Transoral thyroidectomy: advantages and limitations.
In this opinion paper of the Journal of Endocrinological Investigation, leading experts in the field report on their current clinical experience with a novel approach for thyroid gland surgery, namely, "transoral thyroidectomy" (TOT). This feasible and novel surgical procedure does not require visible incisions and is, therefore, a truly scarless surgery. Patients meeting the following criteria can be considered as candidates for TOT: (a) an ultrasonographically (US) estimated thyroid diameter ≤10 cm; (b) US-estimated gland volume ≤45 mL; (c) nodule size ≤50 mm; (d) presence of a benign tumor such as a thyroid cyst or a single- or multi-nodular goiter; (e) Bethesda 3 and/or 4 category and (f) papillary microcarcinoma without the evidence of metastasis. The procedure is conducted via a three-port technique at the oral vestibule using a 10-mm port for the 30° endoscope and two additional 5-mm ports for the dissecting and coagulating instruments. TOT is performed using conventional endoscopic instruments and is probably the best scarless approach to the thyroid because of the short distance between the thyroid and the incisions placed intra-orally that do not result in any cutaneous scar and upon following the surgical planes. Experts in TOT organized a working group of general, endocrine, head and neck ENT surgeons and endocrinologist to develop the standards for practicing this emerging technique.


Multiphoton Intrapulse Interference 8. Coherent control through scattering tissue.
We demonstrate experimentally that selective two-photon probe excitation using phase shaped pulses can be achieved even when the laser propagates through scattering tissue. The pre-optimized phase tailored femtosecond pulses were able to identify acidic and basic solutions of a pH sensitive chromophore hidden behind a slab of scattering tissue. This observation has important implications for future applications of coherent control for biomedical imaging and photodynamic therapy.


Disentangling cardiovascular control mechanisms during head-down tilt via joint transfer entropy and self-entropy decompositions.
A full decomposition of the predictive entropy (PE) of the spontaneous variations of the heart period (HP) given systolic arterial pressure (SAP) and respiration (R) is proposed. The PE of HP is decomposed into the joint transfer entropy (JTE) from SAP and R to HP and self-entropy (SE) of HP. The SE is the sum of three terms quantifying the synergistic/redundant contributions of HP and SAP, when taken individually and jointly, to SE and one term conditioned on HP and SAP denoted as the conditional SE (CSE) of HP given SAP and R. The JTE from SAP and R to HP is the sum of two terms attributable to SAP or R plus an extra term describing the redundant/synergistic contribution to the JTE. All quantities were computed during cardiopulmonary loading induced by -25° head-down tilt (HDT) via a multivariate linear regression approach. We found that: (i) the PE of HP decreases during HDT; (ii) the decrease of PE is attributable to a lessening of SE of HP, while the JTE from SAP and R to HP remains constant; (iii) the SE of HP is dominant over the JTE from SAP and R to HP and the CSE of HP given SAP and R is prevailing over the SE of HP due to SAP and R both in supine position and during HDT; (iv) all terms of the decompositions of JTE from SAP and R to HP and SE of HP due to SAP and R were not affected by HDT; (v) the decrease of the SE of HP during HDT was attributed to the reduction of the CSE of HP given SAP and R; (vi) redundancy of SAP and R is prevailing over synergy in the information transferred into HP both in supine position and during HDT, while in the HP information storage synergy and redundancy are more balanced. The approach suggests that the larger complexity of the cardiac control during HDT is unrelated to the baroreflex control and cardiopulmonary reflexes and may be related to central commands and/or modifications of the dynamical properties of the sinus node.


Protein supplementation lowers blood pressure in overweight adults: effect of dietary proteins on blood pressure (PROPRES), a randomized trial.
Dietary protein intake may help to manage blood pressure (BP) and prevent complications associated with elevated BP. The objective of this study was to determine whether 4 wk of increased protein intake (∼25% compared with ∼15% of energy intake that isoenergetically replaces carbohydrate intake) lowers office and daytime BP compared with increased carbohydrate intake. A randomized, double-blind, parallel study compared consumption of 3 × 20 g protein/d (20% pea, 20% soy, 30% egg, and 30% milk-protein isolate) with 3 × 20 g maltodextrin/d. Protein or maltodextrin were isoenergetically substituted for a sugar-sweetened drink. Primary outcomes were office and daytime BP. A total of 99 men and women [age range: 20-70 y; BMI (in kg/m²): 25-35] with untreated elevated BP (BP ≥130/85 and <160/100 mm Hg) were randomly assigned. Ninety-four completers (51 subjects in the maltodextrin group, 43 subjects in the protein group) were included in the analyses. Office systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 4.9 ± 1.7 mm Hg (P = 0.005) and 2.7 ± 1.3 mm Hg (P = 0.05) lower, respectively, in the protein group. Daytime SBP was 4.6 ± 1.7 mm Hg lower in the protein group (P = 0.006), whereas daytime DBP did not differ between groups (P = 0.37). Urinary sodium excretion was higher in the maltodextrin group (P = 0.004). Increased protein intake, at the expense of maltodextrin, lowers BP in overweight adults with upper-range prehypertension and grade 1 hypertension. This trial was registered at www.trialregister.nl as NTR 1362.


Modeling the impact of COVID-19 nonpharmaceutical interventions on respiratory syncytial virus transmission in South Africa.
The South African government employed various nonpharmaceutical interventions (NPIs) to reduce the spread of SARS-CoV-2. Surveillance data from South Africa indicates reduced circulation of respiratory syncytial virus (RSV) throughout the 2020-2021 seasons. Here, we use a mechanistic transmission model to project the rebound of RSV in the two subsequent seasons. We fit an age-structured epidemiological model to hospitalization data from national RSV surveillance in South Africa, allowing for time-varying reduction in RSV transmission during periods of COVID-19 circulation. We apply the model to project the rebound of RSV in the 2022 and 2023 seasons. We projected an early and intense outbreak of RSV in April 2022, with an age shift to older infants (6-23 months old) experiencing a larger portion of severe disease burden than typical. In March 2022, government alerts were issued to prepare the hospital system for this potentially intense outbreak. We then assess the 2022 predictions and project the 2023 season. Model predictions for 2023 indicate that RSV activity has not fully returned to normal, with a projected early and moderately intense wave. We estimate that NPIs reduced RSV transmission between 15% and 50% during periods of COVID-19 circulation. A wide range of NPIs impacted the dynamics of the RSV outbreaks throughout 2020-2023 in regard to timing, magnitude, and age structure, with important implications in a low- and middle-income countries (LMICs) setting where RSV interventions remain limited. More efforts should focus on adapting RSV models to LMIC data to project the impact of upcoming medical interventions for this disease.


Urinary tract infections complicating pregnancy.
Urinary infections, with a spectrum from covert bacteriuria to severe pyelonephritis, commonly complicate pregnancy. Serious infections follow untreated silent bacteriuria in a fourth of cases, and routine screening can be justified in high-risk populations, particularly in those women from lower socioeconomic strata. Despite an initial salutary response to a number of antimicrobial regimens, covert bacteriuria recurs in one-third of treated women whose risk of pyelonephritis again is at 25%. Acute cystitis may be unrelated to these other infections and responds readily to a number of regimens; however, single-dose therapy is not recommended because early pyelonephritis can be mistaken for uncomplicated cystitis. Pyelonephritis is the most common severe bacterial infection complicating pregnancy. These women are frequently quite ill, and hospitalization is recommended. Since 85-90% respond within 72 h to intravenous fluids and antimicrobials, continued fever and evidence for sepsis should prompt a search for underlying obstruction. Perhaps 20% of women with severe pyelonephritis develop complications that include septic shock syndrome or its presumed variants. These latter include renal dysfunction, haemolysis and thrombocytopenia, and pulmonary capillary injury. In most of these women, continued fluid and antimicrobial therapy result in a salutary outcome, but there is occasional maternal morbidity.


Interventions for promoting physical activity in people with cystic fibrosis.
In individuals with cystic fibrosis there are no established targets for participation in physical activity, nor have any ideal strategies to promote participation in physical activity been identified To evaluate the effect of treatment to increase participation in physical activity in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register using the terms 'physiotherapy and exercise'.Date of the most recent search: 05 December 2013.Additionally, we conducted searches of the electronic databases MEDLINE, CINAHL (Ebscohost), PsycINFO (OvidSP) and the Physiotherapy Evidence Database (PEDro). We also searched for potentially relevant, completed but unpublished studies, on several clinical trials registers.Date of the most recent searches: 10 September 2012. All randomised and quasi-randomised controlled studies which investigated strategies designed to promote increased participation in daily physical activity for individuals with cystic fibrosis. Two authors independently selected studies for inclusion, assessed the risk of bias and extracted data. Any disagreements were resolved by discussion and consensus, or in arbitration with a third author. Four studies (199 participants) met the inclusion criteria and were predominantly conducted in children with cystic fibrosis. Only one study had a combined cohort of adult and paediatric participants. The description of study methods was inadequate to assess the risk of bias, particularly with regard to blinding of assessors and selective reporting. One study was conducted in an inpatient setting with follow up in the outpatient setting; while the remaining three studies were conducted in individuals with stable respiratory disease in the outpatient setting. All included studies used exercise training to promote participation in physical activity, with the duration of the intervention period ranging from 18 days to three years. No improvement in physical activity participation was reported with any intervention period less than or equal to six months. Improvements in physical activity participation were only seen where follow up occurred beyond 12 months. There was no significant impact on quality of life from any of the intervention strategies. Although participation in physical activity is generally regarded as beneficial for people with cystic fibrosis, there is a lack of evidence regarding strategies to promote the uptake and the continued participation in physical activity for this population. This review provides very limited evidence that activity counselling and exercise advice, undertaken over at least six months, to engage in a home exercise programme may result in improved physical activity participation in people with cystic fibrosis. Further research is needed to determine the effect of strategies such as health coaching or telemedicine applications, in promoting the uptake and adherence to regular participation in physical activity. In addition, establishing the ideal duration of any interventions that promote physical activity, including exercise training programmes, will be important in addressing issues relating to participation in physical activity for people with cystic fibrosis.


