Single-cell RNA-seq reveals activation of unique gene groups as a consequence of stem cell-parenchymal cell fusion.
Fusion of donor mesenchymal stem cells with parenchymal cells of the recipient can occur in the brain, liver, intestine and heart following transplantation. The therapeutic benefit or detriment of resultant hybrids is unknown. Here we sought a global view of phenotypic diversification of mesenchymal stem cell-cardiomyocyte hybrids and associated time course. Using single-cell RNA-seq, we found hybrids consistently increase ribosome components and decrease genes associated with the cell cycle suggesting an increase in protein production and decrease in proliferation to accommodate the fused state. But in the case of most other gene groups, hybrids were individually distinct. In fact, though hybrids can express a transcriptome similar to individual fusion partners, approximately one-third acquired distinct expression profiles in a single day. Some hybrids underwent reprogramming, expressing pluripotency and cardiac precursor genes latent in parental cells and associated with developmental and morphogenic gene groups. Other hybrids expressed genes associated with ontologic cancer sets and two hybrids of separate experimental replicates clustered with breast cancer cells, expressing critical oncogenes and lacking tumor suppressor genes. Rapid transcriptional diversification of this type garners consideration in the context of cellular transplantation to damaged tissues, those with viral infection or other microenvironmental conditions that might promote fusion.


Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity.
Obstructive sleep apnea is associated with insulin resistance and liver injury. It is unknown whether apnea contributes to insulin resistance and steatohepatitis in severe obesity. To examine whether sleep apnea and nocturnal hypoxemia predict the severity of insulin resistance, systemic inflammation, and steatohepatitis in severely obese individuals presenting for bariatric surgery. We performed sleep studies and measured fasting blood glucose, serum insulin, C-reactive protein, and liver enzymes in 90 consecutive severely obese individuals, 75 women and 15 men, without concomitant diabetes mellitus or preexistent diagnosis of sleep apnea or liver disease. Liver biopsies (n = 20) were obtained during bariatric surgery. Obstructive sleep apnea with a respiratory disturbance index greater than 5 events/hour was diagnosed in 81.1% of patients. The median respiratory disturbance index was 15 +/- 29 events/hour and the median oxygen desaturation during apneic events was 4.6 +/- 1.8%. All patients exhibited high serum levels of C-reactive protein, regardless of the severity of apnea, whereas liver enzymes were normal. Oxygen desaturation greater than 4.6% was associated with a 1.5-fold increase in insulin resistance, according to the homeostasis model assessment index. Histopathology data suggested that significant nocturnal desaturation might predispose to hepatic inflammation, hepatocyte ballooning, and liver fibrosis. Fasting blood glucose levels and steatosis scores were not affected by nocturnal hypoxia. There was no relationship between the respiratory disturbance index and insulin resistance or liver histopathology. Hypoxic stress of sleep apnea may be implicated in the development of insulin resistance and steatohepatitis in severe obesity.


Induction of cell proliferation in the forestomach of F344 rats following subchronic administration of styrene 7,8-oxide and butylated hydroxyanisole.
The question addressed was whether stimulation of cell proliferation could be responsible for tumor induction in the forestomach by styrene 7,8-oxide (SO). Male F344 rats were treated for 4 weeks with 0, 137, 275, and 550 mg/kg SO by p.o. gavage 3 times/week. Positive controls received 0, 0.5, 1, and 2% butylated hydroxyanisole (BHA) in the diet for 4 weeks. Twenty-four h before termination of the experiment, the rats were implanted s.c. with an osmotic minipump delivering 5-bromo-2'-deoxyuridine (BrdU). Cell proliferation in the forestomach was assessed by immunohistochemistry for BrdU incorporated into DNA. Cell number/mm section length and fraction of replicating cells (labeling index) were determined in 3 domains of the forestomach, the saccus caecus, the midregion, and the prefundic region. With the exception of the prefundic region of the low-dose SO group, a significant increase of the labeling index was found in all regions both with SO and BHA. Rats treated with BHA showed, in addition, a dose-dependent increase in number and size of hyperplastic lesions. This was most pronounced in the prefundic region where carcinomas were reported to be localized. In this region, the number of dividing cells/mm section length was increased up to 17-fold. With SO, only marginal morphological changes were occasionally observed, despite the fact that the respective long-term treatment had been reported to result in a higher carcinoma incidence than treatment with BHA. It is concluded that the rate of replicating cells alone, numerically expressed by the labeling index, is an insufficient tool for interpreting the role of cell division in carcinogenesis. It is postulated that SO and BHA induce forestomach tumors via different mechanisms. While hyperplasia in the prefundic region most likely dominates the carcinogenicity of BHA, a mechanism combining marginal genotoxicity with strong promotion by increased cell proliferation appears to be involved in the tumorigenic action of SO.


Acyclovir for treating varicella in otherwise healthy children and adolescents: a systematic review of randomised controlled trials.
Acyclovir has the potential to shorten the course of chickenpox which may result in reduced costs and morbidity. We conducted a systematic review of randomised controlled trials that evaluated acyclovir for the treatment of chickenpox in otherwise healthy children. MEDLINE, EMBASE, and the Cochrane Library were searched. The reference lists of relevant articles were examined and primary authors and Glaxo Wellcome were contacted to identify additional trials. Two reviewers independently screened studies for inclusion, assessed study quality using the Jadad scale and allocation concealment, and extracted data. Continuous data were converted to a weighted mean difference (WMD). Overall estimates were not calculated due to differences in the age groups studied. Three studies were included. Methodological quality was 3 (n = 2) and 4 (n = 1) on the Jadad scale. Acyclovir was associated with a significant reduction in the number of days with fever, from -1.0 (95% CI -1.5,-0.5) to -1.3 (95% CI -2.0,-0.6). Results were inconsistent with respect to the number of days to no new lesions, the maximum number of lesions and relief of pruritus. There were no clinically important differences between acyclovir and placebo with respect to complications or adverse effects. Acyclovir appears to be effective in reducing the number of days with fever among otherwise healthy children with chickenpox. The results were inconsistent with respect to the number of days to no new lesions, the maximum number of lesions and the relief of itchiness. The clinical importance of acyclovir treatment in otherwise healthy children remains controversial.


The origin and impact of embryonic aneuploidy.
Despite the clinical importance of aneuploidy, surprisingly little is known concerning its impact during the earliest stages of human development. This study aimed to shed light on the genesis, progression, and survival of different types of chromosome anomaly from the fertilized oocyte through the final stage of preimplantation development (blastocyst). 2,204 oocytes and embryos were examined using comprehensive cytogenetic methodology. A diverse array of chromosome abnormalities was detected, including many forms never recorded later in development. Advancing female age was associated with dramatic increase in aneuploidy rate and complex chromosomal abnormalities. Anaphase lag and congression failure were found to be important malsegregation causing mechanisms in oogenesis and during the first few mitotic divisions. All abnormalities appeared to be tolerated until activation of the embryonic genome, after which some forms started to decline in frequency. However, many aneuploidies continued to have little impact, with affected embryos successfully reaching the blastocyst stage. Results from the direct analyses of female meiotic divisions and early embryonic stages suggest that chromosome errors present during preimplantation development have origins that are more varied than those seen in later pregnancy, raising the intriguing possibility that the source of aneuploidy might modulate impact on embryo viability. The results of this study also narrow the window of time for selection against aneuploid embryos, indicating that most survive until the blastocyst stage and, since they are not detected in clinical pregnancies, must be lost around the time of implantation or shortly thereafter.


ATP-sensitive K-channels in HIT T15 beta-cells studied by patch-clamp methods, 86Rb efflux and glibenclamide binding.
ATP-sensitive K-channels in the cloned beta-cell line HIT T15 were studied by patch-clamp methods; by measurement of 86Rb efflux; and by [3H]glibenclamide binding to isolated membrane preparations. In inside-out patches a 50 pS K-channel was found which was blocked by ATP or tolbutamide applied to the intracellular membrane surface. A minimum estimate of about 500 channels per beta-cell was obtained by combining whole-cell and single-channel data. The rate of efflux of 86Rb from 86RbCl-loaded HIT cells was markedly increased by intracellular ATP-depletion; 86Rb-efflux was progressively inhibited by increasing concentrations of glibenclamide or tolbutamide. In non-ATP-depleted cells, diazoxide elicited a concentration-dependent stimulation of 86Rb-efflux which was completely blocked by 1 microM glibenclamide. Isolated membranes showed dose-dependent saturable binding of [3H]glibenclamide to both high (Kd = 1.12 nM) and low (Kd = 136 nM) affinity binding sites. We estimate about 5000 high-affinity binding sites per cell. [3H]-glibenclamide binding was inhibited by tolbutamide (IC50 = 125 microM) but was not affected by diazoxide. ADP (0.5 or 1.0 mM) markedly reduced binding; other nucleotides tested were ineffective.


Mimicking arterial thrombosis in a 3D-printed microfluidic in vitro vascular model based on computed tomography angiography data.
Arterial thrombosis is the main instigating factor of heart attacks and strokes, which result in over 14 million deaths worldwide every year. The mechanism of thrombosis involves factors from the blood and the vessel wall, and it also relies strongly on 3D vessel geometry and local blood flow patterns. Microfluidic chip-based vascular models allow controlled in vitro studies of the interaction between vessel wall and blood in thrombosis, but until now, they could not fully recapitulate the 3D geometry and blood flow patterns of real-life healthy or diseased arteries. Here we present a method for fabricating microfluidic chips containing miniaturized vascular structures that closely mimic architectures found in both healthy and stenotic blood vessels. By applying stereolithography (SLA) 3D printing of computed tomography angiography (CTA) data, 3D vessel constructs were produced with diameters of 400 μm, and resolution as low as 25 μm. The 3D-printed templates in turn were used as moulds for polydimethylsiloxane (PDMS)-based soft lithography to create microfluidic chips containing miniaturized replicates of in vivo vessel geometries. By applying computational fluid dynamics (CFD) modeling a correlation in terms of flow fields and local wall shear rate was found between the original and miniaturized artery. The walls of the microfluidic chips were coated with human umbilical vein endothelial cells (HUVECs) which formed a confluent monolayer as confirmed by confocal fluorescence microscopy. The endothelialised microfluidic devices, with healthy and stenotic geometries, were perfused with human whole blood with fluorescently labeled platelets at physiologically relevant shear rates. After 15 minutes of perfusion the healthy geometries showed no sign of thrombosis, while the stenotic geometries did induce thrombosis at and downstream of the stenotic area. Overall, the novel methodology reported here, overcomes important design limitations found in typical 2D wafer-based soft lithography microfabrication techniques and shows great potential for controlled studies of the role of 3D vessel geometries and blood flow patterns in arterial thrombosis.


