF is still high while the mortality of CHF is lower. This registry provides the opportunity to evaluate the management and outcomes of patients with HF and identify areas for improvement.


Quality of life among women recently diagnosed with invasive breast cancer: the Pathways Study.
Few studies have assessed quality of life (QOL) of women diagnosed with breast cancer within the first few weeks of their initial diagnosis. We describe QOL among 950 women recently diagnosed with invasive breast cancer. Starting in January 2006, we invited women aged > or =21 years who were diagnosed with first primary invasive breast cancer within Kaiser Permanente Northern California (KPNC) to enroll in the Pathways Study, a prospective study of breast cancer survivorship. QOL was measured using the Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B), along with sociodemographic and social support information. Clinical characteristics were obtained from the KPNC cancer registry and electronic medical record. We used multivariable linear regression models to identify factors associated with QOL scores calculated from the FACT-B. The mean age +/- SD of the sample was 59.6 years (+/-11.9 years), and the mean time +/-SD from diagnosis until interview was 8.0 weeks (+/-3.2 weeks). Younger age at diagnosis was associated with lower scores in all QOL domains (P < 0.01), and later stage at diagnosis was associated with lower scores in all domains (P < 0.05) except for social well-being. Higher levels of social support were associated with higher QOL except for physical well-being (P < 0.05). These associations were stronger within 2 months of breast cancer diagnosis. Quality of life as influenced by a diagnosis of breast cancer is an important factor in cancer survivorship. Age, stage at diagnosis, and social support are key factors in this important variable.


Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease.
Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic stem-cell transplantation (HSCT). The chemokine receptor CCR5 appears to play a role in alloreactivity. We tested whether CCR5 blockade would be safe and limit GVHD in humans. We tested the in vitro effect of the CCR5 antagonist maraviroc on lymphocyte function and chemotaxis. We then enrolled 38 high-risk patients in a single-group phase 1 and 2 study of reduced-intensity allogeneic HSCT that combined maraviroc with standard GVHD prophylaxis. Maraviroc inhibited CCR5 internalization and lymphocyte chemotaxis in vitro without impairing T-cell function or formation of hematopoietic-cell colonies. In 35 patients who could be evaluated, the cumulative incidence rate (±SE) of grade II to IV acute GVHD was low at 14.7±6.2% on day 100 and 23.6±7.4% on day 180. Acute liver and gut GVHD were not observed before day 100 and remained uncommon before day 180, resulting in a low cumulative incidence of grade III or IV GVHD on day 180 (5.9±4.1%). The 1-year rate of death that was not preceded by disease relapse was 11.7±5.6% without excessive rates of relapse or infection. Serum from patients receiving maraviroc prevented CCR5 internalization by CCL5 and blocked T-cell chemotaxis in vitro, providing evidence of antichemotactic activity. In this study, inhibition of lymphocyte trafficking was a specific and potentially effective new strategy to prevent visceral acute GVHD. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00948753.).


Physician nutrition and cognition during work hours: effect of a nutrition based intervention.
Physicians are often unable to eat and drink properly during their work day. Nutrition has been linked to cognition. We aimed to examine the effect of a nutrition based intervention, that of scheduled nutrition breaks during the work day, upon physician cognition, glucose, and hypoglycemic symptoms. A volunteer sample of twenty staff physicians from a large urban teaching hospital were recruited from the doctors' lounge. During both the baseline and the intervention day, we measured subjects' cognitive function, capillary blood glucose, "hypoglycemic" nutrition-related symptoms, fluid and nutrient intake, level of physical activity, weight, and urinary output. Cognition scores as measured by a composite score of speed and accuracy (Tput statistic) were superior on the intervention day on simple (220 vs. 209, p = 0.01) and complex (92 vs. 85, p < 0.001) reaction time tests. Group mean glucose was 0.3 mmol/L lower (p = 0.03) and less variable (coefficient of variation 12.2% vs. 18.0%) on the intervention day. Although not statistically significant, there was also a trend toward the reporting of fewer hypoglycemic type symptoms. There was higher nutrient intake on intervention versus baseline days as measured by mean caloric intake (1345 vs. 935 kilocalories, p = 0.008), and improved hydration as measured by mean change in body mass (+352 vs. -364 grams, p < 0.001). Our study provides evidence in support of adequate workplace nutrition as a contributor to improved physician cognition, adding to the body of research suggesting that physician wellness may ultimately benefit not only the physicians themselves but also their patients and the health care systems in which they work.


The long non-coding RNA Dali is an epigenetic regulator of neural differentiation.
Many intergenic long noncoding RNA (lncRNA) loci regulate the expression of adjacent protein coding genes. Less clear is whether intergenic lncRNAs commonly regulate transcription by modulating chromatin at genomically distant loci. Here, we report both genomically local and distal RNA-dependent roles of Dali, a conserved central nervous system expressed intergenic lncRNA. Dali is transcribed downstream of the Pou3f3 transcription factor gene and its depletion disrupts the differentiation of neuroblastoma cells. Locally, Dali transcript regulates transcription of the Pou3f3 locus. Distally, it preferentially targets active promoters and regulates expression of neural differentiation genes, in part through physical association with the POU3F3 protein. Dali interacts with the DNMT1 DNA methyltransferase in mouse and human and regulates DNA methylation status of CpG island-associated promoters in trans. These results demonstrate, for the first time, that a single intergenic lncRNA controls the activity and methylation of genomically distal regulatory elements to modulate large-scale transcriptional programmes.


Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation.
Protein aggregation and abnormal lipid homeostasis are both implicated in neurodegeneration through unknown mechanisms. Here we demonstrate that aggregate-membrane interaction is critical to induce a form of cell death called ferroptosis. Importantly, the aggregate-membrane interaction that drives ferroptosis depends both on the conformational structure of the aggregate, as well as the oxidation state of the lipid membrane. We generated human stem cell-derived models of synucleinopathy, characterized by the intracellular formation of α-synuclein aggregates that bind to membranes. In human iPSC-derived neurons with SNCA triplication, physiological concentrations of glutamate and dopamine induce abnormal calcium signaling owing to the incorporation of excess α-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. α-synuclein oligomers further induce lipid peroxidation. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling. Inhibition of lipid peroxidation, and reduction of iron-dependent accumulation of free radicals, further prevents oligomer-induced toxicity in human neurons. In summary, we report that peroxidation of polyunsaturated fatty acids underlies the incorporation of β-sheet-rich aggregates into the membranes, and that additionally induces neuronal death. This suggests a role for ferroptosis in Parkinson's disease, and highlights a new mechanism by which lipid peroxidation causes cell death.


Muscarine-gated K+ channel: subunit stoichiometry and structural domains essential for G protein stimulation.
Coexpression in Xenopus oocytes of the cloned cardiac inward rectifier subunits Kir 3.1 and Kir 3.4 results in G protein-stimulated channel activity closely resembling the muscarinic channel underlying the inwardly rectifying K+ current in atrial myocytes. To determine the stoichiometry and relative subunit positions within the channel, Kir 3.1 and Kir 3.4 were coexpressed in varying ratios with cloned G beta 1 gamma 2 subunits and also as tandemly linked tetramers with different relative subunit positions. The results reveal that the most efficient channel comprises two subunits of each type in an alternating array within the tetramer. To localize regions important for subunit coassembly and G protein sensitivity, chimeric subunits containing domains from either Kir 3.1, Kir 3.4, or the G protein-insensitive subunit Kir 4.1 were expressed. The results demonstrate that the transmembrane domains dictate the potentiation of the coassembled channels and that, although the NH4- or COOH-termini of both subunits alone can confer G protein sensitivity, both termini are required for maximal stimulation by G beta 1 gamma 2.


Delayed cardioprotection afforded by the glycogen synthase kinase 3 inhibitor SB-216763 occurs via a KATP- and MPTP-dependent mechanism at reperfusion.
Previous studies in our laboratory suggest that an acute inhibition of glycogen synthase kinase 3 (GSK3) by SB-216763 (SB21) is cardioprotective when administered just before reperfusion. However, it is unknown whether the GSK inhibitor SB21 administered 24 h before ischemia is cardioprotective and whether the mechanism involves ATP-sensitive potassium (K(ATP)) channels and the mitochondrial permeability transition pore (MPTP). Male Sprague-Dawley rats were administered the GSK inhibitor SB21 (0.6 mg/kg) or vehicle 24 h before ischemia. Subsequently, the rats were acutely anesthetized with Inactin and underwent 30 min of ischemia and 2 h of reperfusion followed by infarct size determination. Subsets of rats received either the sarcolemmal K(ATP) channel blocker HMR-1098 (6 mg/kg), the mitochondrial K(ATP) channel blocker 5-hydroxydecanoic acid (5-HD; 10 mg/kg), or the MPTP opener atractyloside (5 mg/kg) either 5 min before SB21 administration or 5 min before reperfusion 24 h later. The infarct size was reduced in SB21 compared with vehicle (44 +/- 2% vs. 61 +/- 2%, respectively; P < 0.01). 5-HD administered either before SB21 treatment or 5 min before reperfusion the following day abrogated SB21-induced protection (54 +/- 4% and 61 +/- 2%, respectively). HMR-1098 did not affect the SB21-induced infarct size reduction when administered before the SB21 treatment (43 +/- 1%); however, HMR-1098 partially abrogated the SB21-induced infarct size reduction when administered just before reperfusion 24 h later (52 +/- 1%). The MPTP opening either before SB21 administration or 5 min before reperfusion abrogated the infarct size reduction produced by SB21 (61 +/- 2% and 62 +/- 2%, respectively). Hence, GSK inhibition reduces infarct size when given 24 h before the administration via the opening K(ATP) channels and MPTP closure.


