Work ability in midlife as a predictor of mortality and disability in later life: a 28-year prospective follow-up study.
Poor work ability correlates with increased morbidity and early retirement from the workforce, but the association in old age is not known. We investigated work ability in midlife among white-collar and blue-collar employees as a predictor of mortality and disability 28 years later. A total of 5971 occupationally active people aged 44-58 years participated in the Finnish Longitudinal Study of Municipal Employees (FLAME) in 1981. Perceived work ability relative to lifetime best was categorized as excellent, moderate or poor. In 2009, the ability to perform activities of daily living was assessed among 2879 respondents (71.0% of the survivors). Mortality data were available up to July 2009. At the 28-year follow-up, 1918 of the 5971 participants had died and 1403 had some form of disability. Rates of death per 1000 person-years among white-collar men were 7.7 for those with excellent work ability, 14.7 for those with moderate work ability and 23.5 for those with poor work ability. Among blue-collar men, the corresponding rates were 15.5, 20.2 and 25.3. In women, rates ranged between 6.3 and 10.6 per 1000 person-years. The age-adjusted hazard ratios (HRs) for mortality were two to three times higher among blue-collar male employees with lower work ability than among white-collar male employees with excellent work ability in midlife (i.e., the reference group). The odds of death or disability at follow-up compared with white-collar workers with excellent work ability were highest among blue-collar employees with poor work ability in midlife (odds ratio [OR] 4.56, 95% confidence interval [CI] 2.82-7.37 for men; OR 3.37, 95% CI 2.28-4.98 for women). Among the survivors, similar but slightly lower risks of disability 28 years later were found. Perceived poor work ability in midlife was associated with accelerated deterioration in health and functioning and remains evident after 28 years of follow-up.


18FDG-PET-CT improves specificity of preoperative lymph-node staging in patients with intestinal but not diffuse-type esophagogastric adenocarcinoma.
The accuracy of preoperative lymph-node staging in patients with adenocarcinoma of the esophagogastric junction (AEG) or gastric cancer (GC) is low. The aim of this study was to assess the accuracy of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT) for lymph-node staging in patients with AEG or GC, with or without neoadjuvant treatment. 221 consecutive patients with GC (n = 88) or AEG (n = 133) were evaluated. Initial staging included endoscopic ultrasound (EUS), multidetector spiral CT (MDCT) and PET-CT. PET-CT was performed for restaging in patients after neoadjuvant treatment (n = 94). Systematic lymphadenectomy was routinely performed with histopathological assessment of individual mediastinal and abdominal lymph-node stations. Preoperative staging from EUS, MDCT, and PET-CT was correlated with histopathological results. PET-CT showed a high specificity (91%) and positive predictive value (89%) for the preoperative detection of lymph-node metastases. In comparison, EUS was more sensitive (73% versus 50%, P < 0.01) but less specific (60%, P < 0.01). In patients with intestinal/mixed-type tumors, PET-CT improved the detection of extra-regional lymph-node metastases (P = 0.01) and distant metastases (P = 0.01) compared to CT alone. In contrast, lymph-node assessment by PET/CT after neoadjuvant treatment (32%, P < 0.01) and in diffuse-type cancers (24%, P < 0.01) is futile because of low sensitivities. PET-CT does not improve the overall accuracy of N staging, but does improve specificity compared to EUS and MDCT in AEG and GC. We do not recommend routine PET-CT for the initial staging in patients with diffuse-type cancer or for restaging of lymph nodes after neoadjuvant treatment.


Evolution of virulence in malaria.
The pathogenesis of severe malarial disease is not yet fully understood. It is clear that host immunopathology plays a central role, and a recent paper in BMC Evolutionary Biology suggests that the ability of the parasite to stimulate interleukin-10 production is a major factor and speculates on its impact on the coevolution of host and parasite.


A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes.
Using a polymerase chain reaction strategy we identified a serine proteinase inhibitor (serpin) in human bone marrow that is related to the cellular serpin proteinase inhibitor 6 (PI-6) and the viral serpin cytokine response modifier A (CrmA). This serpin, proteinase inhibitor 9 (PI-9), has an unusual reactive center P1(Glu)-P1'(Cys), which suggests that it inhibits serine proteinases that cleave after acidic residues. The only known serine proteinase with this specificity is granzyme B, a granule cytotoxin produced by cytotoxic lymphocytes. To test the interaction of PI-9 with granzyme B we prepared recombinant hexa-histidine tagged PI-9 in a yeast expression system. Addition of the recombinant protein to native granzyme B resulted in an SDS-resistant complex typical of serpin-serine proteinase interactions. Further analysis showed that complex formation followed bimolecular kinetics with a second order rate constant of 1.7 +/- 0.3 x 10(6) M-1 s-1, which is in the range for a physiologically significant serpin-proteinase interaction. Recombinant PI-9 also completely abrogated granzyme B and perforin-mediated cytotoxicity in vitro. Examination of PI-9 mRNA distribution demonstrated that it is expressed in immune tissue, primarily in lymphocytes. The highest levels of PI-9 mRNA and protein were observed in natural killer cell leukemia cell lines and in interleukin-2 stimulated peripheral blood mononuclear cells, which also produce granzyme B. Like PI-6, PI-9 was shown to be a cytosolic protein that is not secreted. Fractionation of natural killer cells and stimulated peripheral blood mononuclear cells demonstrated that PI-9 is in a separate subcellular compartment to granzyme B. These results suggest that PI-9 serves to inactivate misdirected granzyme B following cytotoxic cell degranulation. This may explain why cytotoxic cells are not damaged by their own granzyme B during destruction of abnormal cells.


Redundant control of Ultrabithorax by zeste involves functional levels of zeste protein binding at the Ultrabithorax promoter.
Many biological processes appear to be controlled by functionally redundant genes or pathways, but it has proven difficult to understand the nature of this redundancy. Here, we have analyzed a redundant regulatory interaction between the Drosophila transcription factor zeste and the homeotic gene Ultrabithorax. Mutations in zeste do not affect the cis-regulation of the endogenous Ultrabithorax gene; however, the expression of small Ultrabithorax promoter constructs is strongly dependent upon zeste. We show that this difference is due to redundant cis-regulatory elements in the Ultrabithorax gene, which presumably contain binding sites for factors that share the function of zeste. We also provide evidence suggesting that zeste and the gene encoding the GAGA factor have an overlapping function in regulating Ultrabithorax. Furthermore, we show that the zeste protein is bound at equal levels in vivo to a Ultrabithorax promoter construct, which zeste strongly activates, and to the identical promoter region in the endogenous Ultrabithorax gene, which zeste redundantly regulates. These results suggest that zeste is significantly active in the wild-type animal and not simply a factor that is induced as a back-up when other activators fail.


BBMRI-ERIC as a resource for pharmaceutical and life science industries: the development of biobank-based Expert Centres.
Biological resources (cells, tissues, bodily fluids or biomolecules) are considered essential raw material for the advancement of health-related biotechnology, for research and development in life sciences, and for ultimately improving human health. Stored in local biobanks, access to the human biological samples and related medical data for transnational research is often limited, in particular for the international life science industry. The recently established pan-European Biobanking and BioMolecular resources Research Infrastructure-European Research Infrastructure Consortium (BBMRI-ERIC) aims to improve accessibility and interoperability between academic and industrial parties to benefit personalized medicine, disease prevention to promote development of new diagnostics, devices and medicines. BBMRI-ERIC is developing the concept of Expert Centre as public-private partnerships in the precompetitive, not-for-profit field to provide a new structure to perform research projects that would face difficulties under currently established models of academic-industry collaboration. By definition, Expert Centres are key intermediaries between public and private sectors performing the analysis of biological samples under internationally standardized conditions. This paper presents the rationale behind the Expert Centres and illustrates the novel concept with model examples.


Serial analysis of gene expression in the corneal endothelium of Fuchs' dystrophy.
To compare the gene expression profiles of normal human corneal endothelium with Fuchs' corneal endothelium, by using serial analysis of gene expression (SAGE). Three pairs of normal human corneas were obtained from eye banks. Thirteen bisected Fuchs' corneal buttons were processed at the time of corneal transplantation. The endothelia of normal and Fuchs'-affected corneas were stripped, and total RNA was isolated. Serial analysis of gene expression (SAGE) was performed to identify and quantify gene transcripts. Genes over- and underexpressed by Fuchs' endothelium were limited to P < 0.01 by the method of Audic and Claverie. A total of 19,136 tags were identified with 9,530 from normal and 9,606 from Fuchs' endothelium. The expression of 18 transcripts was upregulated, and 36 transcripts were downregulated in Fuchs' endothelium compared with normal tissue. Upregulated transcripts included serum amyloid A1 and A2, metallothionein, and apolipoprotein D. Of the downregulated transcripts, 26 matched known genes, 3 matched expressed sequence tags (ESTs), and 7 were unknown to current databases. One downregulated transcript involved a newly reported bicarbonate transporter. Decreased transcripts related to antioxidants and proteins conferring protection against toxic stress were noted in Fuchs' versus normal endothelium including nuclear ferritin, glutathione S-transferase-pi, and heat shock 70-kDa protein. Nine different SAGE tags matching mitochondrial sequences accounted for 25% of the ESTs that were decreased in Fuchs' endothelium. SAGE analysis comparing normal to Fuchs' endothelium demonstrates diminished expression of mitochondrial, pump function, and antiapoptotic cell defense genes.


Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.
Genome-wide association studies (GWASs) in European populations have identified more than 100 schizophrenia-associated loci. A schizophrenia GWAS in a unique Indian population offers novel findings. To discover and functionally evaluate genetic loci for schizophrenia in a GWAS of a unique Indian population. This GWAS included a sample of affected individuals, family members, and unrelated cases and controls. Three thousand ninety-two individuals were recruited and diagnostically ascertained via medical records, hospitals, clinics, and clinical networks in Chennai and surrounding regions. Affected participants fulfilled DSM-IV diagnostic criteria for schizophrenia. Unrelated control participants had no personal or family history of psychotic disorder. Recruitment, genotyping, and analysis occurred in consecutive phases beginning January 1, 2001. Recruitment was completed on February 28, 2018, and genotyping and analysis are ongoing. Associations of single-nucleotide polymorphisms and gene expression with schizophrenia. The study population included 1321 participants with schizophrenia, 885 family controls, and 886 unrelated controls. Among participants with schizophrenia, mean (SD) age was 39.1 (11.4) years, and 52.7% were male. This sample demonstrated uniform ethnicity, a degree of inbreeding, and negligible rates of substance abuse. A novel genome-wide significant association was observed between schizophrenia and a chromosome 8q24.3 locus (rs10866912, allele A; odds ratio [OR], 1.27 [95% CI, 1.17-1.38]; P = 4.35 × 10-8) that attracted support in the schizophrenia Psychiatric Genomics Consortium 2 data (rs10866912, allele A; OR, 1.04 [95% CI, 1.02-1.06]; P = 7.56 × 10-4). This locus has undergone natural selection, with the risk allele A declining in frequency from India (approximately 72%) to Europe (approximately 43%). rs10866912 directly modifies the abundance of the nicotinate phosphoribosyltransferase gene (NAPRT1) transcript in brain cortex (normalized effect size, 0.79; 95% CI, 0.6-1.0; P = 5.8 × 10-13). NAPRT1 encodes a key enzyme for niacin metabolism. In Indian lymphoblastoid cell lines, (risk) allele A of rs10866912 was associated with NAPRT1 downregulation (AA: 0.74, n = 21; CC: 1.56, n = 17; P = .004). Preliminary zebrafish data further suggest that partial loss of function of NAPRT1 leads to abnormal brain development. Bioinformatic analyses and cellular and zebrafish gene expression studies implicate NAPRT1 as a novel susceptibility gene. Given this gene's role in niacin metabolism and the evidence for niacin deficiency provoking schizophrenialike symptoms in neuropsychiatric diseases such as pellagra and Hartnup disease, these results suggest that the rs10866912 genotype and niacin status may have implications for schizophrenia susceptibility and treatment.


Sudden unexpected death in epilepsy. A nationwide population-based study.
The incidence of sudden unexpected death in epilepsy (SUDEP) varies between studies. We determined the incidence of SUDEP in the entire Icelandic population during a 20-year period. All individuals in Iceland with epilepsy who died unexpectedly from January 1, 1991 through December 31, 2010 were included. Case ascertainment was based on autopsies, reimbursement for antiepileptic drugs, death certificates, information from neurologists, and medical records. The incidence of SUDEP was calculated according to the total number of residents in Iceland during the study period and an estimated epilepsy population of Iceland. We identified 37 individuals (26 men, 11 women) with definite SUDEP (n = 29), definite SUDEP plus (n = 4), and probable SUDEP (n = 4). Incidence of SUDEP was 0.6 per 100 000 person-years for the general population, and higher among men. The estimated incidence of SUDEP in the epilepsy population was 1.3 per 1000 person-years. SUDEP accounted for 0.1% of all deaths in Iceland during the study period. SUDEP is an important cause of death in working-age people. This study provides the incidence of SUDEP in an unselected population of an entire country. The SUDEP incidence in the epilepsy population is comparable to that of previous studies.


Android Adiposity and Lack of Moderate and Vigorous Physical Activity Are Associated With Insulin Resistance and Diabetes in Aging Adults.
Physical inactivity and excess adiposity are thought to be interdependent "lifestyle" factors and thus, many older adults are at exaggerated risk for preventable diseases. The purposes of this study were to determine the degree of discordance between body mass index (BMI) and adiposity among adults older than 50 years, and to determine the extent to which direct measures of adiposity, and objectively measured sedentary behavior (SB) and physical activity (PA) are associated with insulin resistance (IR) or diabetes. A population representative sample of 2,816 individuals, aged 50-85 years, was included from the combined 2003-2006 National Health and Nutrition Examination Survey (NHANES) datasets. BMI, percent body fat (%BF) and android adiposity as determined by dual energy x-ray absorptiometry, objectively measured SB and PA, established markers of cardiometabolic risk, IR, and type 2 diabetes were analyzed. Approximately 50% of the men and 64% of the women who were normal weight according to BMI had excessive %BF. Adults with the least SB and greatest moderate and vigorous PA exhibited the healthiest cardiometabolic profiles, whereas adults with the greatest SB and lowest activity had highest risk. Greater android adiposity stores were robustly associated with IR or diabetes in all adults, independent of SB and activity. Among men, less moderate-to-vigorous PA was associated with IR or diabetes; whereas among women, less lifestyle moderate activity was associated with IR or diabetes. Android adiposity and low moderate and vigorous PA are the strongest predictors of IR or diabetes among aging adults.


Antioxidant administration attenuates mechanical ventilation-induced rat diaphragm muscle atrophy independent of protein kinase B (PKB Akt) signalling.
Oxidative stress promotes controlled mechanical ventilation (MV)-induced diaphragmatic atrophy. Nonetheless, the signalling pathways responsible for oxidative stress-induced muscle atrophy remain unknown. We tested the hypothesis that oxidative stress down-regulates insulin-like growth factor-1-phosphotidylinositol 3-kinase-protein kinase B serine threonine kinase (IGF-1-PI3K-Akt) signalling and activates the forkhead box O (FoxO) class of transcription factors in diaphragm fibres during MV-induced diaphragm inactivity. Sprague-Dawley rats were randomly assigned to one of five experimental groups: (1) control (Con), (2) 6 h of MV, (3) 6 h of MV with infusion of the antioxidant Trolox, (4) 18 h of MV, (5) 18 h of MV with Trolox. Following 6 h and 18 h of MV, diaphragmatic Akt activation decreased in parallel with increased nuclear localization and transcriptional activation of FoxO1 and decreased nuclear localization of FoxO3 and FoxO4, culminating in increased expression of the muscle-specific ubiquitin ligases, muscle atrophy factor (MAFbx) and muscle ring finger-1 (MuRF-1). Interestingly, following 18 h of MV, antioxidant administration was associated with attenuation of MV-induced atrophy in type I, type IIa and type IIb/IIx myofibres. Collectively, these data reveal that the antioxidant Trolox attenuates MV-induced diaphragmatic atrophy independent of alterations in Akt regulation of FoxO transcription factors and expression of MAFbx or MuRF-1. Further, these results also indicate that differential regulation of diaphragmatic IGF-1-PI3K-Akt signalling exists during the early and late stages of MV.


Crossover from Classical to Quantum Kibble-Zurek Scaling.
The Kibble-Zurek (KZ) hypothesis identifies the relevant time scales in out-of-equilibrium dynamics of critical systems employing concepts valid at equilibrium: It predicts the scaling of the defect formation immediately after quenches across classical and quantum phase transitions as a function of the quench speed. Here, we study the crossover between the scaling dictated by a slow quench, which is ruled by the critical properties of the quantum phase transition, and the excitations due to a faster quench, where the dynamics is often well described by the classical model. We estimate the value of the quench rate that separates the two regimes and support our argument using numerical simulations of the out-of-equilibrium many-body dynamics. For the specific case of a ϕ^{4} model we demonstrate that the two regimes exhibit two different power-law scalings, which are in agreement with the KZ theory when applied to the quantum and classical cases. This result contributes to extending the prediction power of the Kibble-Zurek mechanism and to providing insight into recent experimental observations in systems of cold atoms and ions.


[Usefulness of C-reactive protein for the diagnosis of bacterial infections in children. A review].
Although C-Reactive protein (CRP) was described more than 70 years ago and it still is commonly used in practice, studies exploring its usefulness persist while some propose its replacement by other inflammatory acute-phase-mediators. The aim of this clinical review is to answer the question if CRP measurement warrant clinical decisions for febrile children because it discriminates between bacterial from non bacterial etiologies. We made a systematic search by means of MEDLINE, SciELO and LILACS with the following MESH terms: "C-reactive protein", "bacterial", "infection", "children", "diagnosis" or "detection", besides the Haynes selector for articles on diagnosis, between 1950 and 2004. Selection data extraction and critical appraisal were independently made by the two authors, following standard criteria. We selected 7 primary articles, 3 clinical reviews and two randomized clinical trials. There was no disagreement between reviewers. Only one of the clinical reviews followed standard guidelines; two reviews concluded that no isolated CRP values would warrant to make decisions on starting or withholding antimicrobial therapy in febrile children. All primary articles showed methodological flaws in basic validity criteria. Both randomized clinical trials showed that CRP results did not change either doctor's decisions about antimicrobial prescriptions nor the studied patients' prognosis. We did not find evidences that could warrant the use of CRP for the defined problem in Pediatrics. Main problems affecting validity of studies on CRP as diagnostic resource are the lack of laboratory methods uniformity--including the gold standard make up--the heterogeneity of cut off points, clinical spectrum inappropriateness of study groups as well as the resulting diversity of the fixed indexes values. Moreover, no validation of this test in children population has been made so far.


Identification of transcription factors perturbed by the synthesis of high levels of a foreign protein in yeast Saccharomyces cerevisiae.
For years, micro-organisms have been used for the industrial production of heterologous proteins. However, the production of foreign proteins causes undesirable problems for the host organism. The analysis of this phenomenon is desirable to improve the production of relevant proteins and so far no analysis of the effects of recombinant protein production on genetic regulation has been reported. In this work, network component analysis (NCA) was used to deduce transcription factor activities (TFAs) in a recombinant strain of Saccharomyces cerevisiae that produces a foreign protein, human superoxide dismutase (SOD) and compared the behavior of this yeast strain to the wild-type host to see the effect of the expression of the protein at the regulatory level. NCA identified a network of 817 genes regulated by 87 transcription factors (TFs). From the identified TFs, 45 show significant change in their activities at least in one of the three phases of diauxic growth (glucose, ethanol, and early stationary phase). The major effect of the expression of SOD on the activity of the TFs was observed in the early stationary phase with 34 of them perturbed in comparison with 12 on glucose and 20 on ethanol. These TFs cover the main functions of the cell, such as developmental processes, cell cycle, metabolism, and environmental response. Five of them are present in all growth phases: Hal9, Mac1, Oaf3, Stp1, and Urc2. In addition, TFA analysis corroborates the hypothesis that copper plays a key role as a stress factor and suggests that YJL206C, a TF with unknown function, could be related to Ace2, a cell cycle regulator.