Age and genetics: how do prognostic factors at diagnosis explain disparities in acute myeloid leukemia?
Survival disparities in acute myeloid leukemia (AML) among blacks and Hispanics have been described but not studied extensively in adults. Although younger age and cytogenetic profiles of t(8;21) and acute promyelocytic leukemia (APL) subtypes of AML are associated with improved survival, these factors have not been investigated by race. The purpose is to evaluate whether the observed survival differences for blacks and Hispanics with AML are attributable to older age at diagnosis or lower rates of favorable cytogenetic profiles at diagnosis. The hypothesis is that survival disparities for blacks and Hispanics with AML will be explained by older age at diagnosis and lower rates of favorable cytogenetics. Patients with AML were identified in the Surveillance Epidemiology and End Results database (1999 to 2008). Kaplan-Meier (KM) survival curves predicted survival by race/ethnicity, stratified by age. Cox proportional hazard models estimated mortality by race with adjustment for age, sex, year of diagnosis, t(8;21), and APL subtypes. A total of 25,692 patients were included. Blacks and Hispanics were diagnosed at younger ages (younger than 61 y), and had higher rates of t(8;21) and APL compared with non-Hispanic whites (NHWs). The overall KM curve shows that NHWs had a worse survival compared with other races/ethnicities. However, when KM curves were stratified by age, blacks and Hispanics had worse survival in younger age categories (younger than 61 y). In multivariable models, black race was associated with an increased risk of death compared with NHWs (HR, 1.10; 95% CI, 1.04-1.16). Adjustment for t(8;21) and APL subtypes did not attenuate the disparity. Despite younger age and higher prevalence of favorable cytogenetics at diagnosis, blacks and Hispanics have an increased mortality from AML compared with other racial/ethnic groups. Future studies should investigate other factors that may influence outcomes among minority populations.


Characteristics Associated with Non-Disclosure of Suicidal Ideation in Adults.
Suicide prevention efforts often depend on the willingness or ability of people to disclose current suicidal behavior. The aim of this study is to identify characteristics that are associated with non-disclosure of suicidal ideation. Data from the Dutch cross-sectional survey Health Monitor 2016 were used, resulting in 14,322 respondents (age 19+). Multiple logistic regression analyses were conducted to assess the strength of the associations between demographics and health-related characteristics as independent variables, and non-disclosure of suicidal ideation as the dependent variable. The mean age of the respondents was 60 years (SD 16.7) and 45% were male. Of these adults, 5% (n = 719) reported suicidal ideation in the past year, nearly half of which (48%) did not disclose suicidal ideation. Non-disclosure was significantly associated with social loneliness (OR = 1.29). Inverse significant associations were found for age (35⁻49 years, OR = 0.53), poor health status (OR = 0.63), frequent suicidal ideation (OR = 0.48), and severe psychological distress (OR = 0.63). The accuracy of this model was fair (AUC = 0.73). To conclude, non-disclosure is a substantial problem in adults experiencing suicidal ideation. Adults who do not disclose suicidal ideation are more likely to have few social contacts, while they are less likely to experience poor (mental) health and frequent suicidal thoughts.


Effects of a program of human interaction and alterations in diet composition on activity of the hypothalamic-pituitary-adrenal axis in dogs housed in a public animal shelter.
To determine whether a program of human interaction or alterations in diet composition would alter activity of the hypothalamic-pituitary-adrenal (HPA) axis in dogs housed in an animal shelter. Prospective study. 40 dogs. Dogs were (n = 20) or were not (20) enrolled in a program of regular supplemental human interaction (20 min/d, 5 d/wk, for 8 weeks) involving stroking, massaging, and behavioral training. In addition, half the dogs in each group were fed a typical maintenance-type diet, and the other half were fed a premium diet. Plasma cortisol and ACTH concentrations were measured during weeks 0, 2, 4, and 8 and before and after exposure to a battery of novel situations during weeks 0 and 8. Plasma cortisol concentration was significantly decreased by week 2, but plasma ACTH concentration was not significantly decreased until week 8 and then only in dogs fed the premium diet. Following exposure to novel situations, plasma cortisol and ACTH concentrations were significantly increased. However, during week 8, dogs enrolled in the program of human interaction had significantly lower increases in cortisol concentration than did dogs not enrolled in the program. Results suggest that both a program of human interaction and alterations in diet composition have moderating effects on activity of the HPA axis in dogs housed in an animal shelter and that activity of the HPA axis may be increased for a longer period during shelter housing than measurement of plasma cortisol concentration alone would suggest.


Behavioral Benefits of Camel Milk in Subjects with Autism Spectrum Disorder.
To investigate the possible therapeutic effects of camel milk on behavioral characteristics as an interventional strategy in autistic children. Double-blind, Randomized Clinical Trial (RCT). Autism Research and Treatment Center, Al-Amodi Autism Research Chair, Department of Physiology, Faculty of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia, from October 2012 to May 2013. Changes in behavioral characteristics in 65 (boys=60, girls=5) children with autism (aged from 2 to 12 years) were assessed. The behavioral symptoms were evaluated by Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Autism Treatment Evaluation Checklist (ATEC) before and after the 2 weeks of camel milk therapy. Significant differences were detected on Autism Spectrum Disorder (ASD) by CARS, SRS and ATEC scales, following 2 weeks of camel milk consumption, but not in the placebo group. The present study demonstrates that camel milk could be very promising therapeutic intervention in ASD. Further wide scale studies are strongly recommended.


FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia.
Despite their known transforming properties, the effects of leukemogenic FLT3-ITD mutations on hematopoietic stem and multipotent progenitor cells and on hematopoietic differentiation are not well understood. We report a mouse model harboring an ITD in the murine Flt3 locus that develops myeloproliferative disease resembling CMML and further identified FLT3-ITD mutations in a subset of human CMML. These findings correlated with an increase in number, cell cycling, and survival of multipotent stem and progenitor cells in an ITD dose-dependent manner in animals that exhibited alterations within their myeloid progenitor compartments and a block in normal B cell development. This model provides insights into the consequences of constitutive signaling by an oncogenic tyrosine kinase on hematopoietic progenitor quiescence, function, and cell fate.


Endocrine disrupters. Panel cautiously confirms low-dose effects.
Faced with conflicting results from studies of the effects of small amounts of hormonelike chemicals in the environment, the Environmental Protection Agency enlisted the help of an expert panel, which met earlier this month to conduct an extensive review of the data. The panel concluded that estrogenic chemicals can cause biological effects in lab animals at levels below those normally found to be safe--which runs counter to the conventional wisdom in toxicology. But the implications for human health are unclear.


The Relations Between HSG Proven Tubal Occlusion, Stimulated Intrauterine Insemination and Pregnancy Rate.
Tubal factor infertility is one of the main causes of female infertility. Although its sensitivity is low, hysterosalpingography (HSG) is remains the first-line method for evaluating tubal patency. To compare pregnancy rates in patients with HSG proven proximal or distal unilateral tubal occlusion, and unexplained infertility undergoing both controlled ovarian stimulation (COS) and intrauterine insemination (IUI). Case control study. In total, 237 patients undergoing ovulation induction (OI) with gonadotropins and IUI were divided into two groups and evaluated. Study group consisted 59 patients with HSG proven unilateral tubal pathology, and 178 patients with unexplained infertility taken as control subjects. Cumulative pregnancy rate was the primary endpoint. Cumulative pregnancy rates after three cycles of OI and IUI were 15.25% in study group and 20.79% in control group. Pregnancy rates between two groups were not statistically significant. Although, pregnancy rates in patients with proximal tubal occlusion (21.8%) were higher than in those with distal tubal occlusion (7.4%), the difference was not statistically significant. Our study data shows that, regardless of the HCG proven occlusion area, COS and IUI might be a preferred treatment modality in patient with unilateral tubal occlusion.


Job strain and cognitive change: the Baltimore Epidemiologic Catchment Area follow-up study.
To investigate the association between job strain and subsequent cognitive change over approximately 11 years, using data from the population-based Baltimore Epidemiologic Catchment Area follow-up study. The sample ranged from 555 to 563 participants, depending on the outcome, who reported psychosocial characteristics corresponding to the full-time job they held at baseline (1993-1996). Overall cognitive performance was measured by the Mini-Mental State Examination (MMSE), and verbal memory was measured by the ImmediateWord Recall Task and Delayed Word Recall Task at baseline and follow-up (2004-2005). Multiple linear regression was used to examine the association between job strain and cognitive change, and inverse probability weighting was used to account for differential attrition. Participants with high job demands (psychological or physical demands) and/or low job control had greater decrease in the MMSE and memory scores than those with low job demands and high job control. After adjustment for baseline outcome scores, age and sex, the greatest decrease was observed in participants with high job demands and low job control (MMSE: -0.24, 95% CI -0.36 to -0.11; verbal memory scores: -0.26, 95% CI -0.44 to -0.07). The differences were partially explained by sociodemographic characteristics, occupational prestige and health factors. Findings from this prospective study suggest that job strain is associated with and may be a potential modifiable risk factor for adverse cognitive outcomes.


Embryonic development of identified neurons: segment-specific differences in the H cell homologues.
Although all of the segmental ganglia of the grasshopper come from identical sets of embryonic precursor cells, there are striking differences in the number and properties of the neurons in the mature ganglia. In every segment, midline precursor 3 (MP3) divides once and gives rise to two progeny. We describe the fate of the two MP3 progeny in different segments. The morphology, physiology, and survival of the MP3 progeny depend upon their segmental position in the embryo. In the meso- and metathoracic segments (T2 and T3), one of the two progeny of MP3 transforms into the H cell. In many of the abdominal segments, beginning with the fourth (A4), both MP3 progeny die. A gradient of transformation and cell death is seen in the intervening first three abdominal segments (A1 to A3). From A1 to A3, the MP3 progeny acquire fewer of the morphological phenotypes of the H cell. This is paralleled by the partial acquisition of the physiological phenotypes of the H cell. Thus, cells that are the progeny of the same precursor cell in different segments can either live or die and, if they survive, can develop different morphological and physiological properties.