Finding pathways to national-scale land-sector sustainability.
The 17 Sustainable Development Goals (SDGs) and 169 targets under Agenda 2030 of the United Nations map a coherent global sustainability ambition at a level of detail general enough to garner consensus amongst nations. However, achieving the global agenda will depend heavily on successful national-scale implementation, which requires the development of effective science-driven targets tailored to specific national contexts and supported by strong national governance. Here we assess the feasibility of achieving multiple SDG targets at the national scale for the Australian land-sector. We scaled targets to three levels of ambition and two timeframes, then quantitatively explored the option space for target achievement under 648 plausible future environmental, socio-economic, technological and policy pathways using the Land-Use Trade-Offs (LUTO) integrated land systems model. We show that target achievement is very sensitive to global efforts to abate emissions, domestic land-use policy, productivity growth rate, and land-use change adoption behaviour and capacity constraints. Weaker target-setting ambition resulted in higher achievement but poorer sustainability outcomes. Accelerating land-use dynamics after 2030 changed the targets achieved by 2050, warranting a longer-term view and greater flexibility in sustainability implementation. Simultaneous achievement of multiple targets is rare owing to the complexity of sustainability target implementation and the pervasive trade-offs in resource-constrained land systems. Given that hard choices are needed, the land-sector must first address the essential food/fibre production, biodiversity and land degradation components of sustainability via specific policy pathways. It may also contribute to emissions abatement, water and energy targets by capitalizing on co-benefits. However, achieving targets relevant to the land-sector will also require substantial contributions from other sectors such as clean energy, food systems and water resource management. Nations require globally coordinated, national-scale, comprehensive, integrated, multi-sectoral analyses to support national target-setting that prioritizes efficient and effective sustainability interventions across societies, economies and environments.


Fatty acid transport protein-2 regulates glycemic control and diabetic kidney disease progression.
Kidney disease is one of the most devastating complications of diabetes, and tubular atrophy predicts diabetic kidney disease (DKD) progression to end-stage renal disease. We have proposed that fatty acids bound to albumin contribute to tubular atrophy by inducing lipotoxicity, after filtration across damaged glomeruli, and subsequent proximal tubule reabsorption by a fatty acid transport protein-2-dependent (FATP2-dependent) mechanism. To address this possibility, genetic (Leprdb/db eNOS-/-) and induced (high-fat diet plus low-dose streptozotocin) mouse models of obesity and DKD were bred with global FATP2 gene-deleted mice (Slc27a2) and then phenotyped. DKD-prone mice with the Slc27a2-/- genotype demonstrated normalization of glomerular filtration rate, reduced albuminuria, improved kidney histopathology, and longer life span compared with diabetic Slc27a2+/+ mice. Genetic and induced DKD-prone Slc27a2-/- mice also exhibited markedly reduced fasting plasma glucose, with mean values approaching euglycemia, despite increased obesity and decreased physical activity. Glucose lowering in DKD-prone Slc27a2-/- mice was accompanied by β cell hyperplasia and sustained insulin secretion. Together, our data indicate that FATP2 regulates DKD pathogenesis by a combined lipotoxicity and glucotoxicity (glucolipotoxicity) mechanism.


Identification of a sequence in the unique 5' open reading frame of the gene encoding glycosylated Gag which influences the incubation period of neurodegenerative disease induced by a murine retrovirus.
Neonatal inoculation of the wild-mouse ecotropic retrovirus CasBrE (clone 15-1) causes a noninflammatory spongiform neurodegenerative disease with an incubation period of > or = 6 months. Introduction of sequences from Friend murine leukemia virus (clone FB29) into the genome of CasBrE results in a marked shortening of the incubation period. The FB29 sequences which influence the incubation period were previously localized to the 5' leader sequence of the viral genome (M. Czub, F. J. McAtee, and J. L. Portis, J. Virol. 66:3298-3305, 1992). In the current study, we constructed a series of chimeric viruses consisting of the genome of CasBrE containing various segments of the leader sequence from FB29. A 41-nucleotide element (positions 481 through 521) near the 3' end of the leader was found to have a strong influence on the incubation period. This element influenced the kinetics of virus replication and/or spread in nonneuronal tissues, a property which was shown previously to determine the extent of central nervous system infection (M. Czub, F. J. McAtee, and J. L. Portis, J. Virol. 66:3298-3305, 1992). Curiously, this sequence had no demonstrable effect on virus replication in vitro in a fibroblastic cell line from Mus dunni. This segment encodes 14 of the unique 88-amino-acid N terminus of pr75gag, the precursor of a glycosylated form of the gag polyprotein which is expressed at the cell surface. Previous in vitro studies of mutants of Moloney murine leukemia virus lacking expression of glycosylated Gag failed to reveal a function for this protein in virus replication. We mutated the Kozak consensus sequence around the initiation codon for this protein in the chimeric virus CasFrKP, a virus which induces neurologic disease with a short (18- to 23-day) incubation period. M. dunni cells infected with the mutants lacked detectable cell surface Gag, but, compared with CasFrKP, no effect on replication kinetics in vitro was observed. In contrast, there was a marked slowing of the replication kinetics in vivo and a dramatic attenuation of neurovirulence. These studies indicate that glycosylated Gag has an important function in virus replication and/or spread in the mouse and further suggest that the sequence of its N terminus is a critical, though likely indirect, determinant of neurovirulence.


Iodine Supplementation Decreases Hypercholesterolemia in Iodine-Deficient, Overweight Women: A Randomized Controlled Trial.
In iodine deficiency, thyrotropin (TSH) may increase to stimulate thyroidal iodine uptake. In iodine-sufficient populations, higher TSH predicts higher total cholesterol. Whether higher TSH caused by iodine deficiency affects serum lipids is uncertain. Our aim was to determine if iodine repletion decreases serum TSH and improves the lipid profile. In this randomized controlled intervention, iodine-deficient, overweight or obese Moroccan women (n = 163) received 200 μg oral iodine or a placebo daily for 6 mo. Main outcomes were serum TSH and plasma total and LDL cholesterol. Secondary outcomes included thyroid hormones and measures of lipid and glucose metabolism and urinary iodine concentration (UIC). Data were compared by using mixed-model analysis. In the intervention group, median UIC increased from 38 (95% CI: 34, 45) μg/L to 77 (95% CI: 59, 89) μg/L (P < 0.001). After 6 mo of intervention, TSH was 33% lower in the treatment group than in the placebo group (P = 0.024). The triiodothyronine (T3) to thyroxine (T4) ratio and thyroglobulin decreased with treatment [-15% (P = 0.002) and -32% (P < 0.001), respectively], whereas T4 concentrations were higher in the treatment group (P < 0.001). Total cholesterol in subjects with elevated baseline cholesterol (>5 mmol/L) was reduced by 11% after the intervention (P = 0.034). At 6 mo, only 21.5% of treated women remained hypercholesterolemic (total cholesterol >5 mmol/L) vs. 34.8% of controls (baseline: 44.2% in the intervention and 36.8% in the control group; P = 0.015). The reduction in the prevalence of elevated LDL cholesterol (>3 mmol/L) in the intervention group (50.6% to 35.4% compared with 47.4% to 44.9% in the control group) was not significant (P-interaction = 0.23). Our findings suggest that moderate to severe iodine deficiency in overweight women elevates serum TSH and produces a more atherogenic lipid profile and that iodine supplementation in this group reduces the prevalence of hypercholesterolemia. Thus, iodine prophylaxis may reduce cardiovascular disease risk in overweight adults. This trial was registered at clinicaltrials.gov as NCT01985204.


An in vivo drug screening model using glucose-6-phosphate dehydrogenase deficient mice to predict the hemolytic toxicity of 8-aminoquinolines.
Anti-malarial 8-aminoquinolines drugs cause acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDD). Efforts to develop non-hemolytic 8-aminoquinolines have been severely limited caused by the lack of a predictive in vivo animal model of hemolytic potential that would allow screening of candidate compounds. This report describes a G6PDD mouse model with a phenotype closely resembling the G6PDD phenotype found in the African A-type G6PDD human. These G6PDD mice, given different doses of primaquine, which used as a reference hemolytic drug, display a full array of hemolytic anemia parameters, consistently and reproducibly. The hemolytic and therapeutic indexes were generated for evaluation of hemotoxicity of drugs. This model demonstrated a complete hemolytic toxicity response to another known hemolytic antimalarial drug, pamaquine, but no response to non-hemolytic drugs, chloroquine and mefloquine. These results suggest that this model is suitable for evaluation of selected 8-AQ type candidate antimalarial drugs for their hemolytic potential.


Long-Term Efficacy of Insecticidal Wall Painting for Controlling Visceral Leishmaniasis Vectors in Bangladesh.
The success of the visceral leishmaniasis (VL) elimination program largely depends on cost-effective vector control measures. Our goal was to investigate the longevity of the efficacy of insecticidal wall painting (IWP), a new vector control tool, compared with a routine indoor residual spraying (IRS) program for reducing the VL vector density in Bangladesh. This study is the extension of our recent IWP study for VL vector management in Bangladesh, which was undertaken in seven highly VL endemic villages of the Mymensingh district with a 12-month follow-up. In this 24-months follow-up study, we collected sand flies additionally at 15, 18, 21, and 24 months since the interventions from the IWP and control (where the program did routine IRS) clusters to examine the longevity of the efficacy of IWP on sand fly density reduction and mortality. The difference-in-differences regression models were used to estimate the effect of IWP on sand fly reduction against Program IRS. The IWP showed excellent performance in reducing sand fly density and increasing sand fly mortality compared with Program IRS. The effect of IWP for controlling sand flies was statistically significant for up to at least 24 months. The mean female Phlebotomus argentipes density reduction ranged from -56% to -83%, and the P. argentipes sand fly mortality ranged from 81% to 99.5% during the 24-month follow-up period. Considering the duration of the efficacy of IWP for controlling VL vectors, Bangladesh National Kala-azar Elimination Program may consider IWP as the best alternative to IRS for the subsequent phases of the program.


Optimal pathways for the assembly of the Apaf-1·cytochrome c complex into apoptosome.
The formation of a heptameric apoptosome is a crucial event in the intrinsic cell death pathway. Considerable progress has been made towards unraveling the constituents and the structure of the apoptosome as well as the mechanism of apoptosome-mediated caspase-9 activation. However, a significant gap remains in the understanding of this process, i.e., how seven Apaf-1·cytochrome c complexes stepwisely assemble into an apoptosome. Here, we construct a biophysical model that incorporates current biochemical knowledge about the formation of apoptosome. We propose 11 elementary routes and enumerate all 2047 possible assembly pathways from the Apaf-1·cytochrome c complex to the heptameric apoptosome. By combining mathematical analysis and numerical simulation, we find that two elementary routes are the most favorable biochemical reaction routes and there are 52 optimal assembly pathways which are economical and relatively fast. Our study yields the first comprehensive analysis of apoptosome assembly and provides insights into complex assembly pathways.