Progeny of high muscling sires have reduced muscle response to adrenaline in sheep.
This study investigated the impact of variation in Australian sheep breeding values (ASBVs) for yearling eye muscle depth (YEMD) within Merino and Poll Dorset sires on intermediary metabolism of progeny. Specifically, the change in the blood concentrations of lactate, non-esterified fatty acids (NEFA) and glucose in response to administration of an exogenous dose of adrenaline was studied. The experiment used 20 Merino and Merino cross Poll Dorset mixed sex sheep. The sires were selected across a range of YEMD ASBVs. The sheep were fitted with indwelling jugular catheters and administered seven levels of adrenaline over a period of 4 days at 4 months of age (0.1, 0.2, 0.4, 0.6, 0.9, 1.2 and 1.6 μg/kg liveweight (LW)) and 16 months of age (0.1, 0.2, 0.6, 1.2, 1.8, 2.4 and 3.0 μg/kg LW). A total of 16 blood samples were collected between -30 min and 130 min relative to administration of the adrenaline challenge and were later measured for the plasma concentrations of lactate, NEFA and glucose. These data were then used to calculate the time to maximum substrate concentration, the maximum concentration and the area under curve (AUC) between 0 and 10 min, thus reflecting the substrate's response to exogenous adrenaline. Selection for muscling led to decreased muscle response due to adrenaline, as indicated by lower maximum concentrations and AUC for lactate. The muscles' response to adrenaline was more prominent at 16 months of age than at 4 months of age. Thus, animals selected for increased muscling have lower levels of glycogenolysis in situations where endogenous adrenaline levels are increased like pre-slaughter. This may minimise the risk of poor meat quality in these animals, as they will express higher muscle concentrations of glycogen at slaughter. Adipose tissue was more sensitive to adrenaline in young lambs from high YEMD sires. This shows that high muscled growing lambs utilise their adipose tissue deposits in times of stress to produce energy. This may explain the phenotypic leanness of these animals. Blood glucose levels that are indicative of liver response to adrenaline decreased with selection for muscling. This response may indicate a potential limiting of glucose that is available within animals selected for muscling, leanness and growth for brain function.


Intramedullary blastomycosis in a child: case report.
To report a case of spinal intramedullary blastomycosis causing myelopathy. An otherwise healthy 13-year-old patient was diagnosed with respiratory North American blastomycosis. She subsequently received a five-month course of itraconazole with presumed resolution of the infection. The patient presented again at 14 years of age with a lumbar myelopathy. Magnetic resonance imaging revealed an intramedullary lesion of 1 cm diameter at the level of T12-L1. A T12-L1 laminectomy was performed with a gross total resection of the lesion. Pathological examination and microbiological culture of the specimen was consistent with blastomycosis. Postoperatively, the patient was placed on a five week course of amphotericin B. The patient showed substantial improvement in neurological function. Blastomycosis can present as an isolated intramedullary lesion causing compromised function. It should be considered in the differential diagnosis of a patient with a myelopathy and previously recognized blastomycosis. The prognosis is good with surgical resection.


Impact of high resolution 3 tesla MR neurography (MRN) on diagnostic thinking and therapeutic patient management.
To evaluate the impact of magnetic resonance neurography (MRN) on diagnostic thinking and therapeutic choices in patients with suspected peripheral neuropathy. IRB approval was obtained for this HIPAA-compliant study. Questionnaires were administered to six surgeons regarding the diagnosis and treatment in 85 patients suspected of having peripheral neuropathy, before (pretest) and after (posttest) MRN. Multiple outcome measures related to diagnostic confidence and surgical decision-making were assessed. The final cohort included 81 patients (30 men and 51 women, age 47 ± 17 years). The following changes were observed from pretest to posttest questionnaires: 23% in nerve involvement (P < 0.05), 48% in degree of confidence of nerve involvement (P < 0.01), 27% in grade of injury (P < 0.05), 33% in differential diagnosis (P < 0.05), 63% in degree of confidence in need for surgery (P < 0.001), 41% in timing of surgery (P < 0.01), 30% in approach to surgery (P < 0.05), 58% in degree of confidence in approach to surgery (P < 0.001), 30% in estimated length of surgery (P < 0.05) and 27% in length of incision (P < 0.05). The dichotomous decision regarding surgical or nonsurgical treatment changed from pro to con in 17%. MRN results significantly influenced the diagnostic thinking and therapeutic recommendations of peripheral nerve surgeons. • In patients with peripheral neuropathy, MRN significantly impacts diagnostic thinking. • In patients with peripheral neuropathy, MRN significantly impacts therapeutic choices. • 3-T MRN should be considered in presurgical planning of patients with peripheral neuropathy.


Characterization of risk factors for adjuvant radiotherapy-associated pain in a tri-racial/ethnic breast cancer population.
Pain related to cancer or treatment is a critical quality of life issue for breast cancer survivors. In a prospective study of 375 patients with breast cancer (enrolled during 2008-2014), we characterized the risk factors for adjuvant radiotherapy (RT)-associated pain. Pain score was assessed at pre-RT and post-RT as the mean of 4 pain severity items (ie, pain at its worst, least, average, and now) from the Brief Pain Inventory with 11-point numeric rating scale (0-10). Pain scores of 4 to 10 were considered clinically relevant pain. The study consists of 58 non-Hispanic whites (15%), 78 black or African Americans (AA; 21%), and 239 Hispanic whites (HW; 64%). Overall, the prevalence of pre-RT, post-RT, and RT-associated clinically relevant pain was 16%, 31% and 20%, respectively. In univariate analysis, AA and HW had significantly higher pre-RT and post-RT pain than non-Hispanic whites. In multivariable logistic regression analysis, pre-RT pain was significantly associated with HW and obesity; post-RT pain was significantly associated with AA, HW, younger age, ≥2 comorbid conditions, above-median hotspot volume receiving >105% prescribed dose, and pre-RT pain score ≥4. Radiotherapy-associated pain was significantly associated with AA (odds ratio [OR] = 3.27; 95% confidence interval [CI] = 1.09-9.82), younger age (OR = 2.44, 95% CI = 1.24-4.79), and 2 or ≥3 comorbid conditions (OR = 3.06, 95% CI = 1.32-7.08; OR = 4.61, 95% CI = 1.49-14.25, respectively). These risk factors may help to guide RT decision-making process, such as hypofractionated RT schedule. Furthermore, effective pain management strategies are needed to improve quality of life in patients with breast cancer with clinically relevant pain.


A novel risk score model of esophageal stricture for patients undergoing endoscopic submucosal dissection.
Endoscopic submucosal dissection (ESD) is a promising technique for superficial esophageal lesions. However, stricture is a frequent adverse complication. This study was performed to develop a precise and convenient score prediction model for esophageal strictures after ESD, and compare its efficacy with a previously published predictive model. This study enrolled clinical data of patients who underwent esophageal ESD for superficial esophageal lesions. Possible risk factors for esophageal stricture were identified by univariate and multivariate logistic regression analysis. Then we developed a prediction model according to the Framingham system for the first time and presented a convenient table containing the risk probability for each patient. In addition, we validated our score model and the previously published model in our center. A total of 838 patients were enrolled in this study and 6 variables, including age, surgery time, location of the lesion, circumference of the lesion, longitudinal resection length, and depth of infiltration were comprised in the score model. The total score ranged from 0 to 16 points and the risk probability was presented in one concise table for each patient. Areas under receiver-operator characteristic curves for the prediction model were 0.715 in derivation group and 0.804 in validation group. We designed and validated a prediction score model for esophageal stricture after ESD, which can be applied conveniently to stratify the stricture risk after esophageal ESD and may facilitate appropriate clinical decision-making for these patients.


Imaging of hydrogel episcleral buckle fragmentation as a late complication after retinal reattachment surgery.
Hydrogel encircling bands were introduced in the early 1980s as a product that was superior to bands composed of silicone rubber or silicone sponge for the surgical treatment of retinal detachment. Late complications consisting of orbital swelling and diplopia requiring band removal began to be reported in the early 1990s. Pathologic studies of these expanded fragments of hydrogel material after removal showed in vivo hydrolysis with foreign body reaction and dystrophic calcification. We report the imaging findings in five patients in whom this late complication developed. Hydrogel fragmentation has a characteristic imaging appearance consisting of a circumferential orbital mass associated with rim enhancement. This appearance should prompt inquiries regarding previous scleral buckle procedures with hydrogel bands. Familiarity with this appearance will avoid misinterpretation and unwarranted biopsy before band removal.


Morphological control of heterostructured nanowires synthesized by sol-flame method.
Heterostructured nanowires, such as core/shell nanowires and nanoparticle-decorated nanowires, are versatile building blocks for a wide range of applications because they integrate dissimilar materials at the nanometer scale to achieve unique functionalities. The sol-flame method is a new, rapid, low-cost, versatile, and scalable method for the synthesis of heterostructured nanowires, in which arrays of nanowires are decorated with other materials in the form of shells or chains of nanoparticles. In a typical sol-flame synthesis, nanowires are dip-coated with a solution containing precursors of the materials to be decorated, then dried in air, and subsequently heated in the post-flame region of a flame at high temperature (over 900°C) for only a few seconds. Here, we report the effects of the precursor solution on the final morphology of the heterostructured nanowire using Co3O4 decorated CuO nanowires as a model system. When a volatile cobalt salt precursor is used with sufficient residual solvent, both solvent and cobalt precursor evaporate during the flame annealing step, leading to the formation of Co3O4 nanoparticle chains by a gas-solid transition. The length of the nanoparticle chains is mainly controlled by the temperature of combustion of the solvent. On the other hand, when a non-volatile cobalt salt precursor is used, only the solvent evaporates and the cobalt salt is converted to nanoparticles by a liquid-solid transition, forming a conformal Co3O4 shell. This study facilitates the use of the sol-flame method for synthesizing heterostructured nanowires with controlled morphologies to satisfy the needs of diverse applications.