Outborns or Inborns: Where Are the Differences? A Comparison Study of Very Preterm Neonatal Intensive Care Unit Infants Cared for in Australia and New Zealand and in Canada.
Very preterm infants born outside tertiary centers are at higher risks of adverse outcomes than inborn infants. Regionalization of perinatal care has been introduced worldwide to improve outcomes. To compare the risk-adjusted outcomes of both inborn and outborn infants cared for in tertiary neonatal intensive care units in Australia and New Zealand and in Canada. Deidentified data of infants <32 weeks' gestational age from the 29 Australian and New Zealand Neonatal Network units (ANZNN; n = 9,893) and 26 Canadian Neonatal Network units (CNN; n = 7,133) between 2005 and 2007 were analyzed for predischarge adverse outcomes. ANZNN had lower rates of outborns compared to CNN (13 vs. 19%), particularly of late admissions (>2 days of age; 5.8 vs. 22.2% of outborns) who had high morbidity rates. After adjusting for confounding variables including gestation, ANZNN inborn infants had lower odds of chronic lung disease [CLD; 17.0 vs. 23.3%; adjusted odds ratio (AOR) = 0.70, 95% CI: 0.64-0.77], severe neurological injuries on ultrasound (SNI; 4.1 vs. 6.7%; AOR = 0.62, 95% CI: 0.53-0.73), severe retinopathy (5.6 vs. 7%; AOR = 0.71, 95% CI: 0.59-0.84) and necrotizing enterocolitis (3.5 vs. 5.4%; AOR = 0.67, 95% CI: 0.56-0.79), but no difference in mortality odds. After excluding the late outborn admissions, ANZNN outborns had lower odds of SNI (AOR = 0.43, 95% CI: 0.32-0.58) and CLD (AOR = 0.63, 95% CI: 0.49-0.81) than CNN. ANZNN inborn and early admitted outborn infants had lower odds of neonatal morbidities than their CNN counterparts. However, compared to ANZNN, the higher CNN rates of outborns and their late admissions are likely related to the differences in regionalization and referral practices, and may explain differences in outcomes.


Diagnostic and management approaches to pediatric and adolescent varicocele: a survey of pediatric urologists.
To assess current diagnosis and management of adolescent varicoceles by pediatric urologists. Online questionnaires assessing diagnosis and management approaches to pediatric and adolescent varicocele were distributed electronically to a national listing of pediatric urologists. Of 242 pediatric urologists surveyed, 131 (54%) responded to the survey. Only 3% of respondents operate on varicoceles at diagnosis, whereas 14% observe, and 83% base treatment on further indications. Varicocelectomy is most commonly performed for decreased ipsilateral testicular size (96%), testicular pain (79%), and altered semen analysis parameters (39%), with the mean age for varicocelectomy being 12.5 ± 3.1 years. Most physicians use ultrasonography (US) or Doppler US to aid in the diagnosis of varicoceles, and half of physicians would not repair incidental findings of varicocele on US. In an otherwise asymptomatic patient with a varicocele, 28% of physicians would consider varicocelectomy depending on varicocele grade. The most common surgical approaches to varicocelectomy were laparascopic (38%), subinguinal microsurgical (28%), inguinal (14%), and retroperitoneal (13%), and most physicians used loupes for these procedures. The most common complication experienced after adolescent varicocelectomy was hydrocele followed by hematoma, testicular atrophy, chronic pain, paresthesia, and varicocele recurrence or persistence. Only 58% of physicians had follow-up data on their varicocele patients, and 89% did not know whether patients developed infertility. Of patients who developed infertility, 39% had undergone varicocele repair. Significant variation in diagnostic approaches, decision to treat, and operative approaches exists among pediatric urologists, and combined with a dearth of objective data, limits development of management guidelines.


Robust in-fiber spatial interferometer using multicore fiber for vibration detection.
We report the demonstration of a novel in-fiber spatially integrated Michelson interferometer based on weakly coupled multicore fiber (MCF) for vibration sensing. The compact interferometer is constructed by using two separate cores of the MCF, where the fiber end is cleaved in order to generate strong Fresnel reflection, and independent light coupling between the cores of MCF and the single mode fibers (SMFs) is enabled by the fan-in coupler. Vibration gives rise to differential strain variation between cores which results in the modification of phase difference of the interferometer. A narrow linewidth laser is employed, in order to interrogate the phase change induced reflection power variation. Vibration event can be identified and the vibration frequency can be retrieved by processing the measured reflection power with fast Fourier transform (FFT). Broad vibration frequency response range up to 12 kHz (limited by the cut-off frequency of the voltage driver of the vibration source) has been achieved. Performance of the sensor has been shown to be independent of the selection of different core pairs, where the MCF is wound to a piezoelectric transducer (PZT). The proposed in-fiber integrated spatial interferometer does not require any special processing of the fiber (e.g., tapering, splicing, and so forth). The unique sensor structure provides some extraordinary merits, including ultra-compact size, high mechanical strength, high sensitivity and temperature insensitivity.


In-silico identification of phenotype-biased functional modules.
Phenotypes exhibited by microorganisms can be useful for several purposes, e.g., ethanol as an alternate fuel. Sometimes, the target phenotype maybe required in combination with other phenotypes, in order to be useful, for e.g., an industrial process may require that the organism survive in an anaerobic, alcohol rich environment and be able to feed on both hexose and pentose sugars to produce ethanol. This combination of traits may not be available in any existing organism or if they do exist, the mechanisms involved in the phenotype-expression may not be efficient enough to be useful. Thus, it may be required to genetically modify microorganisms. However, before any genetic modification can take place, it is important to identify the underlying cellular subsystems responsible for the expression of the target phenotype. In this paper, we develop a method to identify statistically significant and phenotypically-biased functional modules. The method can compare the organismal network information from hundreds of phenotype expressing and phenotype non-expressing organisms to identify cellular subsystems that are more prone to occur in phenotype-expressing organisms than in phenotype non-expressing organisms. We have provided literature evidence that the phenotype-biased modules identified for phenotypes such as hydrogen production (dark and light fermentation), respiration, gram-positive, gram-negative and motility, are indeed phenotype-related. Thus we have proposed a methodology to identify phenotype-biased cellular subsystems. We have shown the effectiveness of our methodology by applying it to several target phenotypes. The code and all supplemental files can be downloaded from (http://freescience.org/cs/phenotype-biased-biclusters/).


Friendship trumps ethnicity (but not sexual orientation): comfort and discomfort in inter-group interactions.
An experience sampling study tested the degree to which interactions with out-group members evoked negative affect and behavioural inhibition after controlling for level of friendship between partners. When friendship level was statistically controlled, neither White nor Black participants reported feeling more discomfort interacting with ethnic out-group members compared to ethnic in-group members. When partners differed in sexual orientation, friendship level had a less palliating effect. Controlling for friendship, both gay and straight men - but not women - felt more behaviourally inhibited when interacting with someone who differed in sexual orientation, and heterosexual participants of both genders continued to report more negative affect with gay and lesbian interaction partners. However, gay and lesbian participants reported similar levels of negative affect interacting with in-group (homosexual) and out-group (heterosexual) members after friendship level was controlled. Results suggest that much of the discomfort observed in inter-ethnic interactions may be attributable to lower levels of friendship with out-group partners. The discomfort generated by differences in sexual orientation, however, remains a more stubborn barrier to comfortable inter-group interactions.


Whole genomic sequence analysis of Bacillus infantis: defining the genetic blueprint of strain NRRL B-14911, an emerging cardiopathogenic microbe.
We recently reported the identification of Bacillus sp. NRRL B-14911 that induces heart autoimmunity by generating cardiac-reactive T cells through molecular mimicry. This marine bacterium was originally isolated from the Gulf of Mexico, but no associations with human diseases were reported. Therefore, to characterize its biological and medical significance, we sought to determine and analyze the complete genome sequence of Bacillus sp. NRRL B-14911. Based on the phylogenetic analysis of 16S ribosomal RNA (rRNA) genes, sequence analysis of the 16S-23S rDNA intergenic transcribed spacers, phenotypic microarray, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry, we propose that this organism belongs to the species Bacillus infantis, previously shown to be associated with sepsis in a newborn child. Analysis of the complete genome of Bacillus sp. NRRL B-14911 revealed several virulence factors including adhesins, invasins, colonization factors, siderophores and transporters. Likewise, the bacterial genome encodes a wide range of methyl transferases, transporters, enzymatic and biochemical pathways, and insertion sequence elements that are distinct from other closely related bacilli. The complete genome sequence of Bacillus sp. NRRL B-14911 provided in this study may facilitate genetic manipulations to assess gene functions associated with bacterial survival and virulence. Additionally, this bacterium may serve as a useful tool to establish a disease model that permits systematic analysis of autoimmune events in various susceptible rodent strains.


Acceptability of smartphone applications for global positioning system (GPS) and ecological momentary assessment (EMA) research among sexual minority men.
Emerging research is using global positioning system (GPS) and ecological momentary assessment (EMA) methods among sexual minority men (SMM), a population that experiences multiple health disparities. However, we are not aware of any research that has combined these approaches among SMM, highlighting the need for acceptability and feasibility research. The purpose of this study was to examine the acceptability of implementing GPS and EMA research protocols using smartphone applications among SMM as well as related socio-demographic correlates. Data come from a sample of SMM on a popular geosocial-networking app in Paris, France (n = 580). We assessed the acceptability of implementing GPS and EMA research protocols on smartphone apps as well as socio-demographic characteristics (i.e., age, sexual orientation, country of origin, employment status, and relationship status). We examined the anticipated acceptability of GPS and EMA data collection methods as well as socio-demographic correlates of acceptability of GPS and EMA methods. We found that over half (54.1%) of the sample was willing to download a smartphone app for GPS-based research and we found that almost 60% of the participants were willing to download a smartphone app for EMA-based research. In total, 44.0% reported that they were willing to download both GPS and EMA apps. In addition, we found that older participants were less willing to download a smartphone app for EMA research than younger participants aged 18-24 (40-49 years: aPR = 0.40; 95% CI = 0.20, 0.78) and students were more willing to download smartphone apps for both GPS and EMA research (aPR = 1.41; 95% CI = 1.02, 1.95). Results from this study suggest that using smartphone apps to implement GPS and EMA methods among some SMM are acceptable. However, care should be taken as segments of SMM are less likely to be willing to engage in this type of research.