Optimization of protein samples for NMR using thermal shift assays.
Maintaining a stable fold for recombinant proteins is challenging, especially when working with highly purified and concentrated samples at temperatures >20 °C. Therefore, it is worthwhile to screen for different buffer components that can stabilize protein samples. Thermal shift assays or ThermoFluor(®) provide a high-throughput screening method to assess the thermal stability of a sample under several conditions simultaneously. Here, we describe a thermal shift assay that is designed to optimize conditions for nuclear magnetic resonance studies, which typically require stable samples at high concentration and ambient (or higher) temperature. We demonstrate that for two challenging proteins, the multicomponent screen helped to identify ingredients that increased protein stability, leading to clear improvements in the quality of the spectra. Thermal shift assays provide an economic and time-efficient method to find optimal conditions for NMR structural studies.


Safety and long-term effects of renal denervation: Rationale and design of the Dutch registry.
Percutaneous renal denervation (RDN) has recently been introduced as a treatment for therapy-resistant hypertension. Also, it has been suggested that RDN may be beneficial for other conditions characterised by increased sympathetic nerve activity. There are still many uncertainties with regard to efficacy, safety, predictors for success and long-term effects. To answer these important questions, we initiated a Dutch RDN registry aiming to collect data from all RDN procedures performed in the Netherlands. The Dutch RDN registry is an ongoing investigator-initiated, prospective, multicentre cohort study. Twenty-six Dutch hospitals agreed to participate in this registry. All patients who undergo RDN, regardless of the clinical indication or device that is used, will be included. Data are currently being collected on eligibility and screening, treatment and follow-up. Procedures have been performed since August 2010. At present, data from 306 patients have been entered into the database. The main indication for RDN was hypertension (n = 302, 99%). Patients had a mean office blood pressure of 177/100 (±29/16) mmHg with a median use of three (range 0-8) blood pressure lowering drugs. Mean 24-hour blood pressure before RDN was 157/93 (±18/13) mmHg. RDN was performed with different devices, with the Simplicity™ catheter currently used most frequently. Here we report on the rationale and design of the Dutch RDN registry. Enrolment in this investigator-initiated study is ongoing. We present baseline characteristics of the first 306 participants.


Enhanced Kerr Nonlinearity and Nonlinear Figure of Merit in Silicon Nanowires Integrated with 2D Graphene Oxide Films.
Layered two-dimensional (2D) graphene oxide (GO) films are integrated with silicon-on-insulator (SOI) nanowire waveguides to experimentally demonstrate an enhanced Kerr nonlinearity, observed through self-phase modulation (SPM). The GO films are integrated with SOI nanowires using a large-area, transfer-free, layer-by-layer coating method that yields precise control of the film thickness. The film placement and coating length are controlled by opening windows in the silica cladding of the SOI nanowires. Owing to the strong mode overlap between the SOI nanowires and the highly nonlinear GO films, the Kerr nonlinearity of the hybrid waveguides is significantly enhanced. Detailed SPM measurements using picosecond optical pulses show significant spectral broadening enhancement for SOI nanowires coated with 2.2 mm long films of 1-3 layers of GO and 0.4 mm long films with 5-20 layers of GO. By fitting the experimental results with theory, the dependence of GO's Kerr nonlinearity on layer number and pulse energy is obtained, showing interesting physical insights and trends of the layered GO films from 2D monolayers to quasi bulk-like behavior. Finally, we show that by coating SOI nanowires with GO films, the effective nonlinear parameter of SOI nanowires is increased 16-fold, with the effective nonlinear figure of merit (FOM) increasing by about 20 times to FOM > 5. These results reveal the strong potential of using layered GO films to improve the Kerr nonlinear optical performance of silicon photonic devices.


A Facile Electrochemical Preparation of Reduced Graphene Oxide@Polydopamine Composite: A Novel Electrochemical Sensing Platform for Amperometric Detection of Chlorpromazine.
We report a novel and sensitive amperometric sensor for chlorpromazine (CPZ) based on reduced graphene oxide (RGO) and polydopamine (PDA) composite modified glassy carbon electrode. The RGO@PDA composite was prepared by electrochemical reduction of graphene oxide (GO) with PDA. The RGO@PDA composite modified electrode shows an excellent electro-oxidation behavior to CPZ when compared with other modified electrodes such as GO, RGO and GO@PDA. Amperometric i-t method was used for the determination of CPZ. Amperometry result shows that the RGO@PDA composite detects CPZ in a linear range from 0.03 to 967.6 μM. The sensor exhibits a low detection limit of 0.0018 μM with the analytical sensitivity of 3.63 ± 0.3 μAμM(-1 )cm(-2). The RGO@PDA composite shows its high selectivity towards CPZ in the presence of potentially interfering drugs such as metronidazole, phenobarbital, chlorpheniramine maleate, pyridoxine and riboflavin. In addition, the fabricated RGO@PDA modified electrode showed an appropriate recovery towards CPZ in the pharmaceutical tablets.


Five amphibian mortality events associated with ranavirus infection in south central Ontario, Canada.
Using field, molecular and histological methods, an epizootic, systemic disease causing death within wood frog Rana sylvatica tadpoles and leopard frog Rana pipiens metamorphs at 3 different locations within Southern Ontario, Canada, has been investigated. Our results demonstrated that the probable cause of this disease was a ranavirus. Affected amphibians were found to exhibit necrosis within the hematopoietic cells. Liver tissue samples were found positive for the virus by PCR amplification of the ranavirus (Family: Iridoviridae) major capsid protein (MCP). Positive samples were confirmed by sequence analysis. Clinically normal, laboratory-raised wood frog egg broods were also found to test weakly positive for ranavirus. The population effects of disease on these amphibian communities have not yet been conclusively associated with population declines, but warrant more focused consideration.


Proteomics: applications to the study of rheumatoid arthritis and osteoarthritis.
The study of both DNA and protein technologies has been marked by unprecedented achievement over the last decade. The completion of the Human Genome Project in 2003 is representative of a new era in genomics; likewise, proteomics research, which has revolutionized the way we study disease, offers the potential to unlock many of the pathophysiologic mechanisms underlying the clinical problems encountered by orthopaedic surgeons. These new fields are extending our approach to and investigation of the etiology and progression of musculoskeletal disorders, notably rheumatoid arthritis and osteoarthritis. Advances in proteomics technology may lead to the development of biomarkers for both rheumatoid arthritis and osteoarthritis. Such biomarkers would improve early detection of these diseases, measure response to treatment, and expand knowledge of disease pathogenesis.


Variability in rates of affective disorders in relatives of depressed and normal probands.
Familial studies of depressed probands vary in the absolute rates of affective disorders in relatives. In a study of 215 mild and severely depressed nonbipolar major depressives and normal probands and 1,331 adult first-degree relatives, attempts were made to account for the sources of variance. The results demonstrated familial aggregation, although degree of aggregation of absolute rates of affective disorders varied among relatives according to the definition of depression used for the relatives, the source of data, and the composition of the relative sample. Despite this variability, the magnitude of the difference in rates between relatives of the normal persons and of the depressed probands remained constant. The rates of affective disorders were always higher in the relatives of the depressed than in the relatives of the normal probands. The magnitude of the difference in rates of depression between the relatives of the depressed subjects and the relatives of the normal probands ranged approximately between twofold and fivefold.


A Comparison of Landraces vs. Modern Varieties of Lettuce in Organic Farming During the Winter in the Mediterranean Area: An Approach Considering the Viewpoints of Breeders, Consumers, and Farmers.
The interest of farmers in growing lettuce landraces is increasing, as landrace varieties prove particularly appealing to consumers striving to purchase natural, local, and high-quality produce. Although high genetic diversity exists in the landrace gene pool, this has scarcely been studied, thus hindering landrace utilization in agriculture. In this study, we analyzed the genetic diversity and the agronomic and quality traits of lettuce landraces in organic agrosystems, by characterizing 16 landraces and 16 modern varieties. We compared 29 morphological descriptors, and several traits relating to agronomic behavior (total and commercial weight, resistance to Bremia lactucae) and quality (color, chlorophyll, dry matter, and total sugars). Trials were conducted in two localities and managed following organic farming practices. Moreover, farmers and consumers participated in the phenotyping of accessions by scoring yield, resistance to B. lactucae, appearance, and taste acceptance. Results show that cultivar group, rather than the genetic origin (modern vs. landrace), is the major source of variation for all agronomic and quality traits. Batavia and Butterhead were highly homogeneous cultivar groups, while Cos accessions showed a much higher intra-varietal diversity. There was also a clear separation between modern and landrace varieties of Oak leaf. Fifteen out of the 16 evaluated landraces presented a high susceptibility to the particular B. lactucae race isolated from the experimental field - a new race not reported before. Breeding programs intended to introgress genetic resistance to this pathogen are a major priority to recover the cultivation of lettuce landraces. Principal component analysis (PCA), conducted on all quantitative data, showed a clear differentiation between modern varieties and landraces, mostly related to their commercial weight and susceptibility to B. lactucae. These seem the most important traits influencing farmer and consumer evaluations. Farmers showed a high capacity for characterizing the samples and agreed with consumers when scoring for the external appearance. It is proposed that farmers and consumers should be included in the phenotyping platforms in future research projects aiming for recovery of landraces.