Advancing single-cell proteomics and metabolomics with microfluidic technologies.
Recent advances in single-cell analysis have unraveled substantial heterogeneity among seemingly identical cells at genomic and transcriptomic levels. These discoveries have urged scientists to develop new tools that are capable of investigating single cells from a broader set of "omics". Proteomics and metabolomics, for instance, are of particular interest as they are closely correlated with a dynamic picture of cellular behaviors and phenotypic identities. The development of such tools requires highly efficient isolation and processing of a large number of individual cells, where techniques such as microfluidics are extremely useful. Here, we review the recent advances in single-cell proteomics and metabolomics, with a focus on microfluidics-based platforms. We highlight a vast array of emerging microfluidic formats for single-cell isolation and manipulation, and how the state-of-the-art analytical tools are coupled with such platforms for proteomic and metabolomic profiling.


Control of cavity lifetime of 1.5 µm wafer-fused VCSELs by digital mirror trimming.
Digital chemical etching is used to trim the output mirror thickness of wafer-fused VCSELs emitting at a wavelength near 1.5µm. The fine control of the photon cavity lifetime thus achieved is employed to extract important device parameters and optimize the combination of the threshold current, output power, and direct current modulation characteristics. The fabrication process is compatible with industrial production and should help in improving device yield and in reducing manufacturing costs.


Childhood epilepsy in a tropical child psychiatric unit: challenges of providing care in a resource-constrained environment.
Epilepsy is an important cause of childhood morbidity and its care is fraught with challenges. Itinerant search for remedy and manifestation as or with psychiatric disorders could result in presentation in a psychiatric unit. Identification of these challenges is essential to providing optimal care. The objective was to identify caregiver challenges in the provision of care to children with epilepsy presenting in a psychiatric unit. Administration of a structured questionnaire to caregivers of children with epilepsy presenting, between September and December 2011, in the newly constituted Child and Adolescent Mental Health(CAMH) Unit of the Federal NeuroPsychiatric Hospital, Kaduna Nigeria. A total of 84 caregivers were interviewed. The age range of the caregivers was 23 to 62 years (mean 38 ± 9.2 years) and a female preponderance (50, 59.5%). Most of the caregivers were in the upper social classes (I-III, 79.8%). A high number of challenges were indicated by majority 65, 77.4%) of the caregivers. The recurrence of seizures (84,100%) was the commonest challenge while the experience of discrimination (17, 20.2%) was the least. All caregivers had sought remedy from multiple health care options. Challenges were significantly (P < 0.05) associated with the female caregiver, age < 40 years, generalized type of epilepsy and residing outside Kaduna. The study identified multi dimensional caregiver challenges and highlighted the need for provision of comprehensive health and social services to children with epilepsy and their families.


MUSIC, selective pulses, and tuned delays: amino acid type-selective (1)H-(15)N correlations, II.
Amino acid type-selective experiments help to remove ambiguities in either manual or automated assignment procedures. Here we present modified triple-resonance experiments that yield amino acid type-selective (1)H-(15)N correlations. They are based on the MUSIC coherence transfer scheme which replaces the initial INEPT transfer and is selective for XH(2) or XH(3) (where X is either (15)N or (13)C). Signals of the desired amino acid types are thus selected based on the topology of the side chain. MUSIC is combined with selective pulses and carefully tuned delays to create experiments for Ser (S-HSQC); Val, Ile, and Ala (VIA-HSQC); Leu and Ala (LA-HSQC); Asp, Asn, and Gly (DNG-HSQC), as well as Glu, Gln, and Gly (EQG-HSQC). The new experiments are recorded as two-dimensional spectra and their performance is demonstrated by their application to two protein domains of 83 and 115 residues.


Meta-assessment of bias in science.
Numerous biases are believed to affect the scientific literature, but their actual prevalence across disciplines is unknown. To gain a comprehensive picture of the potential imprint of bias in science, we probed for the most commonly postulated bias-related patterns and risk factors, in a large random sample of meta-analyses taken from all disciplines. The magnitude of these biases varied widely across fields and was overall relatively small. However, we consistently observed a significant risk of small, early, and highly cited studies to overestimate effects and of studies not published in peer-reviewed journals to underestimate them. We also found at least partial confirmation of previous evidence suggesting that US studies and early studies might report more extreme effects, although these effects were smaller and more heterogeneously distributed across meta-analyses and disciplines. Authors publishing at high rates and receiving many citations were, overall, not at greater risk of bias. However, effect sizes were likely to be overestimated by early-career researchers, those working in small or long-distance collaborations, and those responsible for scientific misconduct, supporting hypotheses that connect bias to situational factors, lack of mutual control, and individual integrity. Some of these patterns and risk factors might have modestly increased in intensity over time, particularly in the social sciences. Our findings suggest that, besides one being routinely cautious that published small, highly-cited, and earlier studies may yield inflated results, the feasibility and costs of interventions to attenuate biases in the literature might need to be discussed on a discipline-specific and topic-specific basis.


Effects of blood pressure and lipid lowering on cognition: Results from the HOPE-3 study.
To assess whether long-term treatment with candesartan/hydrochlorothiazide, rosuvastatin, or their combination can slow cognitive decline in older people at intermediate cardiovascular risk. The Heart Outcomes Prevention Evaluation-3 (HOPE-3) study was a double-blind, randomized, placebo-controlled clinical trial using a 2 × 2 factorial design. Participants without known cardiovascular disease or need for treatment were randomized to candesartan (16 mg) plus hydrochlorothiazide (12.5 mg) or placebo and to rosuvastatin (10 mg) or placebo. Participants who were ≥70 years of age completed the Digit Symbol Substitution Test (DSST), the modified Montreal Cognitive Assessment, and the Trail Making Test Part B at baseline and study end. Cognitive assessments were completed by 2,361 participants from 228 centers in 21 countries. Compared with placebo, candesartan/hydrochlorothiazide reduced systolic blood pressure by 6.0 mm Hg, and rosuvastatin reduced low-density lipoprotein cholesterol by 24.8 mg/dL. Participants were followed up for 5.7 years (median), and 1,626 completed both baseline and study-end assessments. Mean participant age was 74 years (SD ±3.5 years); 59% were women; 45% had hypertension; and 24% had ≥12 years of education. The mean difference in change in DSST scores was -0.91 (95% confidence interval [CI] -2.25 to 0.42) for candesartan/hydrochlorothiazide compared with placebo, -0.54 (95% CI -1.88 to 0.80) for rosuvastatin compared with placebo, and -1.43 (95% CI -3.37 to 0.50) for combination therapy vs double placebo. No significant differences were found for other measures. Long-term blood pressure lowering with candesartan plus hydrochlorothiazide, rosuvastatin, or their combination did not significantly affect cognitive decline in older people. NCT00468923. This study provides Class II evidence that for older people, candesartan plus hydrochlorothiazide, rosuvastatin, or their combination does not significantly affect cognitive decline.


Clinical implications of the organizational and activational effects of hormones.
Debate on the relative contributions of nature and nurture to an individual's gender patterns, sexual orientation and gender identity are reviewed as they appeared to this observer starting from the middle of the last century. Particular attention is given to the organization-activation theory in comparison to what might be called a theory of psychosexual neutrality at birth or rearing consistency theory. The organization-activation theory posits that the nervous system of a developing fetus responds to prenatal androgens so that, at a postnatal time, it will determine how sexual behavior is manifest. How organization-activation was or was not considered among different groups and under which circumstances it is considered is basically understood from the research and comments of different investigators and clinicians. The preponderance of evidence seems to indicate that the theory of organization-activation for the development of sexual behavior is certain for non-human mammals and almost certain for humans. This article also follows up on previous clinical critiques and recommendations and makes some new suggestions.


Performance improvement of FSO/CDMA systems over dispersive turbulence channel using multi-wavelength PPM signaling.
Previous studies show that, compared to on-off keying (OOK) signaling, pulse-position modulation (PPM) is favorable in FSO/CDMA systems thanks to its energy efficiency and simple detection. Nevertheless, when the system bit rate increases and the transmission distance is far, the FSO/CDMA systems using PPM signaling critically suffer from the impact of pulse broadening caused by dispersion, especially when the modulation level is high. In this paper, we therefore propose to use multi-wavelength PPM (MWPPM) signaling to overcome the limitation of PPM. To further improve the system performance, avalanche photodiode (APD) is also used. The performance of the proposed system is theoretically analyzed using a realistic model of Gaussian pulse propagation. To model the impact of intensity fluctuation caused by the atmospheric turbulence, the log-normal channel is used. We find that, by using MWPPM, the effects of both intensity fluctuation and pulse broadening are mitigated, the BER is therefore significantly improved. Additionally, we quantitatively show that the system performance is further improved by using APD, especially when the average APD gain is chosen properly.