Task-Related Modulations of BOLD Low-Frequency Fluctuations within the Default Mode Network.
Spontaneous low-frequency Blood-Oxygenation Level-Dependent (BOLD) signals acquired during resting state are characterized by spatial patterns of synchronous fluctuations, ultimately leading to the identification of robust brain networks. The resting-state brain networks, including the Default Mode Network (DMN), are demonstrated to persist during sustained task execution, but the exact features of task-related changes of network properties are still not well characterized. In this work we sought to examine in a group of 20 healthy volunteers (age 33 ± 6 years, 8 F/12 M) the relationship between changes of spectral and spatiotemporal features of one prominent resting-state network, namely the DMN, during the continuous execution of a working memory n-back task. We found that task execution impacted on both functional connectivity and amplitude of BOLD fluctuations within large parts of the DMN, but these changes correlated between each other only in a small area of the posterior cingulate. We conclude that combined analysis of multiple parameters related to connectivity, and their changes during the transition from resting state to continuous task execution, can contribute to a better understanding of how brain networks rearrange themselves in response to a task.


Community-based FitSTEPS for life exercise program for persons with cancer: 5-year evaluation.
To determine the effects of a community-based program of exercise on quality of life (QOL) of persons with cancer over time. Participants were referred by their physician to participate in an individualized program of exercise at one of 14 community centers. The Medical Outcomes Survey, Short Form, version 2.0 (SF-36) was used to assess QOL. Individual participants were monitored for 2 years. Data collection took place at baseline, every 3 months months during year 1, and every 6 months during year 2. Enrolled participants (n = 701) had been diagnosed with different cancers and were at all stages; 177 completed data collection for 2 years. One-way analysis of variance (n = 177) supported the positive impact of exercise on QOL over time. Significant subscale scores of the SF-36, including Physical Function (F = 2.13, P ≤ .047), Role Physical (F = 3.78, P ≤ .001), Vitality (F = 5.97, P ≤ .001), Social Function (F = 4.46, P ≤ .001), Role Emotional (F = 2.56, P ≤ .01), Mental Health (F = 2.16, P ≤ .05), and General Health (F = 3.42, P ≤ .01), were sustainable over time. This research introduces the concept of a long-term community-based program of individualized exercise as a feasible and effective intervention to improve QOL for persons with all stages of cancer. Improvements, noted at the 3-month time point, appear to be sustainable for extended time (24 months). Attrition is problematic and needs to be addressed. Results from this study have significance for practice recommendations and health policy reimbursement issues.


Comparison of early warning scores for sepsis early identification and prediction in the general ward setting.
The objective of this study was to directly compare the ability of commonly used early warning scores (EWS) for early identification and prediction of sepsis in the general ward setting. For general ward patients at a large, academic medical center between early-2012 and mid-2018, common EWS and patient acuity scoring systems were calculated from electronic health records (EHR) data for patients that both met and did not meet Sepsis-3 criteria. For identification of sepsis at index time, National Early Warning Score 2 (NEWS 2) had the highest performance (area under the receiver operating characteristic curve: 0.803 [95% confidence interval [CI]: 0.795-0.811], area under the precision recall curves: 0.130 [95% CI: 0.121-0.140]) followed NEWS, Modified Early Warning Score, and quick Sequential Organ Failure Assessment (qSOFA). Using validated thresholds, NEWS 2 also had the highest recall (0.758 [95% CI: 0.736-0.778]) but qSOFA had the highest specificity (0.950 [95% CI: 0.948-0.952]), positive predictive value (0.184 [95% CI: 0.169-0.198]), and F1 score (0.236 [95% CI: 0.220-0.253]). While NEWS 2 outperformed all other compared EWS and patient acuity scores, due to the low prevalence of sepsis, all scoring systems were prone to false positives (low positive predictive value without drastic sacrifices in sensitivity), thus leaving room for more computationally advanced approaches.


The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer.
The presence of visceral metastases is adversely prognostic in men with metastatic castration-resistant prostate cancer (mCRPC), but the prognostic impact of the site of visceral metastasis is unclear. Men with mCRPC in the TAX 327 phase 3 trial receiving docetaxel or mitoxantrone every 3 wk or weekly docetaxel, each with prednisone, were analyzed retrospectively to study the impact of the site of visceral metastasis on overall survival (OS). Patients were assessed for OS by site of metastases: liver with or without other sites, lung with or without bone or lymph nodes, bone plus lymph nodes, bone only, and lymph nodes only. Cox proportional hazards regression, adjusted for treatment and stratification factors, was performed. Men with liver metastases with or without other metastases had shorter median OS (10.0 mo; 95% confidence interval [CI], 5.4-11.5) than men with lung metastases with or without bone or nodal metastases (median OS: 14.4 mo; 95% CI, 11.5-22.4). Men with lymph node-only disease had the best median OS (26.7 mo; 95% CI, 22.3-34.2), followed by men with bone-only metastases (median OS: 19.0 mo; 95% CI, 18.2-20.7) and bone-plus-node disease (median OS: 15.7 mo; 95% CI, 14.4-17.2). Thus, pattern of spread including site of visceral metastasis confers a differential prognostic impact. These data require validation and may inform trial design and therapy.


An economic evaluation of colorectal cancer screening in primary care practice.
Recent colorectal cancer screening studies focus on optimizing adherence. This study evaluated the cost effectiveness of interventions using electronic health records (EHRs); automated mailings; and stepped support increases to improve 2-year colorectal cancer screening adherence. Analyses were based on a parallel-design, randomized trial in which three stepped interventions (EHR-linked mailings ["automated"]; automated plus telephone assistance ["assisted"]; or automated and assisted plus nurse navigation to testing completion or refusal [navigated"]) were compared to usual care. Data were from August 2008 to November 2011, with analyses performed during 2012-2013. Implementation resources were micro-costed; research and registry development costs were excluded. Incremental cost-effectiveness ratios (ICERs) were based on number of participants current for screening per guidelines over 2 years. Bootstrapping examined robustness of results. Intervention delivery cost per participant current for screening ranged from $21 (automated) to $27 (navigated). Inclusion of induced testing costs (e.g., screening colonoscopy) lowered expenditures for automated (ICER=-$159) and assisted (ICER=-$36) relative to usual care over 2 years. Savings arose from increased fecal occult blood testing, substituting for more expensive colonoscopies in usual care. Results were broadly consistent across demographic subgroups. More intensive interventions were consistently likely to be cost effective relative to less intensive interventions, with willingness to pay values of $600-$1,200 for an additional person current for screening yielding ≥80% probability of cost effectiveness. Two-year cost effectiveness of a stepped approach to colorectal cancer screening promotion based on EHR data is indicated, but longer-term cost effectiveness requires further study.


Multi-electron reduction of sulfur and carbon disulfide using binuclear uranium(iii) borohydride complexes.
The first use of a dinuclear UIII/UIII complex in the activation of small molecules is reported. The octadentate Schiff-base pyrrole, anthracene-hinged 'Pacman' ligand LA combines two strongly reducing UIII centres and three borohydride ligands in [M(THF)4][{U(BH4)}2(μ-BH4)(LA)(THF)2] 1-M, (M = Li, Na, K). The two borohydride ligands bound to uranium outside the macrocyclic cleft are readily substituted by aryloxide ligands, resulting in a single, weakly-bound, encapsulated endo group 1 metal borohydride bridging the two UIII centres in [{U(OAr)}2(μ-MBH4)(LA)(THF)2] 2-M (OAr = OC6H2t Bu3-2,4,6, M = Na, K). X-ray crystallographic analysis shows that, for 2-K, in addition to the endo-BH4 ligand the potassium counter-cation is also incorporated into the cleft through η5-interactions with the pyrrolides instead of extraneous donor solvent. As such, 2-K has a significantly higher solubility in non-polar solvents and a wider U-U separation compared to the 'ate' complex 1. The cooperative reducing capability of the two UIII centres now enforced by the large and relatively flexible macrocycle is compared for the two complexes, recognising that the borohydrides can provide additional reducing capability, and that the aryloxide-capped 2-K is constrained to reactions within the cleft. The reaction between 1-Na and S8 affords an insoluble, presumably polymeric paramagnetic complex with bridging uranium sulfides, while that with CS2 results in oxidation of each UIII to the notably high UV oxidation state, forming the unusual trithiocarbonate (CS3)2- as a ligand in [{U(CS3)}2(μ-κ2:κ2-CS3)(LA)] (4). The reaction between 2-K and S8 results in quantitative substitution of the endo-KBH4 by a bridging persulfido (S2)2- group and oxidation of each UIII to UIV, yielding [{U(OAr)}2(μ-κ2:κ2-S2)(LA)] (5). The reaction of 2-K with CS2 affords a thermally unstable adduct which is tentatively assigned as containing a carbon disulfido (CS2)2- ligand bridging the two U centres (6a), but only the mono-bridged sulfido (S)2- complex [{U(OAr)}2(μ-S)(LA)] (6) is isolated. The persulfido complex (5) can also be synthesised from the mono-bridged sulfido complex (6) by the addition of another equivalent of sulfur.


Long-Range Correlations and Memory in the Dynamics of Internet Interdomain Routing.
Data transfer is one of the main functions of the Internet. The Internet consists of a large number of interconnected subnetworks or domains, known as Autonomous Systems (ASes). Due to privacy and other reasons the information about what route to use to reach devices within other ASes is not readily available to any given AS. The Border Gateway Protocol (BGP) is responsible for discovering and distributing this reachability information to all ASes. Since the topology of the Internet is highly dynamic, all ASes constantly exchange and update this reachability information in small chunks, known as routing control packets or BGP updates. In the view of the quick growth of the Internet there are significant concerns with the scalability of the BGP updates and the efficiency of the BGP routing in general. Motivated by these issues we conduct a systematic time series analysis of BGP update rates. We find that BGP update time series are extremely volatile, exhibit long-term correlations and memory effects, similar to seismic time series, or temperature and stock market price fluctuations. The presented statistical characterization of BGP update dynamics could serve as a basis for validation of existing and developing better models of Internet interdomain routing.


Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases.
Challenges in obtaining tissue specimens from patients with brain tumours limit the diagnosis and molecular characterisation and impair the development of better therapeutic approaches. The analysis of cell-free tumour DNA in plasma (considered a liquid biopsy) has facilitated the characterisation of extra-cranial tumours. However, cell-free tumour DNA in plasma is limited in quantity and may not reliably capture the landscape of genomic alterations of brain tumours. Here, we review recent work assessing the relevance of cell-free tumour DNA from cerebrospinal fluid in the characterisation of brain cancer. We focus on the advances in the use of the cerebrospinal fluid as a source of cell-free tumour DNA to facilitate diagnosis, reveal actionable genomic alterations, monitor responses to therapy, and capture tumour heterogeneity in patients with primary brain tumours and brain and leptomeningeal metastases. Profiling cerebrospinal fluid cell-free tumour DNA provides the opportunity to precisely acquire and monitor genomic information in real time and guide precision therapies.


High-Yield Synthesis of Enantiopure 1,2-Amino Alcohols from l-Phenylalanine via Linear and Divergent Enzymatic Cascades.
Enantiomerically pure 1,2-amino alcohols are important compounds due to their biological activities and wide applications in chemical synthesis. In this work, we present two multienzyme pathways for the conversion of l-phenylalanine into either 2-phenylglycinol or phenylethanolamine in the enantiomerically pure form. Both pathways start with the two-pot sequential four-step conversion of l-phenylalanine into styrene via subsequent deamination, decarboxylation, enantioselective epoxidation, and enantioselective hydrolysis. For instance, after optimization, the multienzyme process could convert 507 mg of l-phenylalanine into (R)-1-phenyl-1,2-diol in an overall isolated yield of 75% and >99% ee. The opposite enantiomer, (S)-1-phenyl-1,2-diol, was also obtained in a 70% yield and 98-99% ee following the same approach. At this stage, two divergent routes were developed to convert the chiral diols into either 2-phenylglycinol or phenylethanolamine. The former route consisted of a one-pot concurrent interconnected two-step cascade in which the diol intermediate was oxidized to 2-hydroxy-acetophenone by an alcohol dehydrogenase and then aminated by a transaminase to give enantiomerically pure 2-phenylglycinol. Notably, the addition of an alanine dehydrogenase enabled the connection of the two steps and made the overall process redox-self-sufficient. Thus, (S)-phenylglycinol was isolated in an 81% yield and >99.4% ee starting from ca. 100 mg of the diol intermediate. The second route consisted of a one-pot concurrent two-step cascade in which the oxidative and reductive steps were not interconnected. In this case, the diol intermediate was oxidized to either (S)- or (R)-2-hydroxy-2-phenylacetaldehyde by an alcohol oxidase and then aminated by an amine dehydrogenase to give the enantiomerically pure phenylethanolamine. The addition of a formate dehydrogenase and sodium formate was required to provide the reducing equivalents for the reductive amination step. Thus, (R)-phenylethanolamine was isolated in a 92% yield and >99.9% ee starting from ca. 100 mg of the diol intermediate. In summary, l-phenylalanine was converted into enantiomerically pure 2-phenylglycinol and phenylethanolamine in overall yields of 61% and 69%, respectively. This work exemplifies how linear and divergent enzyme cascades can enable the synthesis of high-value chiral molecules such as amino alcohols from a renewable material such as l-phenylalanine with high atom economy and improved sustainability.


Outcomes, experiences and palliative care in major stroke: a multicentre, mixed-method, longitudinal study.
Case fatality after total anterior circulation stroke is high. Our objective was to describe the experiences and needs of patients and caregivers, and to explore whether, and how, palliative care should be integrated into stroke care. From 3 stroke services in Scotland, we recruited a purposive sample of people with total anterior circulation stroke, and conducted serial, qualitative interviews with them and their informal and professional caregivers at 6 weeks, 6 months and 1 year. Interviews were transcribed for thematic and narrative analysis. The Palliative Care Outcome Scale, EuroQol-5D-5L and Caregiver Strain Index questionnaires were completed after interviews. We also conducted a data linkage study of all patients with anterior circulation stroke admitted to the 3 services over 6 months, which included case fatality, place of death and readmissions. Data linkage (n = 219) showed that 57% of patients with total anterior circulation stroke died within 6 months. The questionnaires recorded that the patients experienced immediate and persistent emotional distress and poor quality of life. We conducted 99 interviews with 34 patients and their informal and professional careers. We identified several major themes. Patients and caregivers faced death or a life not worth living. Those who survived felt grief for a former life. Professionals focused on physical rehabilitation rather than preparation for death or limited recovery. Future planning was challenging. "Palliative care" had connotations of treatment withdrawal and imminent death. Major stroke brings likelihood of death but little preparation. Realistic planning with patients and informal caregivers should be offered, raising the possibility of death or survival with disability. Practising the principles of palliative care is needed, but the term "palliative care" should be avoided or reframed.


Unusual presentation of Takayasu's arteritis as posterior reversible encephalopathy syndrome.
Takayasu's arteritis is a chronic, idiopathic, inflammatory disease primarily affecting aorta and its branches. It mainly affects young females in the age group of 10-30 years. Various atypical presentations of Takayasu's arteritis have been described in children. These atypical presentations can cause delayed diagnosis resulting in increased morbidity and mortality. Posterior reversible encephalopathy syndrome (PRES) is a neuroradiologic condition associated with headache, seizures, altered sensorium, visual disturbances, and characteristic lesions on neuroimaging. We report a child with Takayasu's arteritis who presented a posterior reversible encephalopathy syndrome. He also had associated abdominal tuberculosis for which anti-tuberculous treatment was started. PRES was diagnosed by magnetic resonance imaging with fluid-attenuated inversion recovery sequences. The child was started on nifedipine and propranolol. The child regained his consciousness within 48 h of admission. Prompt treatment of hypertension led to rapid reversal of neurological symptoms. In view of hypertension a computed tomography aortogram was done, which showed features suggestive of high grade (>75%) focal proximal left renal artery stenosis. EULAR (European League Against Rheumatism)/PReS (Paediatric Rheumatology European Society) consensus criteria was used for the diagnosis of Takayasu's arteritis in our patient. Percutaneous transluminal balloon angioplasty of the stenotic left renal artery was performed. Post-angioplasty, nifedipine was gradually omitted and oral propranolol was continued.


Can Professional Environments in Schools Promote Teacher Development? Explaining Heterogeneity in Returns to Teaching Experience.
Although wide variation in teacher effectiveness is well established, much less is known about differences in teacher improvement over time. We document that average returns to teaching experience mask large variation across individual teachers and across groups of teachers working in different schools. We examine the role of school context in explaining these differences using a measure of the professional environment constructed from teachers responses to state-wide surveys. Our analyses show that teachers working in more supportive professional environments improve their effectiveness more over time than teachers working in less supportive contexts. On average, teachers working in schools at the 75th percentile of professional environment ratings improved 38% more than teachers in schools at the 25th percentile after 10 years.


[Stem cells of umbilical blood cord - therapeutic use].
For many years, the transplantation of hematopoietic stem cells has been used to treat some diseases of the hematopoietic system. For a very long time, only bone marrow was used as a source of hematopoietic stem cells for this method of treatment. However, to comply with allogeneic bone marrow transplantation, an antigenically compatible donor is necessary. Transplantations from unrelated donors are associated with increased risk of a graft-versus-host reaction, transplant rejection and, consequently, increased mortality. Many years ago, it was found that umbilical cord blood as well as bone marrow and peripheral blood contains hematopoietic stem cells and mesenchymal cells able to differentiate into different cell types and that the umbilical cord blood can be a source of stem cells for transplantation. Following this discovery, numerous attempts were made for its potential use in the treatment of hematologic diseases, metabolic diseases as well as regenerative medicine. Umbilical cord blood stem cells exhibit intermediate characteristics between embryonic and adult stem cells. They are distinguished from the latter by telomere length, telomerase activity, and lower risk of accumulation of DNA mutations or chromosomal aberrations. The only transplantation limitation appears to be the amount of cord blood collected, which on average is sufficient for transplantation in a 40-50 kg child. Collection of cord blood is a simple, short-lasting treatment, not causing any danger for a newborn or the mother. Umbilical cord blood is obtained during labor, and then frozen and stored at cord blood banks all over the world.


Morbidity and mortality according to age following gastrectomy for gastric cancer.
This study investigated age-related differences in surgically treated patients with gastric cancer, and aimed to identify factors associated with outcome. Data from the Dutch Upper Gastrointestinal Cancer Audit were used. All patients with non-cardia gastric cancer registered between 2011 and 2015 who underwent surgery were selected. Patients were analysed by age group (less than 70 years versus 70 years or more). Multivariable logistic regression was used to assess the influence of clinicopathological factors on morbidity and mortality. A total of 1109 patients younger than 70 years and 1206 aged 70 years or more were included. Patients aged at least 70 years had more perioperative or postoperative complications (41·2 versus 32·5 per cent; P < 0·001) and a higher 30-day mortality rate (7·9 versus 3·2 per cent; P < 0·001) than those younger than 70 years. In multivariable analysis, age 70 years or more was associated with a higher risk of complications (odds ratio 1·29, 95 per cent c.i. 1·05 to 1·59). Postoperative mortality was not significantly associated with age. In the entire cohort, morbidity and mortality were influenced most by ASA grade, neoadjuvant chemotherapy and type of resection. ASA grade, neoadjuvant chemotherapy and type of resection are independent predictors of morbidity and death in patients with gastric cancer, irrespective of age.