Gambling and related mental disorders: a public health analysis.
This article reviews the prevalence of gambling and related mental disorders from a public health perspective. It traces the expansion of gambling in North America and the psychological, economic, and social consequences for the public's health, and then considers both the costs and benefits of gambling and the history of gambling prevalence research. A public health approach is applied to understanding the epidemiology of gambling-related problems. International prevalence rates are provided and the prevalence of mental disorders that often are comorbid with gambling problems is reviewed. Analysis includes an examination of groups vulnerable to gambling-related disorders and the methodological and conceptual matters that might influence epidemiological research and prevalence rates related to gambling. The major public health problems associated with gambling are considered and recommendations made for public health policy, practice, and research. The enduring value of a public health perspective is that it applies different 'lenses' for understanding gambling behaviour, analysing its benefits and costs, as well as identifying strategies for action. Harvey A. Skinner (160, p. 286)


Alcohol and adolescent suicide.
Adolescent suicide is a major public health problem. In this review, the authors discuss different aspects of the relation between alcohol abuse and suicidal behavior in adolescents, including epidemiology, role of family history, comorbidity, gender differences, neurobiology, treatment, and prevention. In the general population, about 2,000 adolescents in the United States die by suicide each year. Suicide continually ranks as the second or third leading cause of death of persons between the ages of 15 and 34 years old. The suicide rate in young people has more than doubled during the period from 1956 to 1993. This increasing suicide rate has been blamed on the increase of adolescent alcohol abuse. Availability of alcohol and guns at home may contribute to suicide risk in adolescents. Comorbid psychopathology, which is common among adolescent alcohol abusers, substantially increases risk for suicide completions and attempts. Depressed adolescents may use alcohol to self-medicate depressive symptoms. Alcohol abuse and suicidal behavior in adolescents and in adults has been found to have biochemical, genetic, and psychological correlates. Ideally, treatment of adolescents who receive a diagnosis of an alcohol use disorder and co-occurring suicidality should follow an integrated protocol that addresses both conditions. Future studies of psychological and neurobiological mechanisms of suicidality in adolescents with alcohol and/or substance abuse are merited.


Double-pass and interferometric measures of the optical quality of the eye.
We compare two methods for measuring the modulation transfer function (MTF) of the human eye: an interferometric method similar to that of Campbell and Green [J. Physiol. (London) 181, 576 (1965)] and a double-pass procedure similar to that of Santamaria et al. [J. Opt. Soc. Am. A 4, 1109 (1987)]. We implemented various improvements in both techniques to reduce error in the estimates of the MTF. We used the same observers, refractive state, pupil size (3 mm), and wavelength (632.8 nm) for both methods. In the double-pass method we found close agreement between the plane of subjective best focus for the observer and the plane of objective best focus, suggesting that much of the reflected light is confined within individual cones throughout its double pass through the receptor layer. The double-pass method produced MTF's that were similar to but slightly lower than those of the interferometric method. This additional loss in modulation transfer is probably attributable to light reflected from the choroid, because green light, which reduces the contribution of the choroid to the fundus reflection, produces somewhat higher MTF's that are consistent with the interferometric results. When either method is used, the MTF's lie well below those obtained with the aberroscope method [Vision Res. 28, 659 (1988)]. On the basis of the interferometric method, we propose a new estimate of the monochromatic MTF of the eye.


The follow-up of progressive hypertrophic cardiomyopathy using magnetic resonance rotating frame relaxation times.
Magnetic resonance rotating frame relaxation times are an alternative non-contrast agent choice for the diagnosis of chronic myocardial infarct. Fibrosis typically occurs in progressive hypertrophic cardiomyopathy. Fibrosis has been imaged in myocardial infarcted tissue using rotating frame relaxation times, which provides the possibility to follow up progressive cardiomyopathy without contrast agents. Mild and severe left ventricular hypertrophy were induced in mice by transverse aortic constriction, and the longitudinal rotating frame relaxation times (T1ρ ) and relaxation along the fictitious field (TRAFF2 , TRAFF3 ) were measured at 5, 10, 24, 62 and 89 days after transverse aortic constriction in vivo. Myocardial fibrosis was verified using Masson's trichrome staining. Increases in the relative relaxation time differences of T1ρ , together with TRAFF2 and TRAFF3 , between fibrotic and remote tissues over time were observed. Furthermore, TRAFF2 and TRAFF3 showed higher relaxation times overall in fibrotic tissue than T1ρ . Relaxation time differences were highly correlated with an excess of histologically verified fibrosis. We found that TRAFF2 and TRAFF3 are more sensitive than T1ρ to hypertrophic cardiomyopathy-related tissue changes and can serve as non-invasive diagnostic magnetic resonance imaging markers to follow up the mouse model of progressive hypertrophic cardiomyopathy.


Long-distance spin-transport across the Morin phase transition up to room temperature in ultra-low damping single crystals of the antiferromagnet α-Fe2O3.
Antiferromagnetic materials can host spin-waves with polarizations ranging from circular to linear depending on their magnetic anisotropies. Until now, only easy-axis anisotropy antiferromagnets with circularly polarized spin-waves were reported to carry spin-information over long distances of micrometers. In this article, we report long-distance spin-transport in the easy-plane canted antiferromagnetic phase of hematite and at room temperature, where the linearly polarized magnons are not intuitively expected to carry spin. We demonstrate that the spin-transport signal decreases continuously through the easy-axis to easy-plane Morin transition, and persists in the easy-plane phase through current induced pairs of linearly polarized magnons with dephasing lengths in the micrometer range. We explain the long transport distance as a result of the low magnetic damping, which we measure to be ≤ 10-5 as in the best ferromagnets. All of this together demonstrates that long-distance transport can be achieved across a range of anisotropies and temperatures, up to room temperature, highlighting the promising potential of this insulating antiferromagnet for magnon-based devices.


Modulatory effects of binocular disparity and aging upon the perception of speed.
Two experiments investigated modulatory effects of a surround upon the perceived speed of a moving central region. Both the surround's depth and velocity (relative to the center) were manipulated. The abilities of younger observers (mean age was 23.1 years) were evaluated in Experiment 1, while Experiment 2 was devoted to older participants (mean age was 71.3 years). The results of Experiment 1 revealed that changes in the perceived depth of a surround (in this case caused by changes in binocular disparity) significantly influence the perceived speed of a central target. In particular, the center's motion was perceived as fastest when the surround possessed uncrossed binocular disparity relative to the central target. This effect, that targets that are closer than their background are perceived to be faster, only occurred when the center and surround moved in the same directions (and did not occur when center and surround moved in opposite directions). The results of Experiment 2 showed that the perceived speeds of older adults are different: older observers generally perceive nearer targets as faster both when center and surround move in the same direction and when they move in opposite directions. In addition, the older observers' judgments of speed were less precise. These age-related changes in the perception of speed are broadly consistent with the results of recent neurophysiological investigations that find age-related changes in the functionality of cortical area MT.


Estimation of distribution algorithm for resource allocation in green cooperative cognitive radio sensor networks.
Due to the rapid increase in the usage and demand of wireless sensor networks (WSN), the limited frequency spectrum available for WSN applications will be extremely crowded in the near future. More sensor devices also mean more recharging/replacement of batteries, which will cause significant impact on the global carbon footprint. In this paper, we propose a relay-assisted cognitive radio sensor network (CRSN) that allocates communication resources in an environmentally friendly manner. We use shared band amplify and forward relaying for cooperative communication in the proposed CRSN. We present a multi-objective optimization architecture for resource allocation in a green cooperative cognitive radio sensor network (GC-CRSN). The proposed multi-objective framework jointly performs relay assignment and power allocation in GC-CRSN, while optimizing two conflicting objectives. The first objective is to maximize the total throughput, and the second objective is to minimize the total transmission power of CRSN. The proposed relay assignment and power allocation problem is a non-convex mixed-integer non-linear optimization problem (NC-MINLP), which is generally non-deterministic polynomial-time (NP)-hard. We introduce a hybrid heuristic algorithm for this problem. The hybrid heuristic includes an estimation-of-distribution algorithm (EDA) for performing power allocation and iterative greedy schemes for constraint satisfaction and relay assignment. We analyze the throughput and power consumption tradeoff in GC-CRSN. A detailed analysis of the performance of the proposed algorithm is presented with the simulation results.


The classification of mRNA expression levels by the phosphorylation state of RNAPII CTD based on a combined genome-wide approach.
Cellular function is regulated by the balance of stringently regulated amounts of mRNA. Previous reports revealed that RNA polymerase II (RNAPII), which transcribes mRNA, can be classified into the pausing state and the active transcription state according to the phosphorylation state of RPB1, the catalytic subunit of RNAPII. However, genome-wide association between mRNA expression level and the phosphorylation state of RNAPII is unclear. While the functional importance of pausing genes is clear, such as in mouse Embryonic Stem cells for differentiation, understanding this association is critical for distinguishing pausing genes from active transcribing genes in expression profiling data, such as microarrays and RNAseq. Therefore, we examined the correlation between the phosphorylation of RNAPII and mRNA expression levels using a combined analysis by ChIPseq and RNAseq. We first performed a precise quantitative measurement of mRNA by performing an optimized calculation in RNAseq. We then visualized the recruitment of various phosphorylated RNAPIIs, such as Ser2P and Ser5P. A combined analysis using optimized RNAseq and ChIPseq for phosphorylated RNAPII revealed that mRNA levels correlate with the various phosphorylation states of RNAPII. We demonstrated that the amount of mRNA is precisely reflected by the phased phosphorylation of Ser2 and Ser5. In particular, even the most "pausing" genes, for which only Ser5 is phosphorylated, were detectable at a certain level of mRNA. Our analysis indicated that the complexity of quantitative regulation of mRNA levels could be classified into three categories according to the phosphorylation state of RNAPII.


Glycine receptor antibodies are detected in progressive encephalomyelitis with rigidity and myoclonus (PERM) but not in saccadic oscillations.
Glycine receptor (GlyR) antibodies were recently identified in a few patients with progressive encephalomyelitis with rigidity and myoclonus (PERM); none of these patients had antibodies against glutamic acid decarboxylase (GAD). An inhibitory glycinergic transmission defect has also been implicated in the mechanism underlying saccadic oscillations, including ocular flutter or opsoclonus; GlyR antibodies have not been reported in these patients. The purpose was to determine whether GlyR antibodies are found in patients with PERM, ocular flutter syndrome (OFS), and opsoclonus-myoclonus syndrome (OMS). GlyR antibodies were first measured in archived sera and CSF from five patients, including one patient with GAD antibody-positive PERM, two patients with OFS, and two patients with OMS. GlyR antibodies were also measured in archived sera from nine other adult patients with OMS. GlyR antibodies and GAD antibodies were both found at high titers in the serum and CSF of the patient with PERM, and their levels paralleled disease activity over time. GlyR antibodies were not found at significant levels in 13 patients with saccadic oscillations. GlyR and GAD antibodies can co-exist in PERM and follow the clinical course. Although saccadic oscillations are a feature of this condition, GlyR antibodies are not commonly found in patients with isolated saccadic oscillations.