Transition metal (Mn, Fe, Co, Ni)-doped graphene hybrids for electrocatalysis.
The development of electrocatalysts is crucial for renewable energy applications. Metal-doped graphene hybrid materials have been explored for this purpose, however, with much focus on noble metals, which are limited by their low availability and high costs. Transition metals may serve as promising alternatives. Here, transition metal-doped graphene hybrids were synthesized by a simple and scalable method. Metal-doped graphite oxide precursors were thermally exfoliated in either hydrogen or nitrogen atmosphere; by changing exfoliation atmospheres from inert to reductive, we produced materials with different degrees of oxidation. Effects of the presence of metal nanoparticles and exfoliation atmosphere on the morphology and electrocatalytic activity of the hybrid materials were investigated using electron microscopy, energy-dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, and cyclic voltammetry. Doping of graphene with transition metal nanoparticles of the 4th period significantly influenced the electrocatalysis of compounds important in energy production and storage applications, with hybrid materials exfoliated in nitrogen atmosphere displaying superior performance over those exfoliated in hydrogen atmosphere. Moreover, nickel-doped graphene hybrids displayed outstanding electrocatalytic activities towards reduction of O2 when compared to bare graphenes. These findings may be exploited in the research field of renewable energy.


A role for the deep orange and carnation eye color genes in lysosomal delivery in Drosophila.
Deep orange and carnation are two of the classic eye color genes in Drosophila. Here, we demonstrate that Deep orange is part of a protein complex that localizes to endosomal compartments. A second component of this complex is Carnation, a homolog of Sec1p-like regulators of membrane fusion. Because complete loss of deep orange function is lethal, the role of this complex in intracellular trafficking was analyzed in deep orange mutant clones. Retinal cells devoid of deep orange function completely lacked pigmentation and exhibited exaggerated multivesicular structures. Furthermore, a defect in endocytic trafficking was visualized in developing photoreceptor cells. These results provide direct evidence that eye color mutations of the granule group also disrupt vesicular trafficking to lysosomes.


Angina pectoris and physiological coronarographic findings.
Angina pectoris may be associated with normaln coronary arteries. Normal coronary arteries status is defined as absence of visible disease or the irregularity of lumen (less than 50%) as assessed visually on the interventional cardiologists. In our retrospective study among 1130 patients we have identified 181 patients with normal angiographic findings with various risk factors, as male sex, body mass index (BMI), lipid disorders, smoking, hypertension, diabetes mellitus type 2. The analysis results suggest that 56.3% patients of 181 verified normal coronary findings involve female patients with high BMI, unregulated hypertension and lipid disorders. In order to find real causes of chest pain, patients with normal coronary status need careful examination and treatment. The reduction of risk factors and adequate medications are important preconditions for the good quality of life in these patients.


MON 87411 line, a Maize Tolerant to Glyphosate and Resistant to Coleoptera (Genetically Modified Foods and Feeds).
The Food Safety Commission of Japan (FSCJ) conducted a safety assessment of MON 87411 line, a maize tolerant to glyphosate and resistant to Coleoptera, based on the documents submitted by the applicant. The documents, evaluated based on the "Standards for the Safety Assessment of Genetically Modified Foods (Seed plants)" (Decision of the Commission dated 29 January 2004), included the safety of the inserted genes, toxicity and allergenicity of the protein produced from the inserted genes, post-insertion analyses of the nucleotide sequences, stability of the inserted genes in the successive generations, influence on metabolic pathways in the plants, comparative characterization of nutrients and toxic ingredients in plants. Consequently, no emergences of safety concerns were recognized based on the comparison between this line and the conventional counterpart. The dsRNA originated from DvSnf7 fragment is unlikely to pose unintended adverse effect to human. In conclusion, no concern relevant to human health is raised on the maize MON 87411 line, tolerant to glyphosate and resistant to Coleoptera.


Analysis of the Doxorubicin and Doxorubicinol in the Plasma of Breast Cancer Patients for Monitoring the Toxicity of Doxorubicin.
Doxorubicin is an anthracycline antibiotic used as an anticancer agent. Long-term use of this anticancer agent could accumulate its metabolite, doxorubicinol, and cause cardiomyopathy, due to its cardiotoxicity. This cardiotoxic effect depends on the amount of doxorubicin and doxorubicinol accumulated in the body. This study aimed to analyze doxorubicin and doxorubicinol levels in the blood plasma of breast cancer patients. Participants of this study were 30 breast cancer patients who had received doxorubicin in their therapy regimen. The samples were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the Acquity UPLC BEH C18 Waters chromatography column (2.1 x 100 mm : 1.7 μm). Plasma (250 μL) samples were prepared by protein precipitation, using methanol. The mobile phase consisted of 0.1% acetic acid (eluent A) and acetonitrile (eluent B), with gradient elution; the flow rate was 0.15 mL/min and runtime, 7 min. This method was linear in the range of 1-1000 ng/mL for doxorubicin and 0.5-500 ng/mL for doxorubicinol. This method was successfully used to analyze doxorubicin and doxorubicinol, simultaneously, using hexamethylphosphoramide as the internal standard, in the plasma of breast cancer patients. Results showed that the measured concentrations of doxorubicin and doxorubicinol ranged between 12.54-620.01 ng/mL and 1.10-27.00 ng/mL, respectively. The measured cumulative doses of doxorubicin ranged between 48.76 and 319.01 mg/m2; thus, the risk of cardiomyopathy in the surveyed patients was under 4%, according to literature.


The effect of tau genotype on clinical features in FTDP-17.
The clinical phenotype of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) varies. This variability is seen not only between kindreds with different mutations but also in families sharing the same mutation. Inheritance of tau haplotype (H1) and genotype (H1/H1) has been established as a risk factor for some neurodegenerative disorders with parkinsonism. We assessed the effect of tau polymorphism on the clinical features of FTDP-17 in 61 cases from 30 separately ascertained families with four different tau mutations, including P301L, +16, N279K, and P301S. There were no significant differences of age at symptomatic onset and disease duration between H1/H1 and H1/H2 genotypes. The comparison between tau genotype and type of initial clinical sign showed an association between the H1/H1 genotype and parkinsonian phenotype and between the H1/H2 genotype and frontotemporal dementia phenotype (OR=11.7; 95% confidence interval, 1.4-98.7; P=0.008). Our results suggest that tau genotype does not influence the disease course. However, it may predispose to a specific clinical sign in the early stage of FTDP-17.


Specular, diffuse, and polarized light scattered by two wheat canopies.
Using polarization measurements, the reflectance factor R(theta(i),phi(i),theta(r),phi(r)) of two wheat canopies is divided into components due to specularly and diffusely reflected light. The data show that two key angles may be predicted, the angle of the polarizer for minimum flux and the angle of incidence of sunlight specularly reflected by a leaf to a sensor. The results show that specular reflection is a key aspect to radiation transfer by two canopies. Results suggest that the advent of heading in wheat may be remotely sensed from polarization measurements of the canopy reflectance.


Combining M-FISH and Quantum Dot technology for fast chromosomal assignment of transgenic insertions.
Physical mapping of transgenic insertions by Fluorescence in situ Hybridization (FISH) is a reliable and cost-effective technique. Chromosomal assignment is commonly achieved either by concurrent G-banding or by a multi-color FISH approach consisting of iteratively co-hybridizing the transgenic sequence of interest with one or more chromosome-specific probes at a time, until the location of the transgenic insertion is identified. Here we report a technical development for fast chromosomal assignment of transgenic insertions at the single cell level in mouse and rat models. This comprises a simplified 'single denaturation mixed hybridization' procedure that combines multi-color karyotyping by Multiplex FISH (M-FISH), for simultaneous and unambiguous identification of all chromosomes at once, and the use of a Quantum Dot (QD) conjugate for the transgene detection. Although the exploitation of the unique optical properties of QD nanocrystals, such as photo-stability and brightness, to improve FISH performance generally has been previously investigated, to our knowledge this is the first report of a purpose-designed molecular cytogenetic protocol in which the combined use of QDs and standard organic fluorophores is specifically tailored to assist gene transfer technology.


Spousal depression, anxiety, and suicide after myocardial infarction.
Death of a spouse from acute myocardial infarction (AMI) presents hardship, yet few studies have investigated the psychological consequences of fatal and non-fatal AMI on spouses. Several Danish national registries were linked to identify individuals whose spouses had a fatal or non-fatal AMI. Married patients with fatal or non-fatal AMI (1997-2008) were matched with their counterparts dying or hospitalized with a non-AMI cause; incident use of antidepressants and benzodiazepines, incident depression care, and suicides were compared pre- and post-event using Poisson models. Overall, 16 506 spouses of individuals dying of AMI were matched with 49 518 spouses of individuals dying of a non-AMI cause. Similarly, 44 566 spouses of individuals with a non-fatal AMI were matched with 131 563 spouses of individuals with a non-fatal, non-AMI hospitalization. Those whose spouse died of AMI (compared with a non-AMI cause) had increased antidepressant and benzodiazepine use [peak incidence rate ratio (IRR) 5.7 vs. 3.3, and 46.4 vs. 13.0, respectively; P< 0.001]. Those whose spouse had a non-fatal AMI (compared with a non-AMI hospitalization) had increased risk for antidepressant and benzodiazepine initiation (IRR 1.5 vs. 1.1, and 6.7 vs. 1.3, respectively, P< 0.001). Spouses of fatal AMI patients also had an increased risk of depression and suicide. Male individuals whose spouse had a fatal or non-fatal AMI had a relatively higher increased risk of depression than female individuals. Spouses of those who experience AMIs-both fatal and non-fatal-are at elevated risk for psychological consequences; therefore, the care needs of AMI patients and their spouses need to be considered.