Biomimetic engineering of conductive curli protein films.
Bioelectronic systems derived from peptides and proteins are of particular interest for fabricating novel flexible, biocompatible and bioactive devices. These synthetic or recombinant systems designed for mediating electron transport often mimic the proteinaceous appendages of naturally occurring electroactive bacteria. Drawing inspiration from such conductive proteins with a high content of aromatic residues, we have engineered a fibrous protein scaffold, curli fibers produced by Escherichia coli bacteria, to enable long-range electron transport. We report the genetic engineering and characterization of curli fibers containing aromatic residues of different nature, with defined spatial positioning, and with varying content on single self-assembling CsgA curli subunits. Our results demonstrate the impressive versatility of the CsgA protein for genetically engineering protein-based materials with new functions. Through a scalable purification process, we show that macroscopic gels and films can be produced, with engineered thin films exhibiting a greater conductivity compared with wild-type curli films. We anticipate that this engineered conductive scaffold, and our approach that combines computational modeling, protein engineering, and biosynthetic manufacture will contribute to the improvement of a range of useful bio-hybrid technologies.


Prospects for proton therapy in carcinoma of the cervix.
Carcinoma of the cervix remains a serious problem worldwide. The results of radiation therapy varies from institution to institution, with actuarial 5-year survival rates for Stage IIIB disease of between 28 and 60%. The inferior survival figures can be ascribed to poor local control due to inadequate dosage, partly due to the non-use of intracavitary therapy. Results from the literature were reviewed to assess the optimal dose required to sterilize the primary, para-metrial and nodal disease within the pelvis. The aim of this study is to assess whether the target volume could be reduced to allow an increased dose to be delivered. Protons, in view of their physical characteristics, would aid this objective. From CT scans the minimal target volume was determined, and treatment plans for a 200 MeV proton beam were evaluated. It appears that a volume reduction of up to 60% in the target volume may be achieved with proton therapy when compared to the usual target volume achievable with photon therapy, and thus a 20% dose increment may be reasonable. This increased dose may translate to a 40% improvement in the local control rate without an expected increase in complications. An improved local control rate may lead to improved survival. A compatible technique of well-fractionated high dose rate intracavitary therapy (ICT) based on an indwelling intra-uterine tube is offered that will allow up to 10 fractions of ICT with only a single anaesthetic, to be integrated with a similar number of fractions of proton therapy.


Fate and transport of antibiotic residues and antibiotic resistance genes following land application of manure waste.
Antibiotics are used in animal livestock production for therapeutic treatment of disease and at subtherapeutic levels for growth promotion and improvement of feed efficiency. It is estimated that approximately 75% of antibiotics are not absorbed by animals and are excreted in waste. Antibiotic resistance selection occurs among gastrointestinal bacteria, which are also excreted in manure and stored in waste holding systems. Land application of animal waste is a common disposal method used in the United States and is a means for environmental entry of both antibiotics and genetic resistance determinants. Concerns for bacterial resistance gene selection and dissemination of resistance genes have prompted interest about the concentrations and biological activity of drug residues and break-down metabolites, and their fate and transport. Fecal bacteria can survive for weeks to months in the environment, depending on species and temperature, however, genetic elements can persist regardless of cell viability. Phylogenetic analyses indicate antibiotic resistance genes have evolved, although some genes have been maintained in bacteria before the modern antibiotic era. Quantitative measurements of drug residues and levels of resistance genes are needed, in addition to understanding the environmental mechanisms of genetic selection, gene acquisition, and the spatiotemporal dynamics of these resistance genes and their bacterial hosts. This review article discusses an accumulation of findings that address aspects of the fate, transport, and persistence of antibiotics and antibiotic resistance genes in natural environments, with emphasis on mechanisms pertaining to soil environments following land application of animal waste effluent.


Nutrient intake amongst rural adolescent girls of wardha.
To assess the nutrient intake of rural adolescent girls. The cross-sectional study was carried in four adopted villages of the Department of Community Medicine, M.G.I.M.S., Sewagram. A household survey was carried out in the villages. A list of all the adolescent girls in the age group of 10-19 years was prepared by enumeration through house-to-house visit. All adolescent girls were included in the study. A pre-designed and pre-tested questionnaire was used to collect data on socio-demographic variables and anthropometric variables. A 24 h recall method was used to assess nutrient intake. Data generated was entered and analyzed using epi_info 2000. Nutrient intake was compared with ICMR Recommended Dietary Allowances. Nutritional status was assessed by BMI for age. The mean height of the adolescent girls was 142.9 cm. Overall, 57% of the adolescents were thin (BMI for age <5(th) percentile for CDC 2000 reference) and 43% of the adolescents were normal (BMI for age between 5(th) - 85(th) percentile for CDC 2000 reference). The average energy intake, which was 1239.6±176.4 kcal/day, was deficient of RDA by 39%. The average protein intake was 39.5±7 gm/day. It was deficient by 36% and the average iron intake, which was 13.2±2.5 mg/day, was deficient by 48%. The findings reiterate the dietary deficiency among adolescent girls which adversely affects the nutritional status. If the poor nutritional status is not corrected promptly before they become pregnant, it adversely affects the reproductive outcome. If we have to meet out the goals of Reproductive and Child Health Program, intervention strategies to improve the dietary intake of adolescent girls are needed so that their requirements of energy, protein, vitamins and minerals are met.


Uncoupling of cardiac cells by doxyl stearic acids specificity and mechanism of action.
The influence of doxyl stearic acids (DSAs) on gap junctional conductance (gj) between pairs of neonatal rat heart cells was studied. DSAs are spin probes that perturb the membrane at different depths depending on position of the doxyl group on the fatty acyl chain. 16-DSA and 12-DSA rapidly and reversibly reduced gj to unmeasureable levels in a dose- and time-dependent manner. Single channel events observed when gj was low were of the same unitary size as those observed under control conditions. The methyl esters of 16- and 12-DSA, stearic acid itself, and TEMPO, an analogue of the doxyl group that has no fatty acyl chain, had no effect on gj. Protonation of the carboxyl head group (by acidifying the solution) reduced the potency of 16- or 12-DSA. Spontaneous beating activity and action potentials were observed at concentrations of the DSAs 15-20 times that necessary for uncoupling. These results indicate that uncoupling by the DSAs requires the presence of the charged carboxyl group and localized perturbation of the channel at the lipid-channel interface by the doxyl group. Furthermore, they predict that unsaturated free fatty acids, which accumulate during ischemia, may exert their arrhythmogenic effect by reducing gj, and thereby slowing conduction.


Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial.
Treatment with acetyl L-carnitine (ALCAR) has been shown to improve fatigue in patients with chronic fatigue syndrome, but there have been no trials on the effect of ALCAR for treating fatigue in multiple sclerosis (MS). To compare the efficacy of ALCAR with that of amantadine, one of the drugs most widely used to treat MS-related fatigue, 36 MS patients presenting fatigue were enrolled in a randomised, double-blind, crossover study. Patients were treated for 3 months with either amantadine (100 mg twice daily) or ALCAR (1 g twice daily). After a 3-month washout period, they crossed over to the alternative treatment for 3 months. Patients were rated at baseline and every 3 months according to the Fatigue Severity Scale (FSS), the primary endpoint of the study. Secondary outcome variables were: Fatigue Impact Scale (FIS), Beck Depression Inventory (BDI) and Social Experience Checklist (SEC). Six patients withdrew from the study because of adverse reactions (five on amantadine and one on ALCAR). Statistical analysis showed significant effects of ALCAR compared with amantadine for the Fatigue Severity Scale (p = 0.039). There were no significant effects for any of the secondary outcome variables. The results of this study show that ALCAR is better tolerated and more effective than amantadine for the treatment of MS-related fatigue.


Racial differences in factors that influence the willingness to participate in medical research studies.
The relative absence of racial/ethnic minorities among medical research subjects is receiving considerable attention because of recent government mandates for their inclusion in all human subject research. We examined racial differences in the prevalence of sociocultural barriers as a possible explanation for the underrepresentation of African Americans in medical research studies. During 1998-1999, a total of 198 residents of the Detroit Primary Metropolitan Statistical Area (PMSA) participated in a survey that examined impediments to participation in medical research studies. Chi square tests and logistic regression analyses were used to examine the association between race, issues related to trust of medical researchers, and the willingness to participate in medical research studies. Study results indicate that African Americans and whites differ in their willingness to participate in medical research. Racial differences in the willingness to participate in a medical research are primarily due to the lower level of trust of medical research among African Americans. African American respondents were also somewhat less willing to participate if they attribute high importance to the race of the doctor when seeking routine medical care, believed that minorities bear most of the risks of medical research, and if their knowledge of the Tuskegee Study resulted in less trust in medical researchers. These data reiterate the need for medical researchers to build trusting relationships with minority communities. Researchers can begin by acknowledging the previous medical abuse of minority research participants, discussing their specific plans to assure the protection of study participants, and explaining the need for the participation of racial/ethnic minorities including studies that specifically target or that are likely to result in disproportionate representation of racial/ethnic minorities among study participants.


Nonsinusoidal phase modulations for high-power laser performance control: stimulated Brillouin scattering and FM-to-AM conversion.
High-power lasers, such as the Laser MegaJoule (LMJ), have to be phase modulated to avoid stimulated Brillouin scattering (SBS) that may strongly damage optics at the end of the laser chain. Current spectral broadening on LMJ is performed with a sinusoidal phase modulation. This pure sinusoidal phase modulation leads to inhomogeneous spectral power densities (SPD). Thus, for a same SBS power threshold, the sinusoidal phase-modulated spectrum has to be larger than the equivalent ideal SPD with isoenergetic peaks. We present in this paper a technique to generate energy-balanced Dirac peaks spectra thanks to nonsinusoidal phase modulations. Thus, we can build a narrower spectrum with a nonsinusoidal phase modulation that has the same SBS threshold as a sinusoidal phase modulation, and we show that FM-to-AM conversion can be strongly reduced, which is of great interest for LMJ laser performance, with reductions up to 40%.


The Plant Ontology: A Tool for Plant Genomics.
The use of controlled, structured vocabularies (ontologies) has become a critical tool for scientists in the post-genomic era of massive datasets. Adoption and integration of common vocabularies and annotation practices enables cross-species comparative analyses and increases data sharing and reusability. The Plant Ontology (PO; http://www.plantontology.org/ ) describes plant anatomy, morphology, and the stages of plant development, and offers a database of plant genomics annotations associated to the PO terms. The scope of the PO has grown from its original design covering only rice, maize, and Arabidopsis, and now includes terms to describe all green plants from angiosperms to green algae.This chapter introduces how the PO and other related ontologies are constructed and organized, including languages and software used for ontology development, and provides an overview of the key features. Detailed instructions illustrate how to search and browse the PO database and access the associated annotation data. Users are encouraged to provide input on the ontology through the online term request form and contribute datasets for integration in the PO database.