Herpes simplex virus triggers activation of calcium-signaling pathways.
The cellular pathways required for herpes simplex virus (HSV) invasion have not been defined. To test the hypothesis that HSV entry triggers activation of Ca2+-signaling pathways, the effects on intracellular calcium concentration ([Ca2+]i) after exposure of cells to HSV were examined. Exposure to virus results in a rapid and transient increase in [Ca2+]i. Pretreatment of cells with pharmacological agents that block release of inositol 1,4,5-triphosphate (IP3)-sensitive endoplasmic reticulum stores abrogates the response. Moreover, treatment of cells with these pharmacological agents inhibits HSV infection and prevents focal adhesion kinase (FAK) phosphorylation, which occurs within 5 min after viral infection. Viruses deleted in glycoprotein L or glycoprotein D, which bind but do not penetrate, fail to induce a [Ca2+]i response or trigger FAK phosphorylation. Together, these results support a model for HSV infection that requires activation of IP3-responsive Ca2+-signaling pathways and that is associated with FAK phosphorylation. Defining the pathway of viral invasion may lead to new targets for anti-viral therapy.


A systematic review of the risk factors for cervical artery dissection.
Cervical artery dissection (CAD) is a recognized cause of ischemic stroke among young and middle-aged individuals. The pathogenesis of dissections is unknown, although numerous constitutional and environmental risk factors have been postulated. To better understand the quality and nature of the research on the pathogenesis of CAD, we performed a systematic review of its risk factors. PubMed [MEDLINE (1966 to February 22, 2005)] and Embase (1980 to February 22, 2005) were searched to identify studies fulfilling the inclusion criteria. Two reviewers independently assessed methodological quality of the primary studies. Relevant data were extracted, including the risk factor(s) investigated, characteristics of the study population, and strength of the association(s). Thirty-one case-control studies were included for analysis. Selection bias, lack of control for confounding, and inadequate method of data analysis were the most common identified methodological shortcomings. Strong associations were reported from individual studies for the following risk factors: aortic root diameter >34 mm (odds ratio [OR=14.2; 95% confidence interval [CI], 3.2 to 63.6), migraine (ORadj, 3.6; 95% CI, 1.5 to 8.6), relative diameter change (>11.8%) during the cardiac cycle of the common carotid artery (ORadj, 10.0; 95% CI, 1.8 to 54.2), and trivial trauma (in the form of manipulative therapy of the neck) (ORadj, 3.8; 95% CI, 1.3 to 11). A weak association was found for homocysteine (2 studies: ORcrude, unknown; 95% CI, 1.05 to 1.52; ORcrude, 1.3; 95% CI, 1.0 to 1.7), and recent infection (ORadj, 1.60; 95% CI, 0.67 to 3.80). Two studies had conflicting findings for low levels of alpha1-antitrypsin, with the methodologically stronger study suggesting no association with CAD. CAD is a multi-factorial disease. Many of the reviewed studies contained 2 or more major sources of bias commonly found in case-control studies. Only one study (of homocysteine) used healthy controls, a robust sample size, and had a low risk of biased results. The relationship between atherosclerosis and CAD has been insufficiently examined.


Fruit vinegars attenuate cardiac injury via anti-inflammatory and anti-adiposity actions in high-fat diet-induced obese rats.
Fruit vinegars (FVs) are used in Mediterranean folk medicine for their hypolipidemic and weight-reducing properties. To investigate the preventive effects of three types of FV, commonly available in Algeria, namely prickly pear [Opuntia ficus-indica (L.) Mill (Cectaceae)], pomegranate [Punica granatum L. (Punicaceae)], and apple [Malus domestica Borkh. (Rosaceae)], against obesity-induced cardiomyopathy and its underlying mechanisms. Seventy-two male Wistar rats were equally divided into 12 groups. The first group served as normal control (distilled water, 7 mL/kg bw), and the remaining groups were respectively treated with distilled water (7 mL/kg bw), acetic acid (0.5% w/v, 7 mL/kg bw) and vinegars of pomegranate, apple or prickly pear (at doses of 3.5, 7 and 14 mL/kg bw, acetic acid content as mentioned above) along with a high-fat diet (HFD). The effects of the oral administration of FV for 18 weeks on the body and visceral adipose tissue (VAT) weights, plasma inflammatory and cardiac enzymes biomarkers, and in heart tissue were evaluated. Vinegars treatments significantly (p < .05) attenuated the HFD-induced increase in bw (0.2-0.5-fold) and VAT mass (0.7-1.8-fold), as well as increase in plasma levels of CRP (0.1-0.3-fold), fibrinogen (0.2-0.3-fold), leptin (1.7-3.7-fold), TNF-α (0.1-0.6-fold), AST (0.9-1.4-fold), CK-MB (0.3-1.4-fold) and LDH (2.7-6.7-fold). Moreover, vinegar treatments preserved myocardial architecture and attenuated cardiac fibrosis. These findings suggest that pomegranate, apple and prickly pear vinegars may prevent HFD-induced obesity and obesity-related cardiac complications, and that this prevention may result from the potent anti-inflammatory and anti-adiposity properties of these vinegars.


VEGF and IGF Delivered from Alginate Hydrogels Promote Stable Perfusion Recovery in Ischemic Hind Limbs of Aged Mice and Young Rabbits.
Biomaterial-based delivery of angiogenic growth factors restores perfusion more effectively than bolus delivery methods in rodent models of peripheral vascular disease, but the same success has not yet been demonstrated in clinically relevant studies of aged or large animals. These studies explore, in clinically relevant models, a therapeutic angiogenesis strategy for the treatment of peripheral vascular disease that overcomes the challenges encountered in previous clinical trials. Alginate hydrogels providing sustained release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF) were injected into ischemic hind limbs in middle-aged and old mice, and also in young rabbits, as a test of the scalability of this local growth factor treatment. Spontaneous perfusion recovery diminished with increasing age, and only the combination of VEGF and IGF delivery from gels significantly rescued perfusion in middle-aged (13 months) and old (20 months) mice. In rabbits, the delivery of VEGF alone or in combination with IGF from alginate hydrogels, at a dose 2 orders of magnitude lower than the typical doses used in past rabbit studies, enhanced perfusion recovery when given immediately after surgery, or as a treatment for chronic ischemia. Capillary density measurements and angiographic analysis demonstrated the benefit of gel delivery. These data together suggest that alginate hydrogels providing local delivery of low doses of VEGF and IGF constitute a safe and effective treatment for hind-limb ischemia in clinically relevant animal models, thereby supporting the potential clinical translation of this concept.


Effect of HPMC - E15 LV premium polymer on release profile and compression characteristics of chitosan/ pectin colon targeted mesalamine matrix tablets and in vitro study on effect of pH impact on the drug release profile.
The study was designed to investigate the in vitro dissolution profile and compression characteristics of colon targeted matrix tablets prepared with HPMC E15 LV in combination with pectin and Chitosan. The matrix tablets were subjected to two dissolution models in various simulated fluids such as pH 1.2, 6, 6.8, 7.2, 5.5. The fluctuations in colonic pH conditions during IBD (inflammatory bowel disease) and the nature of less fluid content in the colon may limit the expected drug release in the polysaccharide-based matrices when used alone. The Hydrophilic hydroxyl propyl methylcellulose ether premium polymer (HPMC E15 LV) of low viscosity grade was used in the formulation design, which made an excellent modification in physical and compression characteristics of the granules. The release studies indicated that the prepared matrices could control the drug release until the dosage form reaches the colon and the addition HPMC E15 LV showed the desirable changes in the dissolution profile by its hydrophilic nature since the colon is known for its less fluid content. The hydrophilic HPMC E15 LV allowed the colonic fluids to enter into the matrix and confirmed the drug release at the target site from a poorly water soluble polymer such as Chitosan and also from water soluble Pectin. The dramatic changes occurred in the drug release profile and physicochemical characteristics of the Pectin, Chitosan matrix tablets when a premium polymer HPMC E15 LV added in the formulation design in the optimized concentration. Various drug release mechanisms used for the examination of drug release characteristics. Drug release followed the combined mechanism of diffusion, erosion, swelling and polymer entanglement. In recent decade, IBD attracts many patents in novel treatment methods by using novel drug delivery systems.


Escalation of Immunosuppressive Therapy for Inflammatory Bowel Disease Is Not Associated With Adverse Outcomes After Infection With Clostridium difficile.
Clostridium difficile infection (CDI) is common in patients with inflammatory bowel disease (IBD), often leading to diagnostic confusion and delays in IBD therapy escalation. This study sought to assess outcomes after CDI in IBD patients exposed to new or escalated immunosuppressive therapy. This multicenter retrospective cohort study included IBD patients with documented CDI at 4 academic medical centers. Data were abstracted from clinical databases at each institution. Outcomes at 30 and 90 days were compared between patients undergoing new or intensified immunosuppressive therapy and those without therapy escalation. Continuous variables were compared using t tests, and proportions using chi-square tests. Multivariable logistic regression was used to determine the association of individual variables with severe outcomes (including death, sepsis, and/or colectomy) within 90 days. Secondary outcomes included CDI recurrence, rehospitalization, worsening of IBD, and severe outcomes within 30 days. A total of 207 adult patients with IBD and CDI were included, of whom 62 underwent escalation to biologic or corticosteroid therapy (median time to escalation, 13 days). Severe outcomes within 90 days occurred in 21 (15.6%) nonescalated and 1 (1.8%) therapy-escalated patients. Serum albumin <2.5 mg/dL, lactate >2.2 mg/dL, intensive care unit admission, hypotension, and comorbid disease were associated with severe outcomes. Likelihood of severe outcomes was decreased in patients undergoing escalation of IBD therapy after CDI (adjusted odds ratio [aOR], 0.12) and increased among patients aged >65 years (aOR, 4.55). Therapy escalation for IBD within 90 days of CDI was not associated with worse clinical outcomes. Initiation of immunosuppression for active IBD may therefore be appropriate in carefully selected patients after treatment of CDI.