Using paired serology and surveillance data to quantify dengue transmission and control during a large outbreak in Fiji.
Dengue is a major health burden, but it can be challenging to examine transmission and evaluate control measures because outbreaks depend on multiple factors, including human population structure, prior immunity and climate. We combined population-representative paired sera collected before and after the 2013/14 dengue-3 outbreak in Fiji with surveillance data to determine how such factors influence transmission and control in island settings. Our results suggested the 10-19 year-old age group had the highest risk of infection, but we did not find strong evidence that other demographic or environmental risk factors were linked to seroconversion. A mathematical model jointly fitted to surveillance and serological data suggested that herd immunity and seasonally varying transmission could not explain observed dynamics. However, the model showed evidence of an additional reduction in transmission coinciding with a vector clean-up campaign, which may have contributed to the decline in cases in the later stages of the outbreak.


Drug-induced liver injury.
Drug hepatoxicity can be nonidiosyncratic (predictable), as in the case of acetaminophen, or idiosyncratic (unpredictable). This review article focuses primarily on idiosyncratic drug-induced liver injury (DILI). New epidemiologic data suggest that approximately 20 new cases of DILI per 100,000 persons occur each year. Idiosyncratic DILI accounts for 11% of the cases of acute liver failure in the United States. Risk factors for DILI include medication dose, drug lipophilicity, and extent of hepatic metabolism. There is mixed evidence to support the role of host factors such as age, sex, and chronic liver disease in the development of DILI. For specific drugs, a genetic predisposition appears to be a risk factor for DILI. Suspected cases of idiosyncratic DILI should be categorized as hepatitic, cholestatic, or mixed on the basis of the degree/ratio of abnormalities in the alanine aminotransferase and alkaline phosphatase. A careful evaluation for other causes of liver disease should be performed, though a liver biopsy is rarely needed. There is evidence that some patients with DILI may actually have hepatitis E and this diagnosis should be considered. Amoxicillin/clavulanate isoniazid, and nonsteroidal anti-inflammatory drugs are among the most common causes of DILI. Drug discontinuation or dechallenge should lead to an improvement in liver biochemistries in most patients, though a bilirubin value of more than 3 g/dL is associated with mortality of at least 10%. New biomarkers for DILI using proteomics and micro RNA appear promising but require further study. New studies on drugs with potential for causing DILI are reviewed herein, including tumor necrosis factor-alpha antagonists, fluoroquinolones, tyrosine kinase inhibitors, statins, and supplements. PubMed was used with search terms of drug induced liver injury OR DILI with filter settings of "English language" and "humans" and custom date range of "January 1, 2000." The authors also manually searched bibliographies from key references and included seminal references before the year 2000.


NTP Toxicology and Carcinogenesis Studies of Propylene Oxide (CAS no. 75-56-9) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
Propylene oxide is a volatile, colorless liquid used as an intermediate in the production of polyether polyols, polyurethane foams, and unsaturated polyester resins and also as a fumigant for sterilizing a variety of materials ranging from plastic medical instruments to foodstuffs. In the United States, propylene oxide is registered as a fumigant for packaged dried prunes and glacé fruits such as candied cherries and as an insecticidal and fungicidal fumigant for bulk quantities of cocoa, gums, and processed spices. The 2-year carcinogenesis studies of propylene oxide (greater than 99.9% pure) were conducted by exposing groups of 50 F344/N rats and 50 B6C3F1 mice of each sex to air containing propylene oxide at concentrations of 0 (chamber control), 200, or 400 ppm for 6 hours per day, 5 days per week, for 103 weeks. The survival of rats exposed to propylene oxide was comparable with that of the controls; terminal body weights were lower than those of the controls for high dose males (8%) and high dose females (6%). Survival of exposed male and female mice decreased relative to that of the controls (male: control, 42/50; low dose, 34/50; high dose, 29/50; female: 38/50; 29/50; 10/50), but the difference was significant only for animals in the high dose groups. High dose female mice had a mean terminal body weight 22% below that of the controls. The respiratory epithelium of the nasal turbinates was one of the primary tissues affected in male and female rats; exposure-related increases occurred in the incidences of suppurative inflammation, epithelial hyperplasia, and squamous metaplasia. Papillary adenomas, involving the respiratory epithelium and underlying submucosal glands of the nasal turbinates, were observed in three female rats and two male rats exposed to propylene oxide at 400 ppm. The incidence of adenomas in females was significant by the trend tests. The proportions of high dose female rats with C-cell adenomas and with C-cell carcinomas of the thyroid gland were increased, but only the combined incidence of these tumors was significant (2/45; 2/35; 7/37). These tumors were not considered to be related to exposure to propylene oxide because there was no other evidence for C-cells' being a target tissue and because there was no increase in C-cell hyperplasia. The combined incidences of female rats with endometrial stromal polyps and endometrial stromal sarcomas of the uterus were significantly increased in the dosed groups (3/49; 12/50; 10/47). However, the occurrence of these lesions in the dosed groups was similar to the average (306/1,502, 20%) seen in untreated controls in NTP carcinogenesis studies, and hence this increase was not regarded as being related to exposure to propylene oxide. The respiratory epithelium of the nasal turbinates was also one of the primary tissues affected in male and female mice; exposure-related increases occurred in the incidences of inflammation, and squamous metaplasia was observed in one low dose male and two high dose female mice. One squamous cell carcinoma and one papilloma occurred in the nasal cavity of different high dose male mice, and two high dose female mice had adenocarcinomas of the nasal cavity. The endothelial cells of the submucosal vascular plexus in the nasal turbinates also appeared to be a major site affected in high dose male mice. Three high dose male and three high dose female mice had a saccular dilation (classified as angiectasis) of submucosal turbinate vessels. Further, hemangiomas were seen in the nasal cavity of 5/50 high dose male mice and 3/50 high dose female mice, and hemangiosarcomas were found in the nasal cavity of 5/50 high dose male mice and 2/50 high dose female mice. The increased incidences of hemangiomas in males and females and of hemangiosarcomas in males were statistically significant. Vascular tumors were not present in the nasal turbinates of any low dose or control mice. Under the conditions of these studies, there was some evidence of carcinogenicity for F344/N rats, as indicated by increased incidences of papillary adenomasncreased incidences of papillary adenomas of the nasal turbinates in male and female rats exposed to propylene oxide at 400 ppm. For male and female B6C3F1 mice, there was clear evidence of carcinogenicity, as indicated by increased incidences of hemangiomas or hemangiosarcomas of the nasal turbinates at 400 ppm. In the respiratory epithelium of the nasal turbinates, propylene oxide also caused suppurative inflammation, hyperplasia, and squamous metaplasia in rats and inflammation in mice.


Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis.
Some subjects with multiple sclerosis (MS) present with low blood iron parameters. Anecdotal reports and a single patient study suggest that iron supplementation may be beneficial in these subjects. Myelin is regenerated continually, but prerequisites for this process are iron and a functional folate-vitamin B12-methylation pathway. The aim of this study was to determine iron status, folate and homocysteine in MS subjects, and to evaluate the effect on MS symptoms if deficiencies were addressed. In relapsing-remitting MS subjects, serum iron concentration correlated significantly with age at diagnosis (r=0.49; p=0.008). In Caucasian female MS subjects, serum iron and ferritin concentrations were significantly lower than in matched controls. In a 6-month pilot study, 12 subjects taking a regimen of nutritional supplements designed to promote myelin regeneration, improved significantly neurologically as measured by the Kurzke EDSS (Total Score means 3.50 to 2.45, 29.9%; p=0.021). These were significantly improved (p=0.002) compared to 6 control group patients taking multivitamins (Kurzke Score increased by 13.9% from 4.83 to 5.50). Both groups had significantly reduced homocysteine concentrations at 6 months, suggesting that methylation is necessary but not sufficient for myelin regeneration.


Marine defaunation: animal loss in the global ocean.
Marine defaunation, or human-caused animal loss in the oceans, emerged forcefully only hundreds of years ago, whereas terrestrial defaunation has been occurring far longer. Though humans have caused few global marine extinctions, we have profoundly affected marine wildlife, altering the functioning and provisioning of services in every ocean. Current ocean trends, coupled with terrestrial defaunation lessons, suggest that marine defaunation rates will rapidly intensify as human use of the oceans industrializes. Though protected areas are a powerful tool to harness ocean productivity, especially when designed with future climate in mind, additional management strategies will be required. Overall, habitat degradation is likely to intensify as a major driver of marine wildlife loss. Proactive intervention can avert a marine defaunation disaster of the magnitude observed on land.


Earth system models underestimate carbon fixation by plants in the high latitudes.
Most Earth system models agree that land will continue to store carbon due to the physiological effects of rising CO2 concentration and climatic changes favoring plant growth in temperature-limited regions. But they largely disagree on the amount of carbon uptake. The historical CO2 increase has resulted in enhanced photosynthetic carbon fixation (Gross Primary Production, GPP), as can be evidenced from atmospheric CO2 concentration and satellite leaf area index measurements. Here, we use leaf area sensitivity to ambient CO2 from the past 36 years of satellite measurements to obtain an Emergent Constraint (EC) estimate of GPP enhancement in the northern high latitudes at two-times the pre-industrial CO2 concentration (3.4 ± 0.2 Pg C yr-1). We derive three independent comparable estimates from CO2 measurements and atmospheric inversions. Our EC estimate is 60% larger than the conventionally used multi-model average (44% higher at the global scale). This suggests that most models largely underestimate photosynthetic carbon fixation and therefore likely overestimate future atmospheric CO2 abundance and ensuing climate change, though not proportionately.


Mutations within the gene encoding the alpha 1 (X) chain of type X collagen (COL10A1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia.
Type X collagen is a homotrimer of alpha 1 (X) chains encoded by the COL10A1 gene. It is synthesised specifically and transiently by hypertrophic chondrocytes at sites of endochondral ossification. Point mutations and deletions in the region of the COL10A1 gene encoding the alpha 1 (X) carboxyl-terminal (NC1) domain have previously been identified in subjects with metaphyseal chondrodysplasia type Schmid (MCDS). To determine whether mutations in other regions of the gene caused MCDS or comparable phenotypes, we used PCR followed by SSCP to analyse the coding and promoter regions of the COL10A1 gene, as well as the intron/exon boundaries of five further subjects with MCDS, one subject with atypical MCDS, and nine subjects with other forms of metaphyseal chondrodysplasia. Using this approach, three of the subjects with MCDS were found to be heterozygous for the deletions 1864delACTT, 1956delT, and 2029delAC in the region of COL10A1 encoding the NC1 domain. These deletions would lead to alterations in the reading frame, premature stop codons, and the translation of truncated protein products. A fourth subject with MCDS was found to be heterozygous for a single base pair transition, T1894C, that would lead to the substitution of the amino acid residue serine at position 600 by proline within the NC1 domain. We did not, however, detect mutations in the coding and non-coding regions of COL10A1 in one subject with MCDS, the subject with atypical MCDS, and in the nine subjects with other forms of metaphyseal chondrodysplasia. We propose that the nature and distribution of mutations within the NC1 domain of COL10A1 causing MCDS argues against the hypothesis that the phenotype arises simply through haploinsufficiency but that an, as yet, unexplained mutation mechanism underlies this phenotype.