Use of tobacco products among rural older adults: prevalence of ever use and cumulative lifetime use.
Tobacco use is a well-documented contributor to morbidity and mortality in the US and worldwide. Information on the comprehensive use of tobacco products is lacking, particularly smokeless tobacco in its various forms. Data from 635 older (>/=60 years) African American, American Indian and White adults in rural North Carolina were analyzed to assess current and lifetime use of cigarettes, cigars, pipe, snuff and chewing tobacco. Participants were classified as being current, former or never users of each product. Lifetime use of each product was determined by asking about typical intensity of use per day and length of time the product has been used. About 70% of participants were current or former users of any tobacco product, and about one-third of participants currently used at least one product. Variations in use were observed by ethnicity and sex, particularly for cigarettes, snuff and chewing tobacco. Variations were also seen according to other demographic and health characteristics. These data add to a limited body of literature on lifetime use of smoked and smokeless tobacco products, and are useful in identifying the impact of these products on morbidity and mortality, particularly for vulnerable populations.


Real-time calibration of laser absorption spectrometer using spectral correlation performed with an in-line gas cell.
A real-time drift correction and calibration method using spectral correlation based on a revolving in-line gas cell for laser-based spectroscopic trace-gas measurements has been developed and evaluated experimentally. This technique is relatively simple to implement in laser spectroscopy systems and assures long-term stability of trace-gas measurements by minimizing the effects of external sources of drift in real-time. Spectroscopic sensitivity sufficient for environmental monitoring and effective drift suppression has been achieved for long-term measurements of CO₂ with a quantum cascade laser based spectrometer.


New strategies for disc repair: novel preclinical trials.
Degeneration of lumbar intervertebral discs is a major cause of low back complaints, an irreversible occurrence with no currently available treatment. Furthermore, various surgical procedures can accelerate disc degeneration. On the other hand, recent experimental studies on disc cells have demonstrated an important role for the nucleus pulposus in preserving overall disc structure. The author's group has already found that nucleus pulposus cells activated annulus fibrous cells, and reinsertion of nucleus pulposus cells slowed further disc degeneration. We have designed three subsequent studies that were designed to examine further possibilities for clinical transplantation: (1) activation of nucleus pulposus cells by mesenchymal stem cells; (2) focus on the multilineage differentiation potential of mesenchymal stem cells as an alternative cell source for cell transplantation therapy of disc degeneration; (3) the possibility of a human nucleus pulposus cell line as a cell source for cell transplantation therapy. Activation of nucleus pulposus could be achieved by co-culture with autogenous mesenchymal stem cells allowed to have direct cellular interaction. This would be a useful clinical cell source. Induction of nucleus pulposus cells by autogenous mesenchymal stem cells also would be an important subject for a clinical trial. Clinical application of the cells derived from a human nucleus pulposus cell line is an important project to be undertaken in the near future.


Association of obstructive sleep apnea and glucose metabolism in subjects with or without obesity.
The purpose of this study was to investigate whether the impact of obstructive sleep apnea (OSA) on glucose metabolism was different according to the presence or absence of obesity. A total of 1,344 subjects >40 years old from the Korean Genome and Epidemiology Study were included. OSA was detected by home portable sleep monitoring. Plasma glucose, HbA1c, and insulin resistance were compared according to OSA and obesity status. The associations between OSA and impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG + IGT, and diabetes were evaluated in subjects with and without obesity after adjusting for several confounding variables. The effect of visceral obesity on this association was evaluated in 820 subjects who underwent abdominal computed tomography scanning. In subjects without obesity, fasting glucose, 2-h glucose after 75-g glucose loading, and HbA1c were higher in those with OSA than in those without after controlling for age, sex, and BMI. In addition, the presence of OSA in nonobese subjects was associated with a higher prevalence of IFG + IGT and diabetes after adjusting for several confounding variables (odds ratio 3.15 [95% CI 1.44-6.90] and 2.24 [1.43-3.50] for IFG + IGT and diabetes, respectively). Further adjustment for visceral fat area did not modify this association. In contrast, in those with obesity, none of the abnormal glucose tolerance categories were associated with OSA. The presence of OSA in nonobese individuals is significantly associated with impaired glucose metabolism, which can be responsible for future risk for diabetes and cardiovascular disease.


Microwave-enhanced Friedländer synthesis for the rapid assembly of halogenated quinolines with antibacterial and biofilm eradication activities against drug resistant and tolerant bacteria.
Herein, we disclose the development of a catalyst- and protecting-group-free microwave-enhanced Friedländer synthesis which permits the single-step, convergent assembly of diverse 8-hydroxyquinolines with greatly improved reaction yields over traditional oil bath heating (increased from 34% to 72%). This rapid synthesis permitted the discovery of novel biofilm-eradicating halogenated quinolines (MBECs = 1.0-23.5 μM) active against MRSA, MRSE, and VRE. These small molecules exhibit activity through mechanisms independent of membrane lysis, further demonstrating their potential as a clinically useful treatment option against persistent biofilm-associated infections.


The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients.
Desmoid tumor (DT; other synonymously used terms: Desmoid-type fibromatosis, aggressive fibromatosis) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterised by a variable and often unpredictable clinical course. Previously surgery was the standard primary treatment modality; however, in recent years a paradigm shift towards a more conservative management has been introduced and an effort to harmonise the strategy amongst clinicians has been made. We present herein an evidence-based, joint global consensus guideline approach to the management of this disease focussing on: molecular genetics, indications for an active treatment, and available systemic therapeutic options. This paper follows a one-day consensus meeting held in Milan, Italy, in June 2018 under the auspices of the European Reference Network for rare solid adult cancers, EURACAN, the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) as well as Sarcoma Patients EuroNet (SPAEN) and The Desmoid tumour Research Foundation (DTRF). The meeting brought together over 50 adult and pediatric sarcoma experts from different disciplines, patients and patient advocates from Europe, North America and Japan.


Oral contraceptive use and risk of breast cancer among women with a family history of breast cancer: a prospective cohort study.
Family history of breast cancer is an established risk factor for breast cancer. In addition, there is evidence that oral contraceptive use may be associated with a moderate increase in breast cancer risk. The three cohort studies that have investigated the relationship between oral contraceptive use and breast cancer risk among women with a family history of breast cancer have yielded mixed results, possibly due to the relatively small sample sizes employed and/or differences in the selection of covariates for inclusion in multivariate models. Therefore, we examined the association between oral contraceptive use and breast cancer risk in a large cohort study in Canada. The cohort consisted of the 27,318 women in the Canadian National Breast Screening Study who reported a family history of breast cancer on enrollment into the study. Linkages to national mortality and cancer databases yielded data on deaths and cancer incidence, with follow-up ending between 1998 and 2000, depending upon the province. During a mean of 16.0 years of follow-up, we observed 1707 incident cases of breast cancer among women with any history of breast cancer of which 795 cases occurred among women with a mother, sister, and/or daughter with breast cancer. Among women with any family history of breast cancer, ever use of oral contraceptives was associated with a 12% reduction in risk of breast cancer (95% confidence interval [CI]=0.73-1.07), and there was an inverse trend with increasing duration of use of borderline statistical significance (p(trend)=0.03). Although we also observed a 25% lower risk of breast cancer associated with oral contraceptive use of greater than 84 months versus never use among women with a first degree relative with breast cancer, this finding was not statistically significant (95% CI=0.47-1.19, p(trend)=0.48). Our data raise the possibility that relatively long duration of oral contraceptive use may be inversely associated with risk among women with a family history of breast cancer.


Electron tunneling in proteins: coupling through a beta strand.
Electron coupling through a beta strand has been investigated by measurement of the intramolecular electron-transfer (ET) rates in ruthenium-modified derivatives of the beta barrel blue copper protein Pseudomonas aeruginosa azurin. Surface histidines, introduced on the methionine-121 beta strand by mutagenesis, were modified with a Ru(2,2'-bipyridine)2(imidazole)2+ complex. The Cu+ to Ru3+ rate constants yielded a distance-decay constant of 1.1 per angstrom, a value close to the distance-decay constant of 1.0 per angstrom predicted for electron tunneling through an idealized beta strand. Activationless ET rate constants in combination with a tunneling-pathway analysis of the structures of azurin and cytochrome c confirm that there is a generally efficient network for coupling the internal (native) redox center to the surface of both proteins.


Drosophila quail, a villin-related protein, bundles actin filaments in apoptotic nurse cells.
Drosophila Quail protein is required for the completion of fast cytoplasm transport from nurse cells to the oocyte, an event critical for the production of viable oocytes. The abundant network of cytoplasmic filamentous actin, established at the onset of fast transport, is absent in quail mutant egg chambers. Previously, we showed that Quail is a germline-specific protein with sequence homology to villin, a vertebrate actin-regulating protein. In this study, we combined biochemical experiments with observations in egg chambers to define more precisely the function of this protein in the regulation of actin-bundle assembly in nurse cells. We report that recombinant Quail can bind and bundle filamentous actin in vitro in a manner similar to villin at a physiological calcium concentration. In contrast to villin, Quail is unable to sever or cap filamentous actin, or to promote nucleation of new actin filaments at a high calcium concentration. Instead, Quail bundles the filaments regardless of the calcium concentration. In vivo, the assembly of nurse-cell actin bundles is accompanied by extensive perforation of the nurse-cell nuclear envelopes, and both of these phenomena are manifestations of nurse-cell apoptosis. To investigate whether free calcium levels are affected during apoptosis, we loaded egg chambers with the calcium indicator Indo-1. Our observations indicate a rise in free calcium in the nurse-cell cytoplasm coincident with the permeabilization of the nuclear envelopes. We also show that human villin expressed in the Drosophila germline could sense elevated cytoplasmic calcium; in nurse cells with reduced levels of Quail protein, villin interfered with actin-bundle stability. We conclude that Quail efficiently assembles actin filaments into bundles in nurse cells and maintains their stability under fluctuating free calcium levels. We also propose a developmental model for the fast phase of cytoplasm transport incorporating findings presented in this study.