The effect of 15 consecutive days of heat-exercise acclimation on heat shock protein 70.
The purpose of this study was to investigate the alterations in serum heat shock protein (Hsp) 70 levels during a 15-consecutive-day intermittent heat-exercise protocol in a 29-year-old male ultra marathon runner. Heat acclimation, for the purpose of physical activities in elevated ambient temperatures, has numerous physiological benefits including mechanisms such as improved cardiac output, increased plasma volume and a decreased core temperature (T (c)). In addition to the central adaptations, the role of Hsp during heat acclimation has received an increasing amount of attention. The acclimation protocol applied was designed to correspond with the athlete's tapering period for the 2007 Marathon Des Sables. The subject (VO(2)max = 50.7 ml.kg(-1).min(-1), peak power output [PPO] = 376 W) cycled daily for 90 min at a workload corresponding to 50% of VO(2)max in a temperature-controlled room (average WBGT = 31.9 +/- 0.9 degrees C). Venous blood was sampled before and after each session for measurement of serum osmolality and serum Hsp70. In addition, T (c), heart rate (HR) and power output (PO) was measured throughout the 90 min to ensure that heat acclimation was achieved during the 15-day period. The results show that the subject was successfully heat acclimated as seen by the lowered HR at rest and during exercise, decreased resting and exercising T (c) and an increased PO. The heat exercise resulted in an initial increase in Hsp70 concentrations, known as thermotolerance, and the increase in Hsp70 after exercise was inversely correlated to the resting values of Hsp70 (Spearman's rank correlation = -0.81, p < 0.01). Furthermore, the 15-day heat-exercise protocol also increased the basal levels of Hsp70, a response different from that of thermotolerance. This is, as far as we are aware, the first report showing Hsp70 levels during consecutive days of intermittent heat exposure giving rise to heat acclimation. In conclusion, a relatively longer heat acclimation protocol is suggested to obtain maximum benefit of heat acclimation inclusive of both cellular and systemic adaptations.


Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification.
The incidence of acute humoral rejection (AHR) in renal allograft biopsies has been difficult to determine because widely accepted diagnostic criteria have not been established. C4d deposition in peritubular capillaries (PTC) of renal allografts has been proposed as a useful marker for AHR. This study was designed to test the relative value of C4d staining, histology, and serology in the diagnosis of AHR. Of 232 consecutive kidney transplants performed at a single institution from July 1995 to July 1999, all patients (n = 67) who developed acute rejection within the first 3 mo and had a renal biopsy with available frozen tissue at acute rejection onset, as well as posttransplant sera within 30 d of the biopsy, were included in this study. Hematoxylin and eosin and periodic acid-Schiff stained sections were scored for glomerular, vascular, and tubulointerstitial pathology. C4d staining of cryostat sections was done by a sensitive three-layer immunofluorescence method. Donor-specific antibodies (DSA) were detected in posttransplant recipient sera using antihuman-globulin-enhanced T cell and B cell cytotoxicity assays and/or flow cytometry. Widespread C4d staining in PTC was present in 30% (20 of 67) of all acute rejection biopsies. The initial histologic diagnoses of the C4d(+) acute rejection cases were as follows: AHR only, 30%; acute cellular rejection (ACR) and AHR, 45%; ACR (CCTT types 1 or 2) alone, 15%; and acute tubular injury (ATI), 10%. The distinguishing morphologic features in C4d(+) versus C4d(-) acute rejection cases included the following: neutrophils in PTC, 65% versus 9%; neutrophilic glomerulitis, 55% versus 4%; neutrophilic tubulitis, 55% versus 9%; severe ATI, 75% versus 9%; and fibrinoid necrosis in glomeruli, 20% versus 0%, or arteries, 25% versus 0%; all P < 0.01. Mononuclear cell tubulitis was more common in the C4d(-) group (70% versus 100%; P < 0.01). No significant difference between C4d(+) and C4d(-) acute rejection was noted for endarteritis, 25% versus 32%; interstitial inflammation (mean % cortex), 27.2 +/- 27% versus 38 +/- 21%; interstitial hemorrhage, 25% versus 15%; or infarcts, 5% versus 2%. DSA were present in 90% (18 of 20) of the C4d(+) cases compared with 2% (1 of 47) in the C4d(-) acute rejection cases (P < 0.001). The pathology of the C4d(+) but DSA(-) cases was not distinguishable from the C4d(+), DSA(+) cases. The C4d(+) DSA(-) cases may be due to non-HLA antibodies or subthreshold levels of DSA. The sensitivity of C4d staining is 95% in the diagnosis of AHR compared with the donor-specific antibody test (90%). Overall, eight grafts were lost to acute rejection in the first year, of which 75% (6 of 8) had AHR. The 1-yr graft failure rate was 27% (4 of 15) for those AHR cases with only capillary neutrophils versus 40% (2 of 5) for those who also had fibrinoid necrosis of arteries. In comparison, the 1-yr graft failure rates were 3% and 7%, respectively, in ACR 1 (Banff/CCTT type 1) and ACR 2 (Banff/CCTT type 2) C4d(-) groups. A substantial fraction (30%) of biopsy-confirmed acute rejection episodes have a component of AHR as judged by C4d staining; most (90%), but not all, have detectable DSA. AHR may be overlooked in the presence of ACR or ATI by histology or negative serology, arguing for routine C4d staining of renal allograft biopsies. Because AHR has a distinct therapy and prognosis, we propose that it should be classified separately from ACR, with further sub-classification into AHR 1 (neutrophilic capillary involvement) and AHR 2 (arterial fibrinoid necrosis).


The evolutionary puzzle of suicide.
Mechanisms of self-destruction are difficult to reconcile with evolution's first rule of thumb: survive and reproduce. However, evolutionary success ultimately depends on inclusive fitness. The altruistic suicide hypothesis posits that the presence of low reproductive potential and burdensomeness toward kin can increase the inclusive fitness payoff of self-removal. The bargaining hypothesis assumes that suicide attempts could function as an honest signal of need. The payoff may be positive if the suicidal person has a low reproductive potential. The parasite manipulation hypothesis is founded on the rodent-Toxoplasma gondii host-parasite model, in which the parasite induces a "suicidal" feline attraction that allows the parasite to complete its life cycle. Interestingly, latent infection by T. gondii has been shown to cause behavioral alterations in humans, including increased suicide attempts. Finally, we discuss how suicide risk factors can be understood as nonadaptive byproducts of evolved mechanisms that malfunction. Although most of the mechanisms proposed in this article are largely speculative, the hypotheses that we raise accept self-destructive behavior within the framework of evolutionary theory.


A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood-brain barrier.
The neurovascular unit is a complex, interdependent system composed of neurons and neural supporting cells, such as astrocytes, as well as cells that comprise the vascular system including endothelial cells, pericytes, and smooth muscle cells. Each cell type in the neurovascular unit plays an essential role, either in transmitting and processing neural signals or in maintaining the appropriate microenvironmental conditions for healthy neural function. In vitro neurovascular models can be useful for understanding the different roles and functions of the cells composing the neurovascular unit, as well as for assessing the effects on neural function of therapeutic compounds after crossing the endothelial barrier. Here, we report a novel three-dimensional neurovascular microfluidic model consisting of primary rat astrocytes and neurons together with human cerebral microvascular endothelial cells. These three cell types in our neurovascular chip (NVC) show distinct cell type-specific morphological characteristics and functional properties. In particular, morphological and functional analysis of neurons enables quantitative assessment of neuronal responses, while human cerebral endothelial cells form monolayers with size-selective permeability similar to existing in vitro blood-brain barrier (BBB) models.


Prevalence and influence of diagnostic tests for acute respiratory tract infections in primary care.
General practitioners (GPs) use diagnostic tests to help distinguish between viral and bacterial acute respiratory tract infections (ARTI). We investigated the prevalence of these tests, and how tests are associated with diagnosis, treatment and patient satisfaction. As part of a clinical trial, 45 GPs screened 1108 patients with ARTI and collected information on signs and symptoms, diagnostic test results, and subsequent diagnosis and treatment. A sample of 636 patients was interviewed after 7 days and their opinions recorded. We used multivariate mixed models to estimate associations between the use of tests and (1) baseline characteristics, (2) subsequent antibiotic treatment, and (3) patient satisfaction. GPs carried out at least one test in 42% of the 1108 patients screened. The tests used were (percentage of patients): CRP (35%), leucocyte count (17%), rapid Strep A (9%), chest X-ray (5%), sinus X-ray (1%), and throat culture (1%). The use of tests was associated with increasing patient age, education, and degree of discomfort. Antibiotic therapy was strongly associated with a positive test, with odds ratios of 26 (95% CI, 10-67) for a CRP above 50 mg/l; 9.6 (95% CI, 3.6-26) for a leucocyte count above 10,000/microl; and 122 (4.4-3435) for a positive StrepA test. There was no evidence of an association between the use of tests and patient satisfaction. Nearly half of these patients with ARTI received a diagnostic test. Older patients, those with higher education and those in more discomfort were more likely to get tests. A positive test was strongly associated with antibiotic treatment.