Preventive Ceftriaxone in Patients with Stroke Treated with Intravenous Thrombolysis: Post Hoc Analysis of the Preventive Antibiotics in Stroke Study.
The Preventive Antibiotics in Stroke Study (PASS), a randomized open-label masked endpoint trial, showed that preventive ceftriaxone did not improve functional outcome at 3 months in patients with acute stroke (adjusted common OR 0.95; 95% CI 0.82-1.09). Post-hoc analyses showed that among patients who received intravenous thrombolysis (IVT), patients who received ceftriaxone had a significantly better outcome as compared with the control group. This study aimed to gain more insight into the characteristics of these patients. In PASS, 2,550 patients were randomly assigned to preventive antibiotic treatment with ceftriaxone or standard care. In current post-hoc analysis, 836 patients who received IVT were included. Primary outcome included functional status on the modified Rankin Scale, analyzed with adjusted ordinal regression. Secondary outcomes included infection rate and symptomatic intracerebral hemorrhage (sICH) rate. For all patients in PASS, the p value for the interaction between IVT and preventive ceftriaxone regarding functional outcome was 0.03. Of the 836 IVT-treated patients, 437 were administered ceftriaxone and 399 were allocated to the control group. Baseline characteristics were similar. In the IVT subgroup, preventive ceftriaxone was associated with a significant reduction in unfavorable outcome (adjusted common OR 0.77; 95% CI 0.61-0.99; p = 0.04). Mortality at 3 months was similar (OR 0.75; 95% CI 0.48-1.18). Preventive ceftriaxone was associated with a reduction in infections (OR 0.43; 95% CI 0.28-0.66), and a trend towards an increased risk for sICH (OR 3.09; 95% CI 0.85-11.31). Timing of ceftriaxone administration did not influence the outcome (aOR 1.00; 95% CI 0.98-1.03; p = 0.85). According to the post-hoc analysis of PASS, preventive ceftriaxone may improve the functional outcome in IVT-treated patients with acute stroke, despite a trend towards an increased rate of post-IVT-sICH.


Windowed phase unwrapping using a first-order dynamic system following iso-phase contours.
In this work, we show a windowed phase-unwrapping technique that uses a first-order dynamic system and scans the phase following its iso-phase contours. In previous works, we have shown that low-pass first-order dynamic systems are very robust and useful in phase-unwrapping problems. However, it is well known that all phase-unwrapping methods have a minimum signal-to-noise ratio that they tolerate. This paper shows that scanning the phase within local windows and using a path following strategy, the first-order unwrapping method increases its tolerance to noise. In this way, using the improved approach, we can unwrap phase maps where the basic dynamic phase-unwrapping system fails. Tests and results are given, as well as the source code in order to show the performance of the proposed method.


Proteomic analysis reveals a novel mechanism induced by the leukemic oncogene Tel/PDGFRβ in stem cells: activation of the interferon response pathways.
Objective proteomic analysis offers opportunities for hypothesis generation on molecular events associated with pathogenesis in stem cells. Relative quantification mass spectrometry was employed to identify pathways affected by Tel/PDGFRβ, an oncogene associated with myeloproliferative neoplasia (MPN). Its effects on over 1800 proteins were quantified with high confidence. Of those up-regulated by Tel/PDGFRβ several were involved in the interferon gamma (IFNγ) response. To validate these observations we employed embryonic and myeloid stem cells models which revealed Tel/PDGFRβ-induced STAT1 up-regulation and activation was responsible for modulating the interferon response. A STAT1 target highly up-regulated was ICSBP, a transcriptional regulator of myeloid and eosinophilic differentiation. ICSBP interacts with CBP/p300 and Ets transcription factors, to promote transcription of additional genes, including the Egr family, key regulators of myelopoiesis. These interferon responses were recapitulated using IFNγ stimulation of stem cells. Thus Tel/PDGFRβ induces aberrant IFN signaling and downstream targets, which may ultimately impact the hematopoietic transcriptional factor network to bias myelomonocytic differentiation in this MPN.


Melioidosis: the tip of the iceberg?
For nearly 80 years clinical melioidosis has been considered a rare disease. This bacterial infection is caused by Pseudomonas pseudomallei, a saprophyte found in soil and surface water of endemic areas. Consequently, those who have most contact with soil, the rural poor, are likely to be at greatest risk of infection. Since the diversity of clinical manifestations necessitates the isolation and identification of the causative organism for a definitive diagnosis of melioidosis and the population at greatest risk within endemic areas rarely have access to an appropriate level of health care, the disease has probably been underrecognized. Melioidosis is now known to be an important cause of human morbidity and mortality in Thailand, and this may be true throughout Southeast Asia, which is usually regarded as the main endemic area for the disease. In Australia, melioidosis causes a smaller number of human infections, while disease among livestock has important economic and possible public health implications. Sporadic reports of the infection indicate its presence in several other tropical regions: in the Indian subcontinent, Africa, and Central and South America. Clinical melioidosis may be highly prevalent in these areas, but underdiagnosed as a result of a lack of awareness of the clinical and microbiological features of the disease, or simply because of a lack of health care facilities. Furthermore, during the last two decades the importation and transmission of melioidosis within nontropical zones have been documented. The causative organism is not difficult to grow, and modern antibiotics have improved disease prognosis. Further studies are needed to determine the true worldwide distribution and prevalence of melioidosis so that improved therapeutic and preventive measures can be developed and applied.


Consensus in networks of mobile communicating agents.
Populations of mobile and communicating agents describe a vast array of technological and natural systems, ranging from sensor networks to animal groups. Here, we investigate how a group-level agreement may emerge in the continuously evolving network defined by the local interactions of the moving individuals. We adopt a general scheme of motion in two dimensions and we let the individuals interact through the minimal naming game, a prototypical scheme to investigate social consensus. We distinguish different regimes of convergence determined by the emission range of the agents and by their mobility, and we identify the corresponding scaling behaviors of the consensus time. In the same way, we rationalize also the behavior of the maximum memory used during the convergence process, which determines the minimum cognitive/storage capacity needed by the individuals. Overall, we believe that the simple and general model presented in this paper can represent a helpful reference for a better understanding of the behavior of populations of mobile agents.


Structure and dynamics of stereo-regular poly(methyl-methacrylate) melts through atomistic molecular dynamics simulations.
Poly(methyl-methacrylate), PMMA, is a disubstituted vinyl polymer whose properties depend significantly on its tacticity. Here we present a detailed study of the structure, conformation, and dynamics of syndiotactic, atactic, and isotactic PMMA melts at various temperatures (580, 550, 520, and 490 K) via all-atom molecular dynamics simulations. The calculated volumetric properties are close to experimental data. The Tg and chain dimensions of PMMA model systems are found to depend strongly on tacticity in agreement with experimental findings. The backbone bonds in trans (t), diads in tt, and inter-diads in t|t torsional states are the most populated for all PMMA stereo-chemistries and their fractions increase with the number of syndiotactic sequences. Also, the effective torsional barrier heights for the backbone, ester side group, and α-methyl group are larger for syndiotactic PMMA compared to the isotactic one. The structure of the PMMA chains is studied by computing the intra- and inter-chain static structure factors, S(q), and the radial pair distribution functions. In the first peak of S(q), both intra- and inter-chain components contribute, whereas the second and third peaks mainly come from inter- and intra-chain parts, respectively. For all PMMA stereo-isomers a clear tendency of ester-methyl groups to aggregate is observed. The local dynamics are studied by analyzing torsional autocorrelation functions for various dihedral angles. A wide spectrum of correlation times and different activation energies are observed for the motions of different parts of PMMA chains. The stereo-chemistry affects the backbone, ester side group, and α-methyl motions, whereas the ester-methyl rotation remains unaffected. The dynamic heterogeneity of the PMMA chains is also studied in detail for the different stereo-chemistries via the temperature dependence of the stretching exponent. Furthermore, the reorientational dynamics at the chain level and translational dynamics for monomer and chain centers-of-mass are analyzed.


Puerariae radix prevents bone loss in ovariectomized mice.
Puerariae radix (PR), the root of Pueraria labata (Willd.) Ohwi, a wild creeper leguminous plant, is one of the earliest and most important crude herbs used in Chinese medicine for various medicinal purposes. PR contains a high amount of isoflavonoids such as daidzein and genistein, which are known to prevent bone loss induced by estrogen deficiency. We have demonstrated that soybean isoflavones prevent bone loss in an osteoporotic animal model. To examine the possible role of PR in bone metabolism, female mice were ovariectomized (OVX), and some OVX mice were fed a diet containing low, middle, and high doses (5%, 10%, and 20% of diet, respectively) of PR for 4 weeks. In OVX mice, the uterine weight declined, and intake of PR at any dose did not affect uterine weight. The total femoral bone mineral density (BMD) was significantly reduced by OVX, and the decrease in BMD caused by OVX was significantly inhibited by intake of the diet with the low dose of PR and completely prevented by the middle dose of PR. Histological analysis of the femoral metaphysis showed that intake of the diet with the middle dose of PR completely prevented decrease in trabecular bone volume (BV/TV) and trabecular thickness (Tb.Th) and restored the increase in trabecular separation (Tb.Sp) in OVX mice. In contrast, intake of the diet with the high dose of PR further increased BV/TV and Tb.Th and decreased Tb.Sp in OVX mice compared with that in the sham-operated mice. These results suggest that PR may represent a potential alternative medicine for hormone replacement therapy (HRT) in the prevention of osteoporosis in postmenopausal women.