Chromosome studies in wild populations of D. melanogaster.
Chromosome studies of wild D. melanogaster populations from Missouri, Mississippi, Louisiana and Texas uncovered 58 inversions. Six were common and cosmopolitan; 52 were new, rare and generally endemic. In one of two Missouri populations tested, structurally heterozygous females carried significantly more sperm at capture than did the homozygotes. In both populations comparisons of wild sperms with the females carrying them indicated significant positive assortative mating and an excess production of homozygotes among the F1 progeny. Wild females structurally heterozygous in up to three major autosomal arms showed no associated nondisjunctional egg lethality; those heterozygous in all four arms produced from 0% to 24% dead eggs, suggesting the presence of intrapopulational gene modifiers of meiosis. Texas populations supported on windfall citrus fruit showed a slight but significant difference in inversion frequencies between flies breeding on oranges and those breeding on grapefruit. Within these populations inversions were not distributed at random among individuals; rather there was an observed excess of individuals carrying intermediate numbers, and a deficiency of those carrying very few or very many inversions. While there was no significant linkage disequilibrium associated with this central tendency, there was a significant interchromosomal interaction: flies carrying inversions in chromosome 2 tended not to carry them in chromosome 3, and vice versa.


Between the Local and the Global: Evaluating European regulation of stem cell regenerative medicine.
Current European regulations hinder the compilation of the evidence that would be required to bring safe and effective autologous stem cell-based interventions (SCBIs) into standard clinical care. European agencies have expanded their regulations to cover all new SCBIs and research. They establish demanding conditions for cell retrieval, processing, and application. Drawing on empirical sociological findings from the implementation of the first phase III stem cell clinical trial in Europe, this article examines ethical problems effected by that policy, such as that the costs of bringing treatments to market means new autologous SCBIs may remain untested and that this plays in favor of the growing direct-to-consumer market, and that the research pathways in regenerative medicine and the role of clinician-scientists in developing new treatments are restricted, because the regulations are biased to enable specific SCBIs that are of interest to industry. This situation contradicts the moral and social concerns in favor of new treatments and patient interests, which the regulations supposedly safeguard. To align the aims and effects of policy better, European regulatory authorities should reconfigure their regulations to advance a fair and effective governance regime that allows pursuit of all promising SCBIs.


Conventional chemotherapy for acute myeloid leukemia: a Brazilian experience.
Young patients affected by acute myeloid leukemia (AML) achieve complete remission (CR) using conventional chemotherapy in about 55-85%. However, 30% of patients fail to achieve CR and the remission duration is often only about 12 months. More intensive treatment after CR seems to be necessary in order to maintain CR and obtain a definitive cure. In Brazil, few reports have been published on this important subject. The aim of this study was to describe a Brazilian experience in the treatment of "de novo" acute myeloid leukemia (AML) in younger adult patients (age < 60 years). Retrospective analysis. University Hospital, Hematology and Hemotherapy Center, State University of Campinas, Brazil. Newly diagnosed cases of "de novo" AML in the period from January 1994 to December 1998 were evaluated retrospectively, in relation to response to treatment, overall survival (OS) and disease free survival (DFS). Cases with acute promyelocytic leukemia (APL) were also included in this analysis. On the basis of an intention to treat, 78 cases of AML, including 17 cases of APL, were evaluated. The overall median follow-up was 272 days. The complete remission (CR) rate was 63.6% in the AML group (excluding APL) and 78% in the APL group. The 5-year estimated disease-free survival (DFS) was 80% for the APL group and 34% for the AML group (P = 0.02). The 5-year estimated overall survival (OS) was 52% for the APL group and 20.5% for the AML group, respectively (P = NS). Relapse was observed in 12/39 (30.7%) patients with AML and 1/11 (9%) with APL. These results are similar to those reported in the literature. However, relapse and mortality rates remain high, and a search for more aggressive strategies in order to prevent relapse is recommended.


Identification by proteomics of oviductal sperm-interacting proteins.
The interactions between oviductal fluid (OF) proteins and spermatozoa play major roles in sperm selection, storage and capacitation before fertilization. However, only a few sperm-interacting proteins in the OF has been identified and very little is known about the regulation of sperm-oviduct interactions across the estrous cycle. Samples of bovine frozen-thawed sperm from three bulls were incubated with OF at pre-, post-ovulatory stages (Pre-/Post-ov) or luteal phase (LP) of the estrous cycle (7 mg/mL proteins, treated groups) or with a protein-free media (control). The proteomes of sperm cells were assessed by nanoLC-MS/MS and quantified by label-free methods. A total of 27 sperm-interacting proteins originating in the OF were identified. Among those, 14 were detected at all stages, eight at Post-ov and LP and five only at LP. The sperm-interacting proteins detected at all stages or at LP and Post-ov were on average more abundant at LP than at other stages (P < 0.05). At Pre-ov, OVGP1 was the most abundant sperm-interacting protein while at Post-ov, ACTB, HSP27, MYH9, MYH14 and OVGP1 were predominant. Different patterns of abundance of sperm-interacting proteins related to the stage were evidenced, which greatly differed from those previously reported in the bovine OF. In conclusion, this study highlights the important regulations of sperm-oviduct interactions across the estrous cycle and provides new protein candidates that may modulate sperm functions.


Chromosome aberrations in lymphocytes of high-voltage laboratory cable splicers exposed to electromagnetic fields.
Thirteen high-voltage laboratory employees and 20 referents participated in a cross-sectional, matched-pairs study of cytogenetic damage. During cable testing the workers were exposed to static, alternating, or pulsed electric and magnetic fields. The alternating magnetic field levels of 50 Hz were 5-10 microT, occasionally much higher. Chromosome aberrations, sister chromatid exchanges, and aneuploidy were studied in peripheral blood lymphocytes. In addition, chromosome aberrations were investigated in lymphocyte cultures treated with hydroxyurea and caffeine, to inhibit deoxyribonucleic acid synthesis and repair. Among seven smoking laboratory employees the mean number of chromosome breaks/200 cells was 2.3, as compared with 0.7 for the job-matched referents. The comparable figures for inhibited cultures were 12.0 versus 6.0. No increase was detected in nonsmokers with either method. The other genetic parameters showed no differences between the exposed workers and the referents. The results support, to some extent, the hypothesis of an increased risk of genotoxic effects among high-voltage laboratory workers.


Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer's disease and vascular cognitive impairment.
An intact blood-brain barrier (BBB) limits entry of proinflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer's disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive, and no interventions are available for treatment or prevention. We and others recently established that inhibition of the mammalian/mechanistic target of rapamycin (mTOR) pathway with rapamycin yields significant neuroprotective effects, improving cerebrovascular and cognitive function in mouse models of AD. To test whether mTOR inhibition protects the BBB in neurological diseases of aging, we treated hAPP(J20) mice modeling AD and low-density lipoprotein receptor-null (LDLR-/-) mice modeling vascular cognitive impairment with rapamycin. We found that inhibition of mTOR abrogates BBB breakdown in hAPP(J20) and LDLR-/- mice. Experiments using an in vitro BBB model indicated that mTOR attenuation preserves BBB integrity through upregulation of specific tight junction proteins and downregulation of matrix metalloproteinase-9 activity. Together, our data establish mTOR activity as a critical mediator of BBB breakdown in AD and, potentially, vascular cognitive impairment and suggest that rapamycin and/or rapalogs could be used for the restoration of BBB integrity. NEW & NOTEWORTHY This report establishes mammalian/mechanistic target of rapamycin as a critical mediator of blood-brain barrier breakdown in models of Alzheimer's disease and vascular cognitive impairment and suggests that drugs targeting the target of rapamycin pathway could be used for the restoration of blood-brain barrier integrity in disease states.


Form and function of early neolithic bifacial stone tools reflects changes in land use practices during the neolithization process in the levant.
For many, climate change is no longer recognized as the primary cause of cultural changes in the Near East. Instead, human landscape degradation, population growth, socioeconomic adjustments, and conflict have been proposed as the mechanisms that shaped the Neolithic Revolution. However, as Bar-Yosef noted, even if there is chronological correlation between climate changes and cultural developments, what is important is to understand how Neolithic societies dealt with these improving or deteriorating environments. Changes in bifacial stone tools provide a framework for examining some of these interactions by focusing on changing land use practices during the Neolithization process. The results of microwear analysis of 40 bifacial artifacts from early Pre-Pottery Neolithic (EPPNB) levels at Motza in the Judean hills document changes during the PPNA-PPNB transition at the onset of the Levantine Moist Period (ca. 8000 cal B.C.) when conditions for agriculture improved. EPPNB villagers added heavy-duty axes to a toolkit they had used for carpentry and began to clear forests for fields and grazing lands. Sustainable forest management continued for the duration of the PPN until the cumulative effects of tree-felling and overgrazing seem to have led to landscape degradation at end of the Pre-Pottery Neolithic C (PPNC), when a cold, dry climatic anomaly (6600-6000 cal B.C.) may have accelerated the reduction of woodlands. Early PPNB components at sites like Motza, with data from nearly five millennia of Neolithic occupations, show how complex hunter-gatherers and early food producers were able to establish sustainable resource management systems even as climate changed, population increased, and social relations were redefined.