Ayahuasca blocks the reinstatement of methylphenidate-induced conditioned place preference in mice: behavioral and brain Fos expression evaluations.
Accumulating evidence suggests that ayahuasca, a hallucinogenic beverage used in traditional Amazonian communities for ritualistic and curative purposes, has been associated with reduced rates of substance use disorders. However, the brain mechanisms underlying the therapeutic effects of ayahuasca have not yet been fully elucidated. The aim of the present study was to investigate the effects of treatment with ayahuasca on the rewarding properties of the psychostimulant methylphenidate. The rewarding properties of ayahuasca (100 mg/kg, orally) and methylphenidate (10 mg/kg, i.p.) were investigated using the conditioned place preference (CPP) model. Furthermore, we evaluated the effects of repeated treatment with ayahuasca on the reinstatement of methylphenidate-induced CPP. Fos expression was evaluated in different limbic structures (cingulate cortex-area 1, prelimbic cortex, infralimbic cortex, orbitofrontal cortex-lateral orbital area, nucleus accumbens core and shell, ventral tegmental area, dorsal striatum, and basolateral amygdala) upon each experimental phase. Both ayahuasca and methylphenidate induced CPP in mice. However, ayahuasca had limited effects on Fos expression, while methylphenidate altered Fos expression in several brain regions associated with the behavioral effects of drugs of abuse. Treatment with ayahuasca after conditioning with methylphenidate blocked the reinstatement of methylphenidate-induced CPP. Those behavioral effects were accompanied by changes in Fos expression patterns, with ayahuasca generally blocking the changes in Fos expression induced by conditioning with methylphenidate and/or reexposure to methylphenidate. Our findings suggest that ayahuasca restored normal brain function in areas associated with the long-term expression of drug wanting/seeking in animals conditioned to methylphenidate.


[The gut microbiome is important in chronic liver disease].
There is increasing evidence of gut dysbiosis being a significant factor in the development and progression of important chronic liver diseases including non-alcoholic steatohepatitis (NASH), alcoholic liver disease, primary sclerosing cholangitis and cirrhosis. Dysbiotic microbiota and their toxic metabolites translocate across the gut epithelium via the portal vein and cause damage to the liver. In NASH, alcohol-producing gut bacteria may be critical for its development. Therapeutic measures to normalise the gut microbiota with diet, probiotics or transplantation of normal microbiota seem to have a beneficial effect.


Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 trial.
Patients with Parkinson's disease chronically treated with levodopa commonly have delayed or unpredictable onset of its benefits after oral intake. In this study, we assessed the safety and efficacy of CVT-301, a self-administered levodopa oral inhalation powder, for the treatment of patients with Parkinson's disease during off periods. In this randomised, double-blind, placebo-controlled, phase 3 trial, patients were recruited at 65 sites in Canada, Poland, Spain, and the USA. Eligible participants were patients with Parkinson's disease aged 30-85 years, who had daily off periods of 2 h or longer and showed an improvement of 25% or greater in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score from off to on state after use of an oral levodopa plus a dopa-decarboxylase inhibitor combination. Patients were assigned (1:1:1) with a computer-generated randomisation code, in fixed blocks of six, to either CVT-301 60 mg, CVT-301 84 mg, or placebo. Spirometry results and modified Hoehn and Yahr disease stage at screening were used for stratification of treatment groups. Patients, the sponsor, and site personnel were masked to treatment assignment. Each study dose consisted of two capsules administered with an inhaler. Patients were instructed to use the study drug as needed for off periods, and could self-administer up to five doses per day. The primary endpoint was the change in UPDRS motor score from predose to 30 min postdose, assessed at week 12 during an in-clinic off period, in the CVT-301 84 mg group compared with the placebo group. Analysis was by intention to treat. Safety was assessed in all patients who received at least one dose of experimental treatment. This trial is registered with ClinicalTrials.gov, number NCT02240030. Between Dec 4, 2014, and Aug 26, 2016, 351 patients were enrolled and randomly assigned to receive CVT-301 60 mg (115 patients), CVT-301 84 mg (120 patients), or placebo (116 patients). Of these, 339 received the assigned study treatment (CVT-301 60 mg, n=113; CVT-301 84 mg, n=114; placebo, n=112) and 290 completed the study (CVT-301 60 mg, n=96; CVT-301 84 mg, n=97; placebo, n=97). The least-squares mean difference in UPDRS motor score change from predose to 30 min postdose was -5·91 (SE 1·50, 95% CI -8·86 to -2·96) for the placebo group and -9·83 (1·51; -12·79 to -6·87) for the CVT-301 84 mg group (between-group difference -3·92 [-6·84 to -1·00]; p=0·0088). Treatments were safe and well tolerated. Severe adverse events were reported by 2 (2%) of 112 patients in the placebo group, 7 (6%) of 113 in the CVT-301 60 mg group, and 5 (4%) of 114 in the CVT-301 84 mg group, with no severe adverse event occurring in more than one patient in any treatment group. 11 (3%) of 339 patients had 19 serious adverse events (three [3%] of 112 patients in placebo, six [5%] of 113 in CVT-301 60 mg, and two [2%] of 114 in CVT-301 84 mg). Of these, hypotension and atrial fibrillation were assessed by investigators to be possibly related to the study drug. CVT-301 can improve UPDRS motor scores of patients with Parkinson's disease during in-clinic off periods, with few severe or serious adverse events. The long-term safety and efficacy of CVT-301 need to be investigated in future studies. Acorda Therapeutics.


Health risk assessment procedures for endocrine disrupting compounds within different regulatory frameworks in the European Union.
In this study we have investigated how different regulatory frameworks in Europe cope with identification and risk assessment of endocrine disrupting compounds (EDCs). Four regulatory groups were selected for the investigation: existing industrial chemicals, environmental pollutants in food, pharmaceuticals and plant protection products. The legislation and guidelines for each of these groups were scrutinized and compared in detail. In addition, one recent European risk assessment document each for three identified EDCs, i.e. bisphenol A, dioxins and vinclozolin, were reviewed and compared. We found that the requirements for toxicity testing and availability and scope of risk assessment guidelines varied between the four regulatory frameworks. Also, the general principles regarding the human relevance of the mode of action identified in animal tests differed in the different risk assessments. In conclusion, there is little conformity in the risk assessment processes between these groups of chemicals. Because of the complicated nature of endocrine disruption, test methods, principles and criteria for data interpretation traditionally used might not be directly applicable to EDCs and further development of a transparent and reliable risk assessment process for this type of substances is needed.


Ascorbic acid status and subsequent diastolic and systolic blood pressure.
Free radicals and oxidation are involved in several aspects of blood pressure physiology. We investigated the relationship between blood pressure and antioxidants, including plasma ascorbic acid (AscA), in a 17-week controlled-diet study. Study subjects included 68 men aged 30 to 59 years who had a mean diastolic blood pressure of 73.4 mm Hg and a mean systolic blood pressure of 122.2 mm Hg. One month of vitamin C depletion was followed by 1-month repletion with 117 mg/d, repeated twice. All food and drink were provided in the study. Subjects did not smoke or drink alcohol, all consumed fruits and vegetables, and body weight was maintained. Plasma was assayed periodically for AscA, alpha-tocopherol, carotenoids, and lipids. Plasma AscA was inversely related to diastolic blood pressure 1 month later (correlation -0.48, P:<0.0001). Persons in the bottom fourth of the plasma AscA distribution had >7 mm Hg higher diastolic blood pressure than did those in the top fourth of the plasma AscA distribution. Multivariate analysis with control for age, body mass index, other plasma antioxidants, and dietary energy, calcium, fiber, sodium, and potassium did not reduce the plasma AscA effect. One fourth of the variance in diastolic blood pressure was accounted for by plasma AscA alone. Plasma AscA was also significantly associated with systolic blood pressure in logistic regression. Vitamin C may be an important component of the effectiveness of fruits and vegetables in the reduction in blood pressure, and tissue AscA levels may be important in the maintenance of low blood pressure. Long-term intervention studies are warranted.


A multi-institutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes.
To investigate a multi-institutional outbreak of highly resistant tuberculosis and evaluate patient outcome. Epidemiologic investigation of every tuberculosis case reported in New York City. Patients cared for at all public and nonpublic institutions from January 1, 1990, to August 1, 1993 (43 months). We reviewed medical and public health records and conducted clinical, epidemiologic, drug susceptibility, and restriction fragment length polymorphism (RFLP) analyses. A case was defined as tuberculosis in a patient with an isolate resistant to isoniazid, rifampin, ethambutol hydrochloride, and streptomycin (and rifabutin, if sensitivity testing included it), and, if RFLP testing was done, a pattern identical to or closely related to strain W. Patient survival and the conversion of sputum cultures from positive to negative. Of the 357 patients who met the case definition, 267 had identical or nearly identical RFLP patterns; isolates from the other 90 patients were not available for RFLP testing. Among these 267 patients, 86% were human immunodeficiency virus (HIV)-infected, 7% were HIV-negative, and 7% had unknown HIV status. All-cause mortality was 83%. Epidemiologic linkages were identified for 70% of patients, of whom 96% likely had nosocomially acquired disease at 11 hospitals. Survival was prolonged among patients who received medications to which their isolate was susceptible, especially capreomycin sulfate, and among patients with a CD4+ T-lymphocyte count greater than 0.200 x 10(9)/L (200/microL). Treatment with isoniazid and a fluoroquinolone antibiotic was also independently associated with longer survival. This outbreak accounted for nearly one fourth of the cases of multidrug-resistant tuberculosis in the United States during a 43-month period. Most patients had nosocomially acquired disease, were infected with HIV, and unless promptly and appropriately treated, died rapidly. With appropriate directly observed treatment, especially combinations including an injectable medication, even severely immunocompromised patients had culture conversion and prolonged, tuberculosis-free survival.


Antibiotic use in Kenyan public hospitals: Prevalence, appropriateness and link to guideline availability.
To examine prescription patterns and explore to what extent guidelines are available and how they might influence treatment appropriateness among hospitalised patients in Kenyan hospitals. Data on antimicrobial usage were collected from hospitalised patients across 14 Kenyan public hospitals. For each prescription, appropriateness of treatment was defined using available local and international treatment guidelines and through consensus with local medical specialists. Association between appropriate treatment, guideline availability and other possible explanatory factors was explored using univariate and multiple regression analysis. There were 1675 (46.7%) of the 3590 hospitalised patients on antimicrobials with 3145(94%) of the 3363 antimicrobial prescriptions being antibiotics. Two patients (0.1%), had treatment based on available antibiotic susceptibility tests. Appropriate treatment was assessed in 1502 patients who had a single diagnosis. Of these, 805 (53.6%) received appropriate treatment. Physical availability of treatment guidelines increased the odds of receiving appropriate treatment Odds Ratio 6.44[95% CI 4.81-8.64]. Appropriate antibiotic prescription remains a challenge in Kenyan public hospitals. This may be improved by the availability of context-specific, up-to-date, and readily accessible treatment guidelines across all the departments, and by providing better diagnostic support.