Efflux pump Lde is associated with fluoroquinolone resistance in Listeria monocytogenes.
Five Listeria monocytogenes isolates (CLIP 21369, CLIP 73298, CLIP 74811, CLIP 75679, and CLIP 79372) were found to be resistant to fluoroquinolones during the screening for antibiotic resistance of 488 L. monocytogenes isolates from human cases of listeriosis in France. On the basis of a fourfold or greater decrease in the ciprofloxacin MIC in the presence of reserpine, fluoroquinolone resistance was attributed to active efflux of the drugs. The lde gene (Listeria drug efflux; formerly lmo2741) encodes a 12-transmembrane-segment putative efflux pump belonging to the major facilitator superfamily of secondary transporters that displayed 44% identity with PmrA from Streptococcus pneumoniae. Insertional inactivation of the lde gene in CLIP 21369 indicated that the corresponding protein was responsible for fluoroquinolone resistance and was involved in the level of susceptibility to dyes such as ethidium bromide and acridine orange.


Clinical approach to the patient with suspected ventilator-associated pneumonia.
Management of ventilator-associated pneumonia needs to balance the avoidance of unnecessary antibiotic overuse with the provision of adequate initial empiric therapy. A clinical diagnosis based on new pulmonary opacity and purulent respiratory secretions plus other signs of inflammation is valuable in screening for patients with suspected ventilator-associated pneumonia. A rational strategy starts with immediate initiation of adequate antibiotics and collection of respiratory secretions to evaluate the causative organism. As a minimum, an endotracheal aspirate with direct staining and quantitative cultures should be obtained. Overall, the need to choose adequate antibiotics correctly and expeditiously calls for the use of broad-spectrum antibiotics, but the choice should be narrowed quickly in the light of microbiologic information. However, some patients (those who develop an infection within 5 days of hospitalization, those without recent antibiotic exposure, and those without hospitalization in the past 3 months) are at low risk of infection by resistant organisms. In that subset, adequate initial selection could be a non-pseudomonal third-generation cephalosporin, since antibiotics should target usual community-acquired organisms in addition to some Enterobacteriaceae and Staphylococcus aureus. Coverage of methicillin-resistant S. aureus should be limited only to intensive care units with concomitant index cases and to patients under antibiotic exposure. Patients at risk of Pseudomonas aeruginosa (e.g., 1 week of prior hospitalization or chronic obstructive pulmonary disease) require initial use of a combination of piperacilin/tazobactam and ciprofloxacin, or amikacin plus imipenem, meropenem, or an antipseudomonal cephalosporin. If risk of Acinetobacter baumannii exists, one of these agents should be a carbapenem. After 48 hours of therapy, each patient should be re-evaluated based mainly on resolution of hypoxemia and fever plus the initial microbiologic information. Whereas broad-spectrum therapy is initially warranted in many patients, this treatment may be narrowed considerably as culture results identify the causative organism and its sensitivity. Recent data suggest that reducing overall treatment duration to a maximum of 1 week is safe, effective and is less likely to promote the growth of resistant organisms in patients who are clinically improving. Optimal management should be based on a strategy combining early high doses of an effective agent for a short period of time, which is then simplified in the light of microbiologic information.


An electromyographic analysis of sumo and conventional style deadlifts.
Strength athletes often employ the deadlift in their training or rehabilitation regimens. The purpose of this study was to compare muscle activity between sumo and conventional style deadlifts, and between belt and no-belt conditions. Six cameras collected 60-Hz video data and 960-Hz electromyographic data from 13 collegiate football players who performed sumo and conventional deadlifts with and without a lifting belt, employing a 12-RM intensity. Variables measured were knee angles and EMG measurements from 16 muscles. Muscle activity were averaged and compared within three 30-degree knee angle intervals from 90 to 0 degrees during the ascent, and three 30-degree knee angle intervals from 0 to 90 degrees during the descent. Overall EMG activity from the vastus medialis, vastus lateralis, and tibialis anterior were significantly greater in the sumo deadlift, whereas overall EMG activity from the medial gastrocnemius was significantly greater in the conventional deadlift. Compared with the no-belt condition, the belt condition produced significantly greater rectus abdominis activity and significantly less external oblique activity. For most muscles, EMG activity was significantly greater in the knee extending intervals compared with the corresponding knee flexing intervals. Quadriceps, tibialis anterior, hip adductor, gluteus maximus, L3 and T12 paraspinal, and middle trapezius activity were significantly greater in higher knee flexion intervals compared with lower knee flexion intervals, whereas hamstrings, gastrocnemius, and upper trapezius activity were greater in lower knee flexion intervals compared with higher knee flexion intervals. Athletes may choose to employ either the sumo or conventional deadlift style, depending on which muscles are considered most important according to their training protocols. Moderate to high co-contractions from the quadriceps, hamstrings, and gastrocnemius imply that the deadlift may be an effective closed kinetic chain exercise for strength athletes to employ during knee rehabilitation.


Platelet-derived interleukin 1 induces human endothelial adhesion molecule expression and cytokine production.
Interleukin 1 (IL-1) plays a central role in the regulation of the body's response to infectious and inflammatory stimuli. Recent evidence has shown that human platelets express a cell associated form of this proinflammatory cytokine very rapidly following activation. Since one of the earliest events in inflammation is frequently the rapid adhesion of platelets to injured endothelium, it was of interest to determine whether platelets express IL-1 in a functionally relevant form that can alter the phenotype of human endothelial cells in vitro. Thrombin activated platelets induced significant expression of the adhesion molecule intercellular adhesion molecule 1, as well as secretion of the IL-1 inducible cytokines IL-6 and granulocyte macrophage colony stimulating factor by cultured human umbilical cord and saphenous vein endothelial cells. This was inhibited by prior treatment of the platelets with antibody specific for IL-1. These results suggest that platelet delivered IL-1 might initiate and regulate some of the earliest phases of the inflammatory response. An additional observation of interest was differential induction of endothelial leucocyte adhesion molecule 1 by activated platelets on saphenous vein but not umbilical vein but not umbilical vein endothelial cells, which suggests functional heterogeneity of the endothelial cells.


Accuracy of sonography in diagnosis of acute appendicitis running.
This study was conducted to assess the efficacy of ultrasound in the diagnosis of acute appendicitis in clinically suspected cases of acute appendicitis. A total of 110 patients clinically suspected to have acute appendicitis admitted to the surgery departments of Golestan and Imam Khomeini hospitals, from March 2006 to 2007. Abdomino-pelvic ultrasonography with focus on RLQ ultrasonographying the graded compression technique was done. Positive ultrasonography was defined as at least one of the criteria of puylaert. The sonographic data were prospectively correlated with clinical, operative and pathological findings. Graded compression ultrasonography results were analyzed and remarked 92.7% sensitivity, 94.5% specificity, 93% accuracy, 94.4% positive predictive value and 92.5% negative predictive value. Ultrasonography is an accurate, safe and reliable method in the diagnosis of suspected cases of acute appendicitis that can help to minimize negative appendectomies and perforation rates.


Quantifying Biodiversity Losses Due to Human Consumption: A Global-Scale Footprint Analysis.
It is increasingly recognized that human consumption leads to considerable losses of biodiversity. This study is the first to systematically quantify these losses in relation to land use and greenhouse gas (GHG) emissions associated with the production and consumption of (inter)nationally traded goods and services by presenting consumption-based biodiversity losses, in short biodiversity footprint, for 45 countries and world regions globally. Our results showed that (i) the biodiversity loss per citizen shows large variations among countries, with higher values when per-capita income increases; (ii) the share of biodiversity losses due to GHG emissions in the biodiversity footprint increases with income; (iii) food consumption is the most important driver of biodiversity loss in most of the countries and regions, with a global average of 40%; (iv) more than 50% of the biodiversity loss associated with consumption in developed economies occurs outside their territorial boundaries; and (v) the biodiversity footprint per dollar consumed is lower for wealthier countries. The insights provided by our analysis might support policymakers in developing adequate responses to avert further losses of biodiversity when population and incomes increase. Both the mitigation of GHG emissions and land use related reduction options in production and consumption should be considered in strategies to protect global biodiversity.


Enhancement of pyocyanin production by subinhibitory concentration of royal jelly in Pseudomonas aeruginosa.
Background:Pseudomonas aeruginosa, a multidrug-resistant Gram-negative bacterium, produces pyocyanin, a virulence factor associated with antibiotic tolerance. High concentrations of royal jelly have an antibacterial effect, which may potentially overcome antibacterial resistance. However, in some cases, antibiotic tolerance can occur due to prolonged stress of low-dose antibacterial agents. This study aimed to investigate the effect of subinhibitory concentrations of royal jelly on bacterial growth, pyocyanin production, and biofilm formation of P. aeruginosa. Methods:Pseudomonas aeruginosa ATCC 10145 and clinical isolates were cultured in a royal jelly-containing medium to test the antibacterial activity. Pyocyanin production was observed by measuring the absorbance at 690 nm after 36 h culture and determined using extinction coefficient 4310 M-1 cm-1. Static microtiter plate biofilm assay performed to detect the biofilm formation, followed by scanning electron microscopy. Results: Royal jelly effectively inhibited the viability of both strains from a concentration of 25%. The highest production of pyocyanin was observed in the subinhibitory concentration group 6.25%, which gradually decreased along with the decrease of royal jelly concentration. Results of one-way ANOVA tests differed significantly in pyocyanin production of the two strains between the royal jelly groups. Tukey HSD test showed concentrations of 12.5%, 6.25%, and 3.125% significantly increased pyocyanin production of ATCC 10145, and the concentrations of 12.5% and 6.25% significantly increased production of the clinical isolates. Concentrations of 12.5% and 6.125% significantly induced biofilm formation of P. aeruginosa ATCC 10145, in line with the results of the SEM analysis. Conclusions: Royal jelly concentrations of 25% or higher can inhibit bacterial growth; however, subinhibitory concentrations could increase pyocyanin production and biofilm formation in P. aeruginosa. It is advisable to determine the appropriate concentration of royal jelly to obtain beneficial virulence inhibiting activity.