RNA sequencing dataset describing transcriptional changes in cervical dorsal root ganglia after bilateral pyramidotomy and forelimb intramuscular gene therapy with an adeno-associated viral vector encoding human neurotrophin-3.
Unilateral or bilateral corticospinal tract injury in the medullary pyramids in adult rats causes anatomical and physiological changes in proprioceptive neurons projecting to the cervical spinal cord accompanied by hyperreflexia and abnormal behavioural movements including spasms. In a previous publication, we showed that "Intramuscular Neurotrophin-3 normalizes low threshold spinal reflexes, reduces spasms and improves mobility after bilateral corticospinal tract injury in rats" (Kathe et al., 2016) [1]. We hypothesize that neurotrophin-3 induces these changes by modifying gene expression in affected cervical dorsal root ganglia (DRG). Therefore in this data article, we analyzed the transcriptomes of cervical DRGs obtained during that previous study from naïve rats and from rats after bilateral pyramidotomy (bPYX) with unilateral intramuscular injections of either AAV1-CMV-NT3 or AAV1-CMV-EGFP applied 24 h after injury (Kathe et al., 2016) [1]. A bioinformatic analysis enabled us to identify genes that are likely to be expressed in TrkC+ neurons after injury and which were regulated by neurotrophin-3 in the direction expected from other datasets involving knockout or overexpression of neurotrophin-3. This dataset will help us and others identify genes in sensory neurons whose expression levels are regulated by neurotrophin-3 treatment. This may help identify novel therapeutic targets to improve sensation and movement after neurological injury. Data has been deposited in the Gene Expression Omnibus (GSE82197), http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=avgpicgcjhknzyv&acc=GSE82197.


Establishing and sustaining research partnerships in Africa: a case study of the UK-Africa Academic Partnership on Chronic Disease.
This paper examines the challenges and opportunities in establishing and sustaining north-south research partnerships in Africa through a case study of the UK-Africa Academic Partnership on Chronic Disease. Established in 2006 with seed funding from the British Academy, the partnership aimed to bring together multidisciplinary chronic disease researchers based in the UK and Africa to collaborate on research, inform policymaking, train and support postgraduates and create a platform for research dissemination. We review the partnership's achievements and challenges, applying established criteria for developing successful partnerships. During the funded period we achieved major success in creating a platform for research dissemination through international meetings and publications. Other goals, such as engaging in collaborative research and training postgraduates, were not as successfully realised. Enabling factors included trust and respect between core working group members, a shared commitment to achieving partnership goals, and the collective ability to develop creative strategies to overcome funding challenges. Barriers included limited funding, administrative support, and framework for monitoring and evaluating some goals. Chronic disease research partnerships in low-income regions operate within health research, practice, funding and policy environments that prioritise infectious diseases and other pressing public health and developmental challenges. Their long-term sustainability will therefore depend on integrated funding systems that provide a crucial capacity building bridge. Beyond the specific challenges of chronic disease research, we identify social capital, measurable goals, administrative support, creativity and innovation and funding as five key ingredients that are essential for sustaining research partnerships.


Cancer cells differentially activate and thrive on de novo lipid synthesis pathways in a low-lipid environment.
Increased lipogenesis is a hallmark of a wide variety of cancers and is under intense investigation as potential antineoplastic target. Although brisk lipogenesis is observed in the presence of exogenous lipids, evidence is mounting that these lipids may adversely affect the efficacy of inhibitors of lipogenic pathways. Therefore, to fully exploit the therapeutic potential of lipid synthesis inhibitors, a better understanding of the interrelationship between de novo lipid synthesis and exogenous lipids and their respective role in cancer cell proliferation and therapeutic response to lipogenesis inhibitors is of critical importance. Here, we show that the proliferation of various cancer cell lines (PC3M, HepG2, HOP62 and T24) is attenuated when cultured in lipid-reduced conditions in a cell line-dependent manner, with PC3M being the least affected. Interestingly, all cell lines--lipogenic (PC3M, HepG2, HOP62) as well as non-lipogenic (T24)--raised their lipogenic activity in these conditions, albeit to a different degree. Cells that attained the highest lipogenic activity under these conditions were best able to cope with lipid reduction in term of proliferative capacity. Supplementation of the medium with very low density lipoproteins, free fatty acids and cholesterol reversed this activation, indicating that the mere lack of lipids is sufficient to activate de novo lipogenesis in cancer cells. Consequently, cancer cells grown in lipid-reduced conditions became more dependent on de novo lipid synthesis pathways and were more sensitive to inhibitors of lipogenic pathways, like Soraphen A and Simvastatin. Collectively, these data indicate that limitation of access to exogenous lipids, as may occur in intact tumors, activates de novo lipogenesis is cancer cells, helps them to thrive under these conditions and makes them more vulnerable to lipogenesis inhibitors. These observations have important implications for the design of new antineoplastic strategies targeting the cancer cell's lipid metabolism.


Genes for selenium dependent and independent formate dehydrogenase in the gut microbial communities of three lower, wood-feeding termites and a wood-feeding roach.
The bacterial Wood-Ljungdahl pathway for CO(2)-reductive acetogenesis is important for the nutritional mutualism occurring between wood-feeding insects and their hindgut microbiota. A key step in this pathway is the reduction of CO(2) to formate, catalysed by the enzyme formate dehydrogenase (FDH). Putative selenocysteine- (Sec) and cysteine- (Cys) containing paralogues of hydrogenase-linked FDH (FDH(H)) have been identified in the termite gut acetogenic spirochete, Treponema primitia, but knowledge of their relevance in the termite gut environment remains limited. In this study, we designed degenerate PCR primers for FDH(H) genes (fdhF) and assessed fdhF diversity in insect gut bacterial isolates and the gut microbial communities of termites and cockroaches. The insects examined herein represent three wood-feeding termite families, Termopsidae, Kalotermitidae and Rhinotermitidae (phylogenetically 'lower' termite taxa); the wood-feeding roach family Cryptocercidae (the sister taxon to termites); and the omnivorous roach family Blattidae. Sec and Cys FDH(H) variants were identified in every wood-feeding insect but not the omnivorous roach. Of 68 novel alleles obtained from inventories, 66 affiliated phylogenetically with enzymes from T. primitia. These formed two subclades (37 and 29 phylotypes) almost completely comprised of Sec-containing and Cys-containing enzymes respectively. A gut cDNA inventory showed transcription of both variants in the termite Zootermopsis nevadensis (family Termopsidae). The gene patterns suggest that FDH(H) enzymes are important for the CO(2)-reductive metabolism of uncultured acetogenic treponemes and imply that the availability of selenium, a trace element, shaped microbial gene content in the last common ancestor of dictyopteran, wood-feeding insects, and continues to shape it to this day.


Persistent vegetative state and dementia in the elderly.
Very few studies have approached the issue of persistent vegetative state (PVS) within the elderly population. This study aims to assess the prevalence, determinants and prognosis of elderly patients with PVS admitted to a long-term geriatric facility. We conducted a cohort study in the setting of a Skilled Geriatric Nursing Department. All patients admitted during a 17-month period (N = 88) were included and tested for a diagnosis of PVS according to the Disability Rating Scale (DRS). A clinical diagnosis of PVS was given to 15% of patients upon admission, whereas the DRS diagnosed 30.5% of patients as having PVS. During the study period, 12 out of 31 patients with PVS died, with a median survival of 127 days (range: 1-517 days). Our study suggests that PVS is an advanced stage in the natural history of dementia in the elderly. The low proportion of patients with PVS recognized as having this disorder upon admission suggests a low awareness among hospital personnel. Further studies of the prevalence and determinants of PVS in the severely disabled elderly population are warranted.


Chronic cough as a neuropathic disorder.
Chronic cough is a common symptom that can be a daunting challenge for clinicians since treatment of the underlying cause does not always provide adequate relief, an obvious cause can remain elusive, and current antitussives have fairly poor efficacy and undesirable side-effects. Patients with chronic cough typically describe a range of sensory symptoms suggestive of upper-airway and laryngeal neural dysfunction. Additionally, patients often report cough triggered by low-level physical and chemical stimuli, which is suggestive of cough-reflex hyperresponsiveness. Pathophysiological mechanisms underlying peripheral and central augmentation of the afferent cough pathways have been identified, and compelling evidence exists for a neuropathy of vagal sensory nerves after upper-respiratory viral infections or exposure to allergic and non-allergic irritants. In this Personal View, we argue that chronic cough is a neuropathic disorder that arises from neural damage caused by a range of inflammatory, infective, and allergic factors. In support of this idea, we discuss evidence of successful treatment of chronic cough with agents used for treatment of neuropathic pain, such as gabapentin and amitriptyline. Regarding cough as a neuropathic disorder could lead to new, more effective antitussives.


Endogenous monocyte chemoattractant protein-1 (MCP-1) protects mice in a model of acute septic peritonitis: cross-talk between MCP-1 and leukotriene B4.
We investigated the involvement of monocyte chemoattractant protein (MCP)-1 in a murine model of septic peritonitis induced by cecal ligation and puncture (CLP). Initial studies demonstrated that CLP induced a dramatic increase in MCP-1 production in the peritoneum, followed by an increase in the recruitment of leukocytes. MCP-1 blockade with anti-MCP-1 antiserum significantly decreased the survival rate following CLP, which was accompanied by an enhanced recovery of viable bacteria from the peritoneum. This was likely due to the reduction in the recruitment and activation of both macrophages and neutrophils. To understand the mechanisms whereby MCP-1 may influence neutrophil infiltration, levels of chemokines known to attract neutrophils were monitored, which showed that peritoneal levels of macrophage-inflammatory protein (MIP)-2, KC, and MIP-1alpha were not altered with anti-MCP-1 Abs. However, anti-MCP-1 Abs reduced the peritoneal levels of leukotriene B4 (LTB4) by 59%. The i.p. injection of MCP-1 into normal mice resulted in elevated levels of LTB4 in the peritoneum. In vitro, MCP-1 stimulated the production of LTB4 from peritoneal macrophages, in a dose-dependent manner. A specific LTB4 receptor antagonist (CP-105, 696) inhibited CLP-induced recruitment of both neutrophils and macrophages, which was accompanied by a reduced level of MCP-1 in the peritoneum. Finally, administration of CP-105,696 was extremely detrimental to the survival of mice following CLP. These experiments demonstrate that endogenous MCP-1 serves as an indirect mediator to attract neutrophils via the production of LTB4, and suggest the cross-talk can occur between MCP-1 and the lipid mediator LTB4 during septic peritonitis.