[Surgery for Atresia auris. Retrospective study of our results and correlation with Jahrsdoerfer prognostic criterium].
The study goal was to evaluate the hearing follow up results in patients who underwent surgery for congenital aural atresia. We studied hearing results and correlated them with Jahrsdoerfer prognostic classification. Protocols management of unilateral and bilateral atresia auris are written considering to our results and other authors. We conducted a retrospective review of 12 ears who underwent surgery for congenital aural atresia between 1989 and 2002. CT scan was used to evaluate Jahrsdoerfer prognostic classification and the correlation with the hearing results. There are significant statistical differences (p = 0.003) in air-bone gap closure before and after surgery, also a lineal significant correlation (p = 0.016) between Jahrsdoerfer prognostic classification and air-bone gap closure. Atresiaplasty surgery in individuals with congenital aural atresia can yield good hearing results in selected cases.


If body fatness is under physiological regulation, then how come we have an obesity epidemic?
Life involves a continuous use of energy, but food intake, which supplies that energy, is episodic. Feeding is switched on and off by a complex array of predominantly gut-derived peptides (and potentially nutrients) that initiate and terminate feeding bouts. Energy is stored as glucose and glycogen to overcome the problem of the episodic nature of intake compared with the continuous demand. Intake is also adjusted to meet immediate changes in demands. Most animals also store energy as fat. In some cases, this serves the purpose of storing energy in anticipation of a known future shortfall (e.g., hibernation, migration, or reproduction). Other animals, however, store fat in the absence of such anticipated needs, and in this case the fat appears to be stored in preparation for unpredictable catastrophic shortfalls in supply. Fat storage, however, brings disadvantages as well as advantages, in particular an increased risk of predation. Hence, many animals seem to have evolved a dual intervention point system preventing them from storing too little or too much fat. The physiological basis of the lower intervention point is well established, but the upper intervention point is much less studied. Human obesity can potentially be understood in an evolutionary context as due to drift in the upper intervention point following release from predation 2 million years ago (the drifty gene hypothesis) combined with a stimulus in modern society to overconsume calories, possibly attempting to satisfy intake of a limiting micro- or macro-nutrient like protein (the protein leverage hypothesis).


Altered hemodynamic responses in patients after subcortical stroke measured by functional MRI.
Blood oxygenation level-dependent (BOLD) functional MRI (fMRI) is a promising method for defining brain recovery after stroke quantitatively. Applications thus far have assumed that the BOLD hemodynamic response in patients after stroke is identical to that in healthy controls. However, because of local vascular compromise or more diffuse vascular disease predisposing to infarction, this assumption may not be justified after stroke. We sought to test whether patients who have suffered a lacunar stroke show BOLD fMRI response characteristics identical to those of healthy controls. We measured the BOLD fMRI signal time course in the sensorimotor cortex contralateral to the affected hand with finger- or hand-tapping tasks for minimally or mildly impaired right-handed patients (n=12) after lacunar strokes causing limb weakness and for healthy controls (n=20). With a right-handed sequential finger-tapping task, the rate of rise and maximum increase of the BOLD signal in the contralateral sensorimotor cortex were > 30% lower (P< or =0.01) in the stroke patients. Similar relative decreases were found for the same task performed with the left hand. These changes were found in patients both in the hemisphere affected by stroke and in the unaffected hemisphere, suggesting that the BOLD fMRI time course differences observed arise from a diffuse functional pathology. The difference between patients and controls is not a result of age alone, since differences were not found between the younger (n=10; aged 22 to 38 years) and the older (n=10; aged 56 to 83 years) healthy controls. The effect also does not seem to be dependent on the specific hand movement task used. The magnitude of the BOLD fMRI response can be reduced in stroke patients even if infarcts do not involve the cortex. This may be a consequence of the stroke, but the observation that the BOLD signal time course is similar in the affected and unaffected hemispheres suggests that it also could result from preexisting pathophysiological changes in the cerebral microvasculature.


Autoimmunity versus tolerance: analysis using transgenic mice.
On the basis of our extensive studies on collagen induced arthritis in HLA class II transgenic mice, we proposed a hypothesis to explain role of shared epitope in rheumatoid arthritis (RA) association. According to our hypothesis, complementation between both DQ and DR molecules is required for susceptibility or protection from disease. While certain DQ alleles predispose individuals to RA, DRB1 molecule can modulate disease by shaping T-cell repertoire in the thymus by providing self-peptides and presented by DQ molecules. Using A beta o.DQ8 transgenic mice, we tested ability of peptides derived from HV3 of DR molecules, implicated in RA positively or negatively, to activate T cells. While the peptides derived from RA susceptible DR molecule were poor binders and poor in activating T cells, the peptides derived from RA resistant DR molecules were high affinity binders and efficient T-cell activators. Our experiments suggest that high affinity DR peptides could induce tolerance to autoimmunity while the low affinity peptides could be permissive to autoimmunity. Using peptide from DRB1*0402 molecule, known to be associated with resistance to RA, prior to induction of collagen induced arthritis prevents the onset of disease. Thus, self-peptides derived from HLA molecules could potentially generate tolerance or autoimmunity depending on their binding affinity with HLA molecules.


Monitoring age-related susceptibility of young mice to oral Salmonella enterica serovar Typhimurium infection using an in vivo murine model.
Neonates and young children are acutely susceptible to infections by gastrointestinal bacterial pathogens, such as Salmonella enterica serovar Typhimurium (S. typhimurium). To reveal age-related differences in susceptibility to this pathogen, we used in vivo bioluminescence imaging (BLI) to monitor the progression of infection in neonatal (1-wk-old), suckling (2-wk-old), juvenile (4-wk-old), and adult (6-wk-old) BALB/c mice. Mice were orally infected with various doses of a bioluminescent-labeled wild-type or mutant S. typhimurium strain, and progression of infection was monitored by BLI for 2 wks. We found that neonatal and suckling mice were more susceptible to the wild-type strain at inoculum sizes 4 and 2 log(10)'s lower for neonatal and suckling mice, respectively, than those for adult mice. At the lower inocula, newborn mice showed disseminated systemic infection as indicated by the pattern of photon emission assessed by BLI, whereas no bioluminescent signals were detectable in adult mice. In addition, an orgA(-) mutant strain of S. typhimurium with reduced virulence in adult mice produced systemic infection in newborn, suckling, and juvenile mice. Furthermore, as low as 3 log(10) CFU could be detected by BLI in tissue. The present study demonstrates that susceptibility to S. typhimurium infection decreases with age. Also, we established that BLI can be used to monitor the progression of infection in mice. Thus, this model of age-related susceptibility to S. typhimurium using BLI can be used to advance our understanding of the mechanisms involved in newborn susceptibility to infection.


"Did I bring it on myself?" An exploratory study of the beliefs that adolescents referred to mental health services have about the causes of their depression.
The causal beliefs which adults have regarding their mental health difficulties have been linked to help-seeking behaviour, treatment preferences, and the outcome of therapy; yet, the topic remains a relatively unexplored one in the adolescent literature. This exploratory study aims to explore the causal beliefs regarding depression among a sample of clinically referred adolescents. Seventy seven adolescents, aged between 11 and 17, all diagnosed with moderate to severe depression, were interviewed using a semi-structured interview schedule, at the beginning of their participation in a randomised controlled trial. Data were analysed qualitatively using framework analysis. The study identified three themes related to causal beliefs: (1) bewilderment about why they were depressed; (2) depression as a result of rejection, victimisation, and stress; and (3) something inside is to blame. Although some adolescents struggled to identify the causes of their depression, many identified stressful life experiences as the cause of their current depression. They also tended to emphasise their own negative ways of interpreting those events, and some believed that their depression was caused by something inside them. Adolescents' causal beliefs are likely to have implications for the way they seek help and engage in treatment, making it important to understand how adolescents understand their difficulties.


Rod-cone crossover connectome of mammalian bipolar cells.
The basis of cross-suppression between rod and cone channels has long been an enigma. Using rabbit retinal connectome RC1, we show that all cone bipolar cell (BC) classes inhibit rod BCs via amacrine cell (AC) motifs (C1-6); that all cone BC classes are themselves inhibited by AC motifs (R1-5, R25) driven by rod BCs. A sparse symmetric AC motif (CR) is presynaptic and postsynaptic to both rod and cone BCs. ON cone BCs of all classes drive inhibition of rod BCs via motif C1 wide-field GABAergic ACs (γACs) and motif C2 narrow field glycinergic ON ACs (GACs). Each rod BC receives ≈10 crossover AC synapses and each ON cone BC can target ≈10 or more rod BCs via separate AC processes. OFF cone BCs mediate monosynaptic inhibition of rod BCs via motif C3 driven by OFF γACs and GACs and disynaptic inhibition via motifs C4 and C5 driven by OFF wide-field γACs and narrow-field GACs, respectively. Motifs C4 and C5 form halos of 60-100 inhibitory synapses on proximal dendrites of AI γACs. Rod BCs inhibit surrounding arrays of cone BCs through AII GAC networks that access ON and OFF cone BC patches via motifs R1, R2, R4, R5 and a unique ON AC motif R3 that collects rod BC inputs and targets ON cone BCs. Crossover synapses for motifs C1, C4, C5, and R3 are 3-4× larger than typical feedback synapses, which may be a signature for synaptic winner-take-all switches. J. Comp. Neurol. 527:87-116, 2019. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.


Analysis of Diagnostic Findings From the European Mobile Laboratory in Guéckédou, Guinea, March 2014 Through March 2015.
A unit of the European Mobile Laboratory (EMLab) consortium was deployed to the Ebola virus disease (EVD) treatment unit in Guéckédou, Guinea, from March 2014 through March 2015. The unit diagnosed EVD and malaria, using the RealStar Filovirus Screen reverse transcription-polymerase chain reaction (RT-PCR) kit and a malaria rapid diagnostic test, respectively. The cleaned EMLab database comprised 4719 samples from 2741 cases of suspected EVD from Guinea. EVD was diagnosed in 1231 of 2178 hospitalized patients (57%) and in 281 of 563 who died in the community (50%). Children aged <15 years had the highest proportion of Ebola virus-malaria parasite coinfections. The case-fatality ratio was high in patients aged <5 years (80%) and those aged >74 years (90%) and low in patients aged 10-19 years (40%). On admission, RT-PCR analysis of blood specimens from patients who died in the hospital yielded a lower median cycle threshold (Ct) than analysis of blood specimens from survivors (18.1 vs 23.2). Individuals who died in the community had a median Ct of 21.5 for throat swabs. Multivariate logistic regression on 1047 data sets revealed that low Ct values, ages of <5 and ≥45 years, and, among children aged 5-14 years, malaria parasite coinfection were independent determinants of a poor EVD outcome. Virus load, age, and malaria parasite coinfection play a role in the outcome of EVD.