Nation-wide breast cancer screening in The Netherlands: results of initial and subsequent screening 1990-1995. National Evaluation Team for Breast Cancer Screening.
Based on an extensive cost-effectiveness analysis, the Dutch nation-wide breast cancer screening programme started in 1990, providing a biennial screen examination to women aged 50 to 69 years. The programme is monitored by the National Evaluation Team, which annually collects tabulated regional evaluation data to determine performance indicators. This study presents (trends in) the outcomes of initial and subsequent screening rounds, 1990-1995, and compares them to the predictions of the cost-effectiveness-analysis. Up to 1996, 88% of the target population was covered by the programme and more than 2.4 x 10(6) women were invited. The overall attendance rate was 77.5% with little differences between screening rounds and age groups; the highest rate was found in non-urbanised areas (82.4%). Of 1,000 initially (and 2 years thereafter) screened women, 13.4 (6.6) were referred for further investigation, 9.7 (4.4) were biopsied and 6.4 (3.4) had breast cancer. The positive predictive values of screen test and biopsy were 47% (51%) and 66% (78%), respectively. DCIS was diagnosed in 0.9 (0.5) and invasive cancers < or = 10 mm in 1.5 (1.0) per 1,000 screens. Lymph node metastases were found in 28% (24%) of the invasive cancers. Except the increasing attendance, which was much higher than expected, the results were fairly constant over the years. Contrary to initial screens, the results of subsequent screens did not fulfil expectations with regard to breast cancer detection and tumour size distribution. We conclude that the nation-wide screening programme is being implemented successfully. Given the results, the programme should contribute to a substantial breast cancer mortality reduction in the future. The discrepancy between observed and expected results in subsequent screens has to be watched carefully.


T1 mapping in children and young adults with hypertrophic cardiomyopathy.
To assess the global and segmental left ventricular (LV) native T1 and extracellular volume fraction (ECV) in children and young adults with hypertrophic cardiomyopathy (HCM) compared to a control cohort. The study population included 21 HCM patients (mean 14.1 ± 4.6 years) and 21 controls (mean 15.7 ± 1.5 years). Native modified Look-Locker inversion recovery sequence was performed before and after contrast injection in 3 short axis planes. Global and segmental LV native T1 and ECV were quantified and compared between HCM patients and controls. Mean native T1 in HCM patients and controls was 1020.4 ± 41.2 and 965.6 ± 30.2 ms respectively (p < 0.0001). Hypertrophied myocardium had significantly higher native global T1 and global ECV compared to non-hypertrophied myocardium in HCM (p < 0.0001, = 0.14 and 0.048, = 0.01 respectively). In a subset of patients, ECV was higher in LV segments with LGE compared to no LGE (p < 0.0001). No significant correlation was identified between global native T1 and ECV and parameters of LV structure and function. Native T1 cut-off of 987 ms provided the highest sensitivity (95 %) and specificity (91 %) to separate HCM patients from controls. Global and segmental native T1 are elevated in HCM patients. LV segments with hypertrophy and/or LGE had higher ECV in a subset of HCM patients. LV native T1 and ECV do not correlate with parameters of LV structure and function. T1 in children and young adults may be used as a non-invasive tool to assess for HCM and related fibrosis.


The stagnation of the Mexican male life expectancy in the first decade of the 21st century: the impact of homicides and diabetes mellitus.
In the first decade of the 21st century, the Mexican life expectancy changed from a long trend of increase to stagnation. These changes concur with an increase in deaths by homicides that the country experienced in that decade, and an obesity epidemic that had developed over the last decades of the 20th century. We quantify the impact of causes of death on life expectancy from 2000 to 2010. Two approaches to analyse causes of death are used: the number of life years lost due to each of the causes of death in a given year, and cause-decomposition techniques for comparisons of life expectancy from 2000 to 2010. The apparent stagnation in life expectancy is the result of an increase in deaths by homicides and diabetes mellitus on the one hand, and the positive improvements observed in other causes of death on the other. The negative impact of homicides is particularly observed for ages 15 and 50, and for that of diabetes mellitus at ages above 45 years. There is little basis for optimism regarding the future scenarios of the health of the Mexican population based on the first decade of the 21st century. Male life expectancy would have increased by 2 years if deaths by homicides and diabetes mellitus had been avoided.


Impaired reflex response to volume expansion in NaCl-sensitive spontaneously hypertensive rats.
Abnormal baroreceptor reflex function that antedates or is a consequence of NaCl loading could contribute to the NaCl-induced exacerbation of hypertension in NaCl-sensitive spontaneously hypertensive rats (SHR-S). The current study tested the hypothesis that an impairment in cardiopulmonary baroreceptor reflex function exists in SHR-S before NaCl loading. The reflex response to volume expansion was compared in SHR-S, NaCl-resistant SHR (SHR-R), and normotensive Wistar-Kyoto (WKY) and Sprague-Dawley rats maintained on a normal NaCl diet. Conscious, free-moving SHR-S, SHR-R, WKY, and Sprague-Dawley rats were volume expanded with whole blood to 15% of blood volume within 6 minutes, and mean arterial pressure, heart rate, and lumbar sympathetic nerve activity were recorded. Heart rate and lumbar sympathetic nerve activity decreased significantly in SHR-R, WKY, and Sprague-Dawley rats after volume expansion. In contrast, in SHR-S neither heart rate after volume expansion nor lumbar sympathetic nerve activity was significantly different from levels before volume expansion. The blunted reflex response of heart rate and lumbar sympathetic nerve activity to volume expansion suggests impaired cardiopulmonary volume receptor function in SHR-S. This likely contributes to NaCl-induced hypertension in SHR-S on a high NaCl diet.


The effects of lactoyl-pepstatin and the pepsin inhibitor peptide on pig cathepsin D.
Lactoyl-pepstatin (an acylated tetrapeptide) is much more readily soluble in aqueous media than the more common isovaleryl- and acetyl-pepstatins (acylated pentapeptides). However, the K1 value for inhibition of cathepsin D by lactoyl-pepstatin at pH 3.5 is approx. 10(-7) M, some two to three orders of magnitude weaker than has been obtained previously for isovaleryl- or acetyl-pepstatins. One of the peptides released during activation of pig pepsinogen is known to be an effective inhibitor of pig pepsin, but it does not alter the activity of the similar aspartic proteinase, pig cathepsin D.


Evaluation of dried blood spots with a multiplex assay for measuring recent HIV-1 infection.
Laboratory-based HIV tests for recent infection (TRIs), which primarily measure a specific serological biomarker(s) that distinguishes recent from long-term HIV infection, have facilitated the estimation of population-based incidence. Dried blood spots (DBS) on filter paper are an attractive sample source for HIV surveillance, given the simplified and cost-effective methods of specimen collection, storage, and shipment. Here, we evaluated the use of DBS in conjunction with an in-house multiplex TRI, the HIV-1-specific Bio-Plex assay, which measures direct antibody binding and avidity to multiple HIV-1 analytes. The assay performance was comparable between matched plasma and DBS samples from HIV-1 infected individuals obtained from diverse sources. The coefficients of variation, comparing the median antibody reactivity for each analyte between plasma and DBS, ranged from 2.78% to 9.40% and the correlation coefficients between the two sample types ranged from 0.89 to 0.97, depending on the analyte. The correlation in antibody reactivity between laboratory and site-prepared DBS for each analyte ranged from 0.87 to 0.98 and from 0.90 to 0.97 between site-prepared DBS and plasma. The correlation in assay measures between plasma and DBS indicate that the sample types can be used interchangeably with the Bio-Plex format, without negatively impacting the misclassification rate of the assay.


Molecular characterisation of the Chlamydia pecorum plasmid from porcine, ovine, bovine, and koala strains indicates plasmid-strain co-evolution.
Background. Highly stable, evolutionarily conserved, small, non-integrative plasmids are commonly found in members of the Chlamydiaceae and, in some species, these plasmids have been strongly linked to virulence. To date, evidence for such a plasmid in Chlamydia pecorum has been ambiguous. In a recent comparative genomic study of porcine, ovine, bovine, and koala C. pecorum isolates, we identified plasmids (pCpec) in a pig and three koala strains, respectively. Screening of further porcine, ovine, bovine, and koala C. pecorum isolates for pCpec showed that pCpec is common, but not ubiquitous in C. pecorum from all of the infected hosts. Methods. We used a combination of (i) bioinformatic mining of previously sequenced C. pecorum genome data sets and (ii) pCpec PCR-amplicon sequencing to characterise a further 17 novel pCpecs in C. pecorum isolates obtained from livestock, including pigs, sheep, and cattle, as well as those from koala. Results and Discussion. This analysis revealed that pCpec is conserved with all eight coding domain sequences (CDSs) present in isolates from each of the hosts studied. Sequence alignments revealed that the 21 pCpecs show 99% nucleotide sequence identity, with 83 single nucleotide polymorphisms (SNPs) shown to differentiate all of the plasmids analysed in this study. SNPs were found to be mostly synonymous and were distributed evenly across all eight pCpec CDSs as well as in the intergenic regions. Although conserved, analyses of the 21 pCpec sequences resolved plasmids into 12 distinct genotypes, with five shared between pCpecs from different isolates, and the remaining seven genotypes being unique to a single pCpec. Phylogenetic analysis revealed congruency and co-evolution of pCpecs with their cognate chromosome, further supporting polyphyletic origin of the koala C. pecorum. This study provides further understanding of the complex epidemiology of this pathogen in livestock and koala hosts and paves the way for studies to evaluate the function of this putative C. pecorum virulence factor.


Facilitators and barriers to adherence with home monitoring using electronic spirometry.
Adherence with prescribed therapies is a key factor in maintaining health in persons with chronic illnesses. The purpose of this descriptive study (which is one segment of a larger study being conducted to develop decision rules for early detection of infection or rejection in posttransplant patients) is to explore facilitators and barriers to adherence with home monitoring. Use of latent analysis revealed that the facilitators to adherence were health promotion, commitment to research, and following advice. Barriers to adherence were poor health status, laziness, and time conflict. Health professionals can use this information to plan strategies to promote adherence to home monitoring.