Canine length in wild male baboons: maturation, aging and social dominance rank.
Canines represent an essential component of the dentition for any heterodont mammal. In primates, like many other mammals, canines are frequently used as weapons. Hence, tooth size and wear may have significant implications for fighting ability, and consequently for social dominance rank, reproductive success, and fitness. We evaluated sources of variance in canine growth and length in a well-studied wild primate population because of the potential importance of canines for male reproductive success in many primates. Specifically, we measured maxillary canine length in 80 wild male baboons (aged 5.04-20.45 years) from the Amboseli ecosystem in southern Kenya, and examined its relationship with maturation, age, and social dominance rank. In our analysis of maturation, we compared food-enhanced baboons (those that fed part time at a refuse pit associated with a tourist lodge) with wild-feeding males, and found that food-enhanced males achieved long canines earlier than wild-feeding males. Among adult males, canine length decreased with age because of tooth wear. We found some evidence that, after controlling for age, longer canines were associated with higher adult dominance rank (accounting for 9% of the variance in rank), but only among relatively high-ranking males. This result supports the idea that social rank, and thus reproductive success and fitness, may depend in part on fighting ability mediated by canine size.


Racial/ethnic differences in hypertension and hypertension treatment and control in the multi-ethnic study of atherosclerosis (MESA).
Most previous studies investigating the association between ethnicity and hypertension focused on differences between African Americans and whites and did not include other racial/ethnic groups such as Chinese or Hispanics. We used data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of 6814 adults without clinical cardiovascular disease, to examine the association between ethnicity and hypertension and hypertension treatment among white, African American, Chinese, and Hispanic ethnic groups. The prevalence of hypertension, defined as systolic blood pressure (BP) <140 mm Hg and diastolic BP <90 mm Hg or self-reported treatment for hypertension, was significantly higher in African Americans compared to whites (60% v 38%; P < .0001), whereas prevalence in Hispanic (42%) and Chinese participants (39%) did not differ significantly from that in whites. After adjustment for age, body mass index, prevalence of diabetes mellitus, and smoking, African American (odds ratio [OR] 2.21; 95% confidence interval [95% CI] 1.91-2.56) and Chinese (OR 1.30; 95% CI 1.07-1.56) ethnicity were significantly associated with hypertension compared to whites. Among hypertensive MESA participants, the percentage of treated but uncontrolled hypertension in whites (24%) was significantly lower than in African Americans (35%, P < .0001), Chinese (33%, P = .003), and Hispanics (32%, P = .0005), but only African-American race/ethnicity remained significantly associated with treated but uncontrolled hypertension after controlling for socioeconomic factors (OR 1.35; 95% CI 1.07-1.71). Diuretic use was lowest in the Chinese (22%) and Hispanic participants (32%) and was significantly lower in these groups compared with white participants (47%; P < .0001 for both comparisons). Programs to improve hypertension treatment and control should focus on a better understanding of differences in the prevalence of hypertension and hypertension control among minority groups in the United States, especially African Americans, compared with whites, and on techniques to prevent hypertension and improve control in high-risk groups.


Use of maropitant for the control of pruritus in non-flea, non-food-induced feline hypersensitivity dermatitis: an open-label, uncontrolled pilot study.
Non-flea, non-food-induced hypersensitivity dermatitis (NFNFIHD) is a common inflammatory and pruritic skin disease in cats. When avoidance and conventional systemic immunosuppressive treatments fail to control the clinical signs, there are limited treatment options. The aim of this study was to evaluate the efficacy and tolerability of maropitant in feline NFNFIHD. In an open-label, uncontrolled study, cats with proven non-seasonal NFNFIHD were treated with maropitant 2 mg/kg PO q24h for 4 weeks. Clinical lesions were evaluated with the Scoring Feline Allergic Dermatitis (SCORFAD) system and pruritus was evaluated with a 10 cm visual analogue scale (VAS) before and at the end of the study. Owners assessed global efficacy and tolerability with a 4-point scale at the end of the study. Adverse events and body weight changes were recorded. Twelve cats were treated with a mean initial maropitant dose of 2.22 mg/kg PO q24h. The treatment decreased both SCORFAD and pruritus VAS (pVAS) scores in all cats except one, in which only pruritus was reduced. The efficacy and the tolerability of the treatment were judged as excellent or good by 83.3% of owners. Treatment did not cause any side effects other than, in a few cases, short-time, self-limiting sialorrhoea. Maropitant seems to be an effective, well-tolerated therapeutic option to control pruritus in cats. Caution is needed in interpreting the results as the pVAS score system has not yet been validated in cats and the trial was uncontrolled. A further, controlled study is required to confirm our findings.


Subjective thirst moderates changes in speed of responding associated with water consumption.
Participants (N = 34) undertook a CANTAB battery on two separate occasions after fasting and abstaining from fluid intake since the previous evening. On one occasion they were offered 500 ml water shortly before testing, and on the other occasion no water was consumed prior to testing. Reaction times, as measured by Simple Reaction Time (SRT), were faster on the occasion on which they consumed water. Furthermore, subjective thirst was found to moderate the effect of water consumption on speed of responding. Response latencies in the SRT task were greater under the "no water" condition than under the "water" condition, but only for those participants with relatively high subjective thirst after abstaining from fluid intake overnight. For those participants with relatively low subjective thirst, latencies were unaffected by water consumption, and were similarly fast as those recorded for thirsty participants who had consumed water. These results reveal the novel finding that subjective thirst moderates the positive effect of fluid consumption on speed of responding. The results also showed evidence that practice also affected task performance. These results imply that, for speed of responding at least, the positive effects of water supplementation may result from an attenuation of the central processing resources consumed by the subjective sensation of thirst that otherwise impair the execution of speeded cognitive processes.


Virtual Consultations Through the Veterans Administration SCAN-ECHO Project Improves Survival for Veterans With Liver Disease.
Access to specialty care has been associated with improved survival in patients with liver disease but universal access is not always feasible. Methods of care delivery using virtual modalities including the SCAN-ECHO (Specialty Access Network-Extension of Community Healthcare Outcome) program were implemented by the Veterans Health Administration (VHA) to address this need but limited data are available on patient outcomes. We sought to evaluate the efficacy of a SCAN-ECHO visit within the context of a regional cohort of patients with liver disease in the VHA (n = 62,237) following implementation in the Ann Arbor SCAN-ECHO Liver Clinic from June 1, 2011, to March 31, 2015. The effect of a SCAN-ECHO visit on all-cause mortality was compared with patients with no liver clinic visit. To adjust for the differences among patients who had a SCAN-ECHO visit versus those with no visit, propensity score matching was performed on condition factors that affect the likelihood of a SCAN-ECHO visit: demographics, geographic location, liver disease diagnosis, severity, and comorbidities. During the study period, 513 patients who had a liver SCAN-ECHO visit were found within the cohort. Patients who had completed a virtual SCAN-ECHO visit were more likely younger, rural, with more significant liver disease, and evidence for cirrhosis. Propensity-adjusted mortality rates using the Cox Proportional Hazard Model showed that a SCAN-ECHO visit was associated with a hazard ratio of 0.54 (95% confidence interval 0.36-0.81, P = 0.003) compared with no visit. Conclusion: Improved survival in patients using SCAN-ECHO suggests that this approach may be an effective method to improve access for selected patients with liver disease, particularly in rural and underserved populations where access to specialty care is limited.


Induced Alkalosis and Gastrointestinal Symptoms After Sodium Citrate Ingestion: a Dose-Response Investigation.
Sodium citrate induces alkalosis and can provide a performance benefit in high-intensity exercise. Previous investigations have been inconsistent in the ingestion protocols used, in particular the dose and timing of ingestion before the onset of exercise. The primary aim of the current study was to quantify blood pH, blood bicarbonate concentration and gastrointestinal symptoms after ingestion of three doses of sodium citrate (500 mg⋅kg-1, 700 mg⋅kg-1 and 900 mg⋅kg-1). Thirteen participants completed four experimental sessions, each consisting of a different dose of sodium citrate or a taste-matched placebo solution. Blood pH and blood bicarbonate concentration were measured at 30-min intervals via analysis of capillary blood samples. Gastrointestinal symptoms were also monitored at 30-min intervals. Statistical significance was accepted at a level of p < .05. Both measures of alkalosis were significantly greater after ingestion of sodium citrate compared with placebo (p < .001). No significant differences in alkalosis were found between the three sodium citrate doses (p > .05). Peak alkalosis following sodium citrate ingestion ranged from 180 to 212 min after ingestion. Gastrointestinal symptoms were significantly higher after sodium citrate ingestion compared with placebo (p < .001), while the 900 mg.kg-1 dose elicited significantly greater gastrointestinal distress than 500 mg⋅kg-1 (p = .004). It is recommended that a dose of 500 mg⋅kg-1 of sodium citrate should be ingested at least 3 hr before exercise, to achieve peak alkalosis and to minimize gastrointestinal symptoms before and during exercise.


Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes.
Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS). The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias. The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations. A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca(2+) affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell-derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca(2+)-dependent inactivation of voltage-gated Ca(2+) current. Neither mutant affected voltage-dependent inactivation. Our findings implicate impaired Ca(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.