Effects of biological response modifiers with different modes of action used separately and together on immune responses in mice with syngeneic tumours.
The effect of a protein-bound polysaccharide (PSK) obtained from cultured mycelia of the Basidiomycetes Coriolus versicolor on activities involved in the host defence mechanism of C57BL/6 mice bearing adenocarcinoma 755 was compared with that of live bacille Calmette-Guérin (BCG). Delayed footpad reaction, the activity of splenic natural killer cells and interferon production induced by concanavalin A in splenic cells of healthy mice were little affected by PSK, but in mice bearing tumours PSK prevented the tumour-induced reduction in these activities. Live BCG augmented these activities in healthy mice but had little effect on the reduction of activities induced by a tumour. The immunosuppressive activity of the serum of tumour-bearing mice was reduced by PSK administration; live BCG did not have this effect. The combined use of live BCG and PSK improved these activities in the host, with synergistic increases in the antitumour effect. These results suggest that the combined use of live BCG and PSK, which have different modes of action, may be useful in the treatment of cancer.


The empirical Bayes approach as a tool to identify non-random species associations.
A statistical challenge in community ecology is to identify segregated and aggregated pairs of species from a binary presence-absence matrix, which often contains hundreds or thousands of such potential pairs. A similar challenge is found in genomics and proteomics, where the expression of thousands of genes in microarrays must be statistically analyzed. Here we adapt the empirical Bayes method to identify statistically significant species pairs in a binary presence-absence matrix. We evaluated the performance of a simple confidence interval, a sequential Bonferroni test, and two tests based on the mean and the confidence interval of an empirical Bayes method. Observed patterns were compared to patterns generated from null model randomizations that preserved matrix row and column totals. We evaluated these four methods with random matrices and also with random matrices that had been seeded with an additional segregated or aggregated species pair. The Bayes methods and Bonferroni corrections reduced the frequency of false-positive tests (type I error) in random matrices, but did not always correctly identify the non-random pair in a seeded matrix (type II error). All of the methods were vulnerable to identifying spurious secondary associations in the seeded matrices. When applied to a set of 272 published presence-absence matrices, even the most conservative tests indicated a fourfold increase in the frequency of perfectly segregated "checkerboard" species pairs compared to the null expectation, and a greater predominance of segregated versus aggregated species pairs. The tests did not reveal a large number of significant species pairs in the Vanuatu bird matrix, but in the much smaller Galapagos bird matrix they correctly identified a concentration of segregated species pairs in the genus Geospiza. The Bayesian methods provide for increased selectivity in identifying non-random species pairs, but the analyses will be most powerful if investigators can use a priori biological criteria to identify potential sets of interacting species.


Effects of morphine administration on the fetal production of oxytocin in labour.
1. Animal and human work has indicated that maternal oxytocin secretion is under the control of endogenous opiates. Previous workers have described the fetal production of oxytocin in addition to maternal production. The study of the interaction between exogenously administered opiates and oxytocin secretion may give insight into the activity of any opiate-mediated regulatory mechanism of oxytocin secretion in the fetus. This study was designed to investigate the effect of an opiate (5 mg of morphine) given to the mother on the fetal production of oxytocin in labour. 2. Morphine was given by the attending clinicians for analgesic purposes to women in the first stage of labour. After delivery umbilical artery vein and maternal vein specimens were taken. 3. Four groups of patients were studied: women after normal vaginal delivery without analgesia in labour (n=10); women after normal vaginal delivery who had morphine administration in the first stage of labour (n=12); women who had an emergency Caesarean section in the first stage of labour (n=11); women who had an elective Caesarean section at term who were not in labour (n=11). 4. Oxytocin levels were measured by radioimmunoassay in the maternal vein, umbilical artery and umbilical vein specimens. Morphine was measured by radioimmunoassay in the umbilical vein specimens. 5. The umbilical artery minus vein concentration of oxytocin was calculated for each patient (A-V). There was no change in the umbilical (A-V) concentration of oxytocin if morphine had been given to the mother in labour; this applied to fetuses delivered vaginally or by Caesarean section. When the fetuses who were exposed to morphine were analysed separately, there was no correlation between the umbilical vein morphine concentration and the umbilical (A-V) oxytocin concentration either in Caesarean or vaginal deliveries. 6. Fetal oxytocin production was not affected by the maternal administration of morphine in the first stage of labour. This applies to the oxytocin production in the first and second stage of labour.


Natronococcus roseus sp. nov., a haloalkaliphilic archaeon from a hypersaline lake.
A novel halophilic archaeon, strain CG-1(T), belonging to the genus Natronococcus was isolated from sediment of the soda lake Chagannor in Inner Mongolia, China. The colonies of this strain were pink pigmented, the intensity of the colour decreased when the cells grew at salt saturation levels. The cells were non-motile cocci and strictly aerobic. Hypotonic treatment did not cause cell lysis, even in distilled water. Strain CG-1(T) grew at 15-30.0 % (w/v) NaCl and at 30-50 °C and pH 8.0-11.0, with optimal growth occurring at 25-30 % (w/v) NaCl, 37-45 °C and pH 9-9.5. MgCl(2) was not required for growth. Strain CG-1(T) was most closely related to the type strains of Natronococcus amylolyticus Ah-36(T), Natronococcus jeotgali B1(T) and Natronococcus occultus SP4(T), with which it shared 98.4 %, 96.2 and 95.7 % 16S rRNA gene sequence similarity, respectively. The polar lipids consisted of C(20)C(20) and C(20)C(25) derivatives of phosphatidylglycerol (PG), phosphatidylglycerol phosphate methyl ester (PGP-Me) and minor phospholipid components. No glycolipids were detected. The DNA G+C content of strain CG-1(T) was 62.1 mol%. DNA-DNA hybridization with N. amylolyticus DSM 10524(T), phylogenetically the most closely related species, was 39 %; this value showed that strain CG-1(T) constituted a different genospecies. The comparison of 16S rRNA gene sequences, detailed phenotypic characterization, polar lipid profile and DNA-DNA hybridization studies revealed that strain CG-1(T) belongs to the genus Natronococcus and constitutes a novel species for which the name Natronococcus roseus sp. nov. is proposed. The type strain is CG-1(T) (=CECT 7984(T)=IBRC-M 10656(T)=JCM 17958(T)).


Equipping community health workers with digital tools for pandemic response in LMICs.
Community health workers (CHWs) are well-positioned to play a pivotal role in fighting the pandemic at the community level. The Covid-19 outbreak has led to a lot of stress and anxiety among CHWs as they are expected to perform pandemic related tasks along with the delivery of essential healthcare services. In addition, movement restrictions, lockdowns, social distancing, and lack of protective gear have significantly affected CHWs' routine workflow and performance. To optimize CHWs' functioning, there is a renewed interest in supporting CHWs with digital technology to ensure an appropriate pandemic response. The current situation has necessitated the use of digital tools for the delivery of Covid-19 related tasks and other essential healthcare services at the community level. Evidence suggests that there has been a significant digital transformation to support CHWs in these critical times such as remote data collection and health assessments, the use of short message service and voice message for health education, use of digital megaphones for encouraging behavior change, and digital contract tracing. A few LMICs such as Uganda and Ethiopia have been successful in operationalizing digital tools to optimize CHWs' functioning for Covid-19 tasks and other essential health services. Yet, in most LMICs, there are some challenges concerning the feasibility and acceptability of using digital tools for CHWs during the Covid-19 pandemic. In most cases, CHWs find it difficult to adopt and use digital health solutions due to lack of training on new digital tools, weak technical support, issues of internet connectivity, and other administrative related challenges. To address these challenges, engaging governments would be essential for training CHWs on user-friendly digital health solutions to improve routine workflow of CHWs during the Covid-19 pandemic.


Molecular Mechanisms of Gonadotropin-Inhibitory Hormone (GnIH) Actions in Target Cells and Regulation of GnIH Expression.
Since gonadotropin-inhibitory hormone (GnIH) was discovered in 2000 as the first hypothalamic neuropeptide that actively inhibits gonadotropin release, researches conducted for the last 18 years have demonstrated that GnIH acts as a pronounced negative regulator of reproduction. Inhibitory effect of GnIH on reproduction is mainly accomplished at hypothalamic-pituitary levels; gonadotropin-releasing hormone (GnRH) neurons and gonadotropes are major targets of GnIH action based on the morphological interaction with GnIH neuronal fibers and the distribution of GnIH receptor. Here, we review molecular studies mainly focusing on the signal transduction pathway of GnIH in target cells, GnRH neurons, and gonadotropes. The use of well-defined cellular model systems allows the mechanistic study of signaling pathway occurring in target cells by demonstrating the direct cause-and-effect relationship. The insights gained through studying molecular mechanism of GnIH action contribute to deeper understanding of the mechanism of how GnIH communicates with other neuronal signaling systems to control our reproductive function. Reproductive axis closely interacts with other endocrine systems, thus GnIH expression levels would be changed by adrenal and thyroid status. We also briefly review molecular studies investigating the regulatory mechanisms of GnIH expression to understand the role of GnIH as a mediator between adrenal, thyroid and gonadal axes.


Canadian 2003 International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema.
C1 inhibitor deficiency (hereditary angioedema [HAE]) is a rare disorder for which there is a lack of consensus concerning diagnosis, therapy, and management, particularly in Canada. European initiatives have driven the approach to managing HAE with 3 C1-INH Deficiency Workshops held every 2 years in Hungary starting in 1999, with the third Workshop having recently been held in May 2003. The European Contact Board has established a European HAE Registry that will hopefully advance our knowledge of this disorder. The Canadian Hereditary Angioedema Society/Société d'Angioédème Héréditaire du Canada organized a Canadian International Consensus Conference held in Toronto, Ontario, Canada, on October 24 to 26, 2003, to foster consensus between major European and North American HAE treatment centers. Papers were presented by investigators from Europe and North America, and this consensus algorithm approach was discussed. There is a paucity of double-blind placebo-controlled trials in the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Enclosed is the consensus algorithm approach recommended for the diagnosis, therapy, and management of HAE and agreed to by the authors of this article. This document is only a consensus algorithm approach and requires validation. As such, participants agreed to make this a living 2003 algorithm (ie, a work in progress) and agreed to review its content at future international HAE meetings. The consensus, however, has strength in that it was arrived at by the meeting of patient-care providers along with patient group representatives and individual patients reviewing information available to date and reaching agreement on how to approach the diagnosis, therapy, and management of HAE circa 2003. Hopefully evidence to support approaches to the management of HAE will approach the level of meta-analysis of randomized controlled trials in the near future.