Methodologic considerations in the study of diet as part of complementary and alternative medicine modalities.
Diet is an essential component of most comprehensive health systems. Food figures prominently in the consciousness of most individuals, and the sensations of taste and smell are fundamentally important in human emotion. Complex configurations of dietary sanctions and strictures exist in virtually every human society, providing additional force to the power of diet. A wide variety of epidemiologic and laboratory-based studies have implicated a number of specific dietary factors in health and disease, with the former producing much in the way of equivocal evidence on most diet-health relationships and the latter often focusing so narrowly as to call into question the relevance of findings to human health. Assessing the role of diet as an important component of complementary and alternative medical treatment and preventive strategies will require a broad understanding of methodologic issues. Careful consideration of what is required to answer substantive questions in this intriguing and important area also will serve to advance the study of complementary and alternative modalities more generally.


Strengthening resistance self-efficacy: influence of teaching approaches and gender on different consumption groups.
Our study focused on strengthening the individual self-efficacy of low achieving 8th graders reducing drug-specific peer pressure through theoretical and practical training. The subject of the intervention was based on a substance-specific life skills program offering both teacher-centered and student-centered teaching approaches. A cluster analysis identified four consumption groups in our pre-test setting: (1) A "potentially curious" sample; (2) an "actually curious" sample; (3) an "experimenter" sample; and (4) a "consumer" sample. Self-efficacy was measured three times in a pre-, post-, and retention-test design. Only the "potentially curious" sub-sample showed higher resistance self-efficacy, boys and girls revealed no differences. Altogether, a short- and middle-term consistent increase was detected in both teaching methods. Consequences to increase the efficiency of drug prevention measurements are being discussed.


A patient-specific in silico model of inflammation and healing tested in acute vocal fold injury.
The development of personalized medicine is a primary objective of the medical community and increasingly also of funding and registration agencies. Modeling is generally perceived as a key enabling tool to target this goal. Agent-Based Models (ABMs) have previously been used to simulate inflammation at various scales up to the whole-organism level. We extended this approach to the case of a novel, patient-specific ABM that we generated for vocal fold inflammation, with the ultimate goal of identifying individually optimized treatments. ABM simulations reproduced trajectories of inflammatory mediators in laryngeal secretions of individuals subjected to experimental phonotrauma up to 4 hrs post-injury, and predicted the levels of inflammatory mediators 24 hrs post-injury. Subject-specific simulations also predicted different outcomes from behavioral treatment regimens to which subjects had not been exposed. We propose that this translational application of computational modeling could be used to design patient-specific therapies for the larynx, and will serve as a paradigm for future extension to other clinical domains.


The pharmacy-level asthma medication ratio and population health.
Community pharmacies may be positioned for an increased role in population health. We sought to develop a population-level measure of asthma medication fills and assess its relationship to asthma-related utilization. We conducted a retrospective, ecological study (2010-2012). Medication data from a chain of pharmacies (n = 27) within 1 county were used to calculate a Pharmacy-level Asthma Medication Ratio (Ph-AMR), defined as controller fills divided by controller plus rescue fills. Higher values are superior because they indicate more controller compared with rescue fills. The outcome was the asthma-related utilization rate among children in the same census tract as the pharmacy, calculated by dividing all emergency visits and hospitalizations by the number of children in that tract. Covariates, including ecological measures of poverty and access to care, were used in multivariable linear regression. Overall, 35 467 medications were filled. The median Ph-AMR was 0.53 (range 0.38-0.66). The median utilization rate across included census tracts was 22.4 visits per 1000 child-years (range 1.3-60.9). Tracts with Ph-AMR <0.5 had significantly higher utilization rates than those with Ph-AMR ≥0.5 (26.1 vs 9.9; P = .001). For every 0.1 increase in Ph-AMR, utilization rates decreased by 9.5 (P = .03), after adjustment for underlying poverty and access. Seasonal variation in fills was evident, but pharmacies in high-utilizing tracts filled more rescue than controller medications at nearly every point during the study period. Ph-AMR was independently associated with ecological childhood asthma morbidity. Pharmacies may be a community-based leverage point for improving population-level asthma control through targeted interventions.


Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Infliximab in Pediatric Inflammatory Bowel Disease: A Systematic Review and Revised Dosing Considerations.
Infliximab (IFX), a monoclonal antibody directed against tumor necrosis factor alpha is a potent treatment option for inflammatory bowel disease (IBD). Dosing regimens in children are extrapolated from adult data using a fixed, weight-based dose, which is often not adequate. While clinical trials have focused on safety and efficacy, there is limited data on pharmacokinetic characteristics and immunogenicity of IFX in children. The objective was to provide a systematic overview of current literature on pharmacokinetic and immunogenicity of IFX in children with IBD, to assess the validity of current adult to pediatric dosing extrapolation. A literature search identified publications up to October 2018. Eligibility criteria were study population consisting of children and/or adolescents with IBD, report of IFX trough levels and/or antibodies-to IFX, full text article or abstract, article in English, and original data. Initial electronic search yielded 2360 potentially relevant articles, with 1831 remaining after removal of duplicates. An additional search yielded another 202 potentially relevant articles. Of the 2033 retrieved articles, 2000 articles were excluded based on title, abstract, or eligibility criteria. Clearance of IFX was increased in young children and children with extensive disease, leading to lower trough levels after extrapolated dosing of 5 mg/kg, antibodies-to IFX emergence, and subsequent reduced efficacy. Adult to pediatric weight-based dosing extrapolation is often inadequate. We provide several considerations for optimal dosing of IFX in children and adolescents with IBD.


Non-B27 MHC associations of ankylosing spondylitis.
Ankylosing spondylitis (AS) has been associated with human leukocyte antigen (HLA)-B27 for over 30 years; however, the mechanism of action has remained elusive. Although many studies have reported associations between AS and other genes in the major histocompatibility complex (MHC) in AS, no conclusive results have emerged. To investigate the contribution of non-B27 MHC genes to AS, a large cohort of AS families and controls were B27 typed and genotyped across the region. Interrogation of the data identified a region of 270 kb, lying from 31 952 649 to 32 221 738 base pairs from the p-telomere of chromosome 6 and containing 23 genes, which is likely to include genes involved with susceptibility to AS.


Investigating long-term effects of cochlear implantation in single-sided deafness: a best practice model for longitudinal assessment of spatial hearing abilities and tinnitus handicap.
To evaluate methods for measuring long-term benefits of cochlear implantation in a patient with single-sided deafness (SSD) with respect to spatial hearing and to document improved quality of life because of reduced tinnitus. A single adult male with profound right-sided sensorineural hearing loss and normal hearing in the left ear who underwent right-sided cochlear implantation. The subject was evaluated at 6, 9, 12, and 18 months after implantation on speech intelligibility with specific target-masker configurations, sound localization accuracy, audiologic performance, and tinnitus handicap. Testing conditions involved the acoustic (NH) ear only, the cochlear implant (CI) ear (acoustic ear plugged), and the bilateral condition (CI+NH). Measures of spatial hearing included speech intelligibility improvement because of spatial release from masking (SRM) and sound localization. In addition, traditional measures known as "head shadow," "binaural squelch," and "binaural summation" were evaluated. The best indicator for improved speech intelligibility was SRM, in which both ears are activated, but the relative locations of target and masker(s) are manipulated. Measures that compare performance with a single ear to performance using bilateral auditory input indicated evidence of the ability to integrate inputs across the ears, possibly reflecting early binaural processing, with 12 months of bilateral input. Sound localization accuracy improved with addition of the implant, and a large improvement with respect to tinnitus handicap was observed. Cochlear implantation resulted in improved sound localization accuracy when compared with performance using only the NH ear, and reduced tinnitus handicap was observed with use of the implant. The use of SRM addresses some of the current limitations of traditional measures of spatial and binaural hearing, as spatial cues related to target and maskers are manipulated, rather than the ear(s) tested. Sound testing methods and calculations described here are therefore recommended for assessing performance of a larger sample size of individuals with SSD who receive a CI.


Metal-mediated crystallization of the xylose transporter XylE from Escherichia coli in three different crystal forms.
XylE is a major facilitator (MFS) xylose transporter, which is homologous to the mammalian glucose transporters (GLUT family). We have previously reported the structure of XylE in fully inward open and partially occluded inward open conformations in space groups P61 and C2, respectively. Here we present the crystallization of a third crystal form, P212121 (~4 Å resolution), also representing an inward facing conformation, and analyze all three forms in terms of crystallization conditions and packing. The crystallization conditions were generally very similar with only slight changes needed to favor one form over another, e.g. the presence of lanthanide ions greatly favors C2 over P212121 under otherwise identical conditions. Cadmium was essential for crystallization of all three forms, which indeed all contain a Cd(2+) ion in a crystal packing interface, though surprisingly in different positions. Cadmium was also found to bind to XylE in solution. The diffraction data were highly anisotropic for all forms, reflecting a lack of ordered crystal contacts along one or two of the cell axes. The best diffracting directions thus consistently correlate with the presence of ordered contacts, most of which are metal-mediated. The data presented here highlight the utility of metal ions in membrane protein crystallization and suggest that metal site engineering may be a productive path towards obtaining additional crystal forms of XylE and other membrane proteins.


Effect of ethanol on intracellular ionized calcium concentrations in synaptosomes and hepatocytes.
The effect of ethanol on intracellular ionized calcium concentrations (Cai) was studied in synaptosomes isolated from mouse whole brain and in hepatocytes isolated from rat liver. The fluorescent calcium chelator, fura-2, was used to quantitate Cai. Incubation of synaptosomes with ethanol (350-700 mM) increased resting Cai and decreased the effectiveness of KCl to raise Cai in a concentration-dependent manner. Ethanol produced an initial rapid (less than 10 sec) increase in resting Cai that remained elevated for at least 14 min in the presence of the drug. The increase in resting Cai was correlated with the inhibitory effect of ethanol on depolarization-induced increases in Cai. Resting Cai was dependent on the external calcium concentration (0-1 mM). However, the ethanol-induced increase in resting Cai (expressed as percent of control) did not differ in the presence of several extracellular calcium concentrations (0.01, 0.1, and 1 mM). Incubation of synaptosomes in a Na-free buffer resulted in a higher resting Cai and slightly enhanced the effect of ethanol to increase resting Cai. In contrast to these results in brain tissue, ethanol (30-600 mM) did not alter resting Cai or vasopressin-stimulated increases in Cai in hepatocytes. Our results suggest that the anesthetic effects of alcohols may be mediated, in part, by increased resting Cai and by decreased calcium influx through voltage-sensitive calcium channels. In addition, our findings suggest possible mechanisms by which ethanol increases resting Cai in neuronal tissue.