Boosting angiogenesis and functional vascularization in injectable dextran-hyaluronic acid hydrogels by endothelial-like mesenchymal stromal cells.
Angiogenesis and neovascularization are fundamental for the success of clinically relevant-sized tissue-engineered (TE) constructs. The next generation of TE constructs relies on providing instructive materials combined with the delivery of angiogenic growth factors and cells to avoid tissue ischemia. However, the majority of materials and cell types screened so far show limited clinical relevance, either due to insufficient number of cells or due to the use of animal-derived matrixes. Here, we investigated whether endothelial-like cells derived from mesenchymal stromal cells (EL-MSCs) can be used for vascular TE in combination with injectable dextran-hyaluronic acid (Dex-g-HA) hydrogels. These hydrogels can be easily modified, as demonstrated by the incorporation of vascular endothelial growth factor (VEGF). We examined in vitro the reciprocal influences between cells and matrix. Dex-g-HA enabled higher EL-MSC metabolic rates associated with optimal cell sprouting in vitro compared to human umbilical vein endothelial cells. In vivo evaluation demonstrated the absence of an acute inflammatory response, and EL-MSCs incorporated within Dex-g-HA formed a functional vascular network integrated with the host vascular system. This work demonstrates that Dex-g-HA is an efficient delivery method of VEGF to induce angiogenesis. Additionally, functional neovascularization can be achieved in vitro and in vivo by the combination of Dex-g-HA with EL-MSC.


Isolation of motoneuron cell bodies from spinal cord stored at -70 degrees C in ethylene glycol.
Pretreatment of spinal cord with ethylene glycol permits long-term storage of the tissue at -70 degrees C prior to isolation and biochemical analysis of the cell bodies of spinal motoneurons. The method is useful for storing spinal tissue from laboratory animals, as well as from human post mortem specimens, where aliquots of tissue may then be used for motoneuron isolation over an indefinitely long period. In addition to inhibiting the loss of soluble proteins from the neurons during freezing and thawing, cryoprotection increases the yield and improves the appearance of the isolated cell bodies. The method should aid biochemical studies of many kinds of neuronal subpopulations isolated from small amounts of starting material.


Optimal linear representations of images for object recognition.
Although linear representations are frequently used in image analysis, their performances are seldom optimal in specific applications. This paper proposes a stochastic gradient algorithm for finding optimal linear representations of images for use in appearance-based object recognition. Using the nearest neighbor classifier, a recognition performance function is specified and linear representations that maximize this performance are sought. For solving this optimization problem on a Grassmann manifold, a stochastic gradient algorithm utilizing intrinsic flows is introduced. Several experimental results are presented to demonstrate this algorithm.


Collateral ventilation and pulmonary arterial smooth muscle in the coati.
Collateral ventilation can participate in ventilation-perfusion regulation by shifting normoxic gas into hypoxic lung regions. In species lacking collateral pathways, such as cattle and swine, ventilation-perfusion balance must rely heavily on hypoxic vasoconstriction, which may explain why their muscular pulmonary arteries are much thicker than those of other animal species. The presence of these unusually muscular vessels in turn may account for the vigorous pressor response to acute hypoxia in these species. The only other species known to lack collateral ventilation is the coati. To determine whether coatis fit the pulmonary circulatory pattern of cattle and swine, we measured pulmonary arterial wall dimensions and pulmonary vascular responsiveness to acute airway hypoxia in 11 adult coatis. Hypoxia caused impressive pulmonary arterial hypertension [normoxia = 17 +/- 1 (SE) Torr, hypoxia = 40 +/- 2 Torr, cardiac output unchanged]. The medial thickness of muscular pulmonary arteries (50-300 microns) was 17.1 +/- 1.8% (SD) of external diameter, a thickness unprecedented in normotensive adult mammals. We conclude that coatis fit the pattern of other species lacking collateral ventilation, since they have thick-walled pulmonary arteries and a vigorous pressor response to hypoxia.


Peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist, WY-14,643, increased transcription of myosin light chain-2 in cardiomyocytes.
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that can be activated by xenobiotics and natural fatty acids. To assess the potential physiological activity of PPAR ligands on cardiac muscular cells, the effects of PPAR alpha agonist, WY-14,643, on both rat hearts and a rat cardiomyocyte cell line (H9c2 cells) were investigated. Male F344 rats were fed a diet containing WY-14,643 at a concentration of 100 ppm for 26 weeks. Cardiac muscular hypertrophy was revealed by morphometric analysis in which the diameter of the muscular fibers in WY-14,643-treated rats was larger than those of control rats. Using H9c2 cells in vitro, the protein content per cell was increased in a dose-dependent manner with the treatment of WY-14,643. The transcription of myosin light chain-2 (MLC-2), a parameter of myocardial hypertrophy, was increased in H9c2 cells transfected with the rat MLC-2/luciferase fusion gene by WY-14,643 as well as other peroxisome proliferators, clofibrate and di(2-ethylhexyl) phthalate. In addition, accumulation of myosin light chain protein was confirmed in H9c2 cells treated with WY-14,643 at 10 micrograms/ml for 7 days or more by immunohistochemistry. These results suggest that PPAR alpha ligands have a potential to regulate MLC-2, which is a contractile protein in cardiomyocytes and may play a part of role in the pathogenesis of cardiac hypertrophy.


How good is the quality of antenatal care in the Colombo district of Sri Lanka in diagnosing and treating anaemia?
Sri Lanka has shown relatively good maternal outcome indicators for a developing country. However, high maternal deaths from haemorrhage and anaemia raise questions about the quality of detection and treatment of anaemia at field antenatal clinics, which is the primary care setting for pregnant women. The aim of the study was to assess the quality of facilities and services and how satisfactory antenatal care is with regard to diagnosis and treatment of anaemia. This study was set in field antenatal clinics and conducted in two stages based on the Lot Quality Assurance Sampling method. In the first stage 55 antenatal clinics were selected, and in the second stage 275 pregnant women were recruited from these 55 clinics. Quality of services and quality of facilities were assessed using observation, and an interviewer administered questionnaire was used to measure client satisfaction. The validity of haemoglobin colour scale results was investigated by comparing them with results from a quality assured laboratory. Eleven health areas, other than the seven areas which had the haemoglobin investigated, were unacceptable as regards the quality of services. The quality of facilities was better than the quality of services in the Colombo district. Information and counselling was provided for only 4% of women in the clinics. The sensitivity and the specificity for the haemoglobin colour scale was 62% (95% CI: 52.9%-71.1%) and 86% (95% CI: 79.6%-93.0%) respectively. Urgent steps should be taken to improve the quality of care in the health areas where care is substandard, in order to reduce morbidity and mortality due to anaemia.


Human plague in the southwestern United States, 1957-2004: spatial models of elevated risk of human exposure to Yersinia pestis.
Plague is a rare but highly virulent flea-borne zoonotic disease caused by the Gram-negative bacterium Yersinia pestis Yersin. Identifying areas at high risk of human exposure to the etiological agent of plague could provide a useful tool for targeting limited public health resources and reduce the likelihood of misdiagnosis by raising awareness of the disease. We created logistic regression models to identify landscape features associated with areas where humans have acquired plague from 1957 to 2004 in the four-corners region of the United States (Arizona, Colorado, New Mexico, and Utah), and we extrapolated those models within a geographical information system to predict where plague cases are likely to occur within the southwestern United States disease focus. The probability of an area being classified as high-risk plague habitat increased with elevation up to approximately 2300 m and declined as elevation increased thereafter, and declined with distance from key habitat types (e.g., southern Rocky Mountain piñon--juniper [Pinus edulis Engelm. and Juniperus spp.], Colorado plateau piñon--juniper woodland, Rocky Mountain ponderosa pine (Pinus ponderosa P.& C. Lawson var. scopulorum), and southern Rocky Mountain juniper woodland and savanna). The overall accuracy of the model was >82%. Our most conservative model predicted that 14.4% of the four-corners region represented a high risk of peridomestic exposure to Y. pestis.


Herpes zoster in immunocompromised patients: incidence, timing, and risk factors.
To evaluate the risk factors for herpes zoster as well as the incidence and timing of this complication in patients who were treated with immunosuppression because of active Wegener's granulomatosis. We studied the 180 Wegener's granulomatosis patients in the Wegener's Granulomatosis Etanercept Trial (WGET). Herpes zoster events during WGET were documented prospectively. Follow-up questionnaires were employed to describe the location, treatment, and complication(s) of herpes zoster and its therapy. Univariate and multivariate analyses were performed to evaluate risk factors, including history of herpes zoster, for the occurrence of herpes zoster during the trial. All analyses were based on the time to first occurrence of herpes zoster. Eighteen patients (10% of the WGET cohort) suffered a total of 19 herpes zoster episodes over a mean follow-up period of 27 months. The annual incidence of herpes zoster in the WGET cohort was 45 cases/1000 patient-years (95% confidence interval [CI]: 27, 70). The median time from enrollment to the occurrence of herpes zoster in the subgroup of patients with that complication was 16.5 months (+/- 9.4). Fifteen of the 19 herpes zoster events (79%) occurred between months 6 and 36, many months after the period of most intensive immunosuppression. In univariate analyses, history of serum creatinine > or =1.5 mg/dL before enrollment was associated with a relative risk (RR) of 3.0 (95% CI: 1.1, 7.8) for herpes zoster during WGET (P=.03). In multivariate analyses, serum creatinine > or =1.5 mg/dL was associated with an RR of 6.3 (95% CI: 2.0, 19.8; P=.002), and female sex with an RR of 4.6 (95% CI: 1.6, 13.2; P=.004). Renal dysfunction and female sex were consistently strong risk factors for herpes zoster events in this population. Contrary to expectation, most herpes zoster events did not occur during periods of most intensive immunosuppression. These data may inform studies of interventions designed to prevent herpes zoster in patients on treatment for immune-mediated diseases.