Early accumulation of intracellular fibrillar oligomers and late congophilic amyloid angiopathy in mice expressing the Osaka intra-Aβ APP mutation.
Pathogenic amyloid-β peptide precursor (APP) mutations clustered around position 693 of APP-position 22 of the Aβ sequence--are commonly associated with congophilic amyloid angiopathy (CAA) and intracerebral hemorrhages. In contrast, the Osaka (E693Δ) intra-Aβ APP mutation shows a recessive pattern of inheritance that leads to AD-like dementia despite low brain amyloid on in vivo positron emission tomography imaging. Here, we investigated the effects of the Osaka APP mutation on Aβ accumulation and deposition in vivo using a newly generated APP transgenic mouse model (E22ΔAβ) expressing the Osaka mutation together with the Swedish (K670N/M671L) double mutation. E22ΔAβ mice exhibited reduced α-processing of APP and early accumulation of intraneuronal fibrillar Aβ oligomers associated with cognitive deficits. In line with our in vitro findings that recombinant E22Δ-mutated Aβ peptides form amyloid fibrils, aged E22ΔAβ mice showed extracellular CAA deposits in leptomeningeal cerebellar and cortical vessels. In vitro results from thioflavin T aggregation assays with recombinant Aβ peptides revealed a yet unknown antiamyloidogenic property of the E693Δ mutation in the heterozygous state and an inhibitory effect of E22Δ Aβ42 on E22Δ Aβ40 fibrillogenesis. Moreover, E22Δ Aβ42 showed a unique aggregation kinetics lacking exponential fibril growth and poor seeding effects on wild-type Aβ aggregation. These results provide a possible explanation for the recessive trait of inheritance of the Osaka APP mutation and the apparent lack of amyloid deposition in E693Δ mutation carriers.


A quantitative description of the dynamics of excitation and inhibition in the eye of Limulus.
By means of intracellular microelectrode techniques, we have measured the dynamics of the several processes which translate light stimulation into spike activity in the Limulus eye. The transductions from light to voltage and from voltage to spike rate, and the lateral inhibitory transduction from spike rate to voltage, we have characterized by transfer functions. We have checked the appropriateness of treating the eye as a system of linear transducers under our experimental conditions. The response of the eye to a large spot of light undergoing sine flicker has been correctly predicted.


Visual short-term memory load reduces retinotopic cortex response to contrast.
Load Theory of attention suggests that high perceptual load in a task leads to reduced sensory visual cortex response to task-unrelated stimuli resulting in "load-induced blindness" [e.g., Lavie, N. Attention, distraction and cognitive control under load. Current Directions in Psychological Science, 19, 143-148, 2010; Lavie, N. Distracted and confused?: Selective attention under load. Trends in Cognitive Sciences, 9, 75-82, 2005]. Consideration of the findings that visual STM (VSTM) involves sensory recruitment [e.g., Pasternak, T., & Greenlee, M. Working memory in primate sensory systems. Nature Reviews Neuroscience, 6, 97-107, 2005] within Load Theory led us to a new hypothesis regarding the effects of VSTM load on visual processing. If VSTM load draws on sensory visual capacity, then similar to perceptual load, high VSTM load should also reduce visual cortex response to incoming stimuli leading to a failure to detect them. We tested this hypothesis with fMRI and behavioral measures of visual detection sensitivity. Participants detected the presence of a contrast increment during the maintenance delay in a VSTM task requiring maintenance of color and position. Increased VSTM load (manipulated by increased set size) led to reduced retinotopic visual cortex (V1-V3) responses to contrast as well as reduced detection sensitivity, as we predicted. Additional visual detection experiments established a clear tradeoff between the amount of information maintained in VSTM and detection sensitivity, while ruling out alternative accounts for the effects of VSTM load in terms of differential spatial allocation strategies or task difficulty. These findings extend Load Theory to demonstrate a new form of competitive interactions between early visual cortex processing and visual representations held in memory under load and provide a novel line of support for the sensory recruitment hypothesis of VSTM.


'The threads in his mind have torn': conceptualization and treatment of mental disorders by neo-prophetic Christian healers in Accra, Ghana.
In many low- and middle-income countries, faith healing is used alongside biomedical treatment for many health problems including mental disorders. Further, Christianity in Africa has seen much transformation in recent decades with the growth of charismatic or neo-prophetic churches whose doctrines include healing, miracles and prophecies. As such, many charismatic pastors have been engaged in faith healing for many years. Such faith healers form a significant portion of the mental health workforce in these countries, partly due to the limited number of biomedically trained professionals. In this study, we sought to examine the beliefs of charismatic/neo-Pentecostal faith healers about mental disorders, as well as to examine the treatments that they employed to treat such disorders. We interviewed neo-prophetic pastors who undertook faith healing, and examined their work relating to mental disorders. Ten pastors from eight churches in the Greater Accra Region of Ghana were interviewed using semi-structured interviews. The data suggest that the pastors' conceptualization of mental illness was generally limited to psychotic disorders. Their beliefs about causation were predominantly supernatural in nature although they acknowledged that drug misuse and road traffic accidents were also potential causes. The pastors' expectations of healing also showed different perceptions of illness chronicity. Their diagnostic and treatment methods revolved around using prayer, prayer aids such as oils and holy water, as well as spiritual counselling for patients and their caregivers. However, they were not opposed to referring patients to hospitals when deemed necessary. We discuss the above results with emphasis on their implications for collaboration between biomedical and alternative healing systems in Ghana. In particular, we advocate a mutual understanding of illness perspectives between biomedical practitioners and faith healers as an important component for integrating different health systems in Ghana.


Systems biologists seek fuller integration of systems biology approaches in new cancer research programs.
Systems biology takes an interdisciplinary approach to the systematic study of complex interactions in biological systems. This approach seeks to decipher the emergent behaviors of complex systems rather than focusing only on their constituent properties. As an increasing number of examples illustrate the value of systems biology approaches to understand the initiation, progression, and treatment of cancer, systems biologists from across Europe and the United States hope for changes in the way their field is currently perceived among cancer researchers. In a recent EU-US workshop, supported by the European Commission, the German Federal Ministry for Education and Research, and the National Cancer Institute of the NIH, the participants discussed the strengths, weaknesses, hurdles, and opportunities in cancer systems biology.


Genotype prevalence and risk factors for severe clinical adenovirus infection, United States 2004-2006.
Recently, epidemiological and clinical data have revealed important changes with regard to clinical adenovirus infection, including alterations in antigenic presentation, geographical distribution, and virulence of the virus. In an effort to better understand the epidemiology of clinical adenovirus infection in the United States, we adopted a new molecular adenovirus typing technique to study clinical adenovirus isolates collected from 22 medical facilities over a 25-month period during 2004-2006. A hexon gene sequence typing method was used to characterize 2237 clinical adenovirus-positive specimens, comparing their sequences with those of the 51 currently recognized prototype human adenovirus strains. In a blinded comparison, this method performed well and was much faster than the classic serologic typing method. Among civilians, the most prevalent adenovirus types were types 3 (prevalence, 34.6%), 2 (24.3%), 1 (17.7%), and 5 (5.3%). Among military trainees, the most prevalent types were types 4 (prevalence, 92.8%), 3 (2.6%), and 21 (2.4%). For both populations, we observed a statistically significant increasing trend of adenovirus type 21 detection over time. Among adenovirus isolates recovered from specimens from civilians, 50% were associated with hospitalization, 19.6% with a chronic disease condition, 11% with a bone marrow or solid organ transplantation, 7.4% with intensive care unit stay, and 4.2% with a cancer diagnosis. Multivariable risk factor modeling for adenovirus disease severity found that age <7 years (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.4-7.4), chronic disease (OR, 3.6; 95% CI, 2.6-5.1), recent transplantation (OR, 2.7; 95% CI, 1.3-5.2), and adenovirus type 5 (OR, 2.7; 95% CI, 1.5-4.7) or type 21 infection (OR, 7.6; 95% CI, 2.6-22.3) increased the risk of severe disease.


Maintenance of Stemlike Glioma Cells and Microglia in an Organotypic Glioma Slice Model.
The therapeutic resistance of gliomas is, at least in part, due to stemlike glioma cells (SLGCs), which self-renew, generate the bulk of tumor cells, and sustain tumor growth. SLGCs from glioblastomas (GB) have been studied in cell cultures or mouse models, whereas little is known about SLGCs from lower grade gliomas. To compare cell and organotypic slice cultures from GBs and lower grade gliomas and study the maintenance of SLGCs. Cells and tissue slices from astrocytomas, oligodendrogliomas, oligoastrocytomas, and GBs were cultivated in (1) serum-free medium supplemented with the growth factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), (2) medium containing 10% serum plus EGF and bFGF (F+GF medium), or (3) medium containing 10% fetal calf serum (F medium). Maintenance of cells and cytoarchitecture was addressed, using several candidate SLGC markers (Nestin, Sox2, CD133, CD44, CD49f/integrin α6, and Notch) as well as CD31 (endothelial cells), ionized calcium-binding adapter molecule 1 (microglia), and vimentin. Cell vitality was determined. SLGCs were present in tissue slices from lower and higher grade gliomas. Preservation of the cytoarchitecture in slices was possible for >3 weeks. Maintenance of SLGCs required the presence of EGF/bFGF in cell and slice cultures, in which F+GF appeared superior to N medium. Constraints were observed regarding the preservation of the microglia but not of the endothelial cells. Maintenance of the microglia was improved by addition of the cytokine macrophage colony-stimulating factor. Medium supplemented with serum and growth factors EGF, bFGF, and macrophage colony-stimulating factor permits the preservation of SLGCs and non-SLGCs in the original glioma microenvironment.


Spontaneously occurring images and early memories in people with body dysmorphic disorder.
A semi-structured interview assessing the presence and characteristics of spontaneous appearance-related images was designed and administered. A total of 18 patients with body dysmorphic disorder (BDD) and 18 normal controls took part. The BDD patients were found to have spontaneously occurring appearance-related images that were significantly more negative, recurrent, and viewed from an observer perspective than control participants. These images were more vivid and detailed and typically involved visual and organic (internal body) sensations. The study also found that BDD images were linked to early stressful memories, and that images were more likely than verbal thoughts to be linked to these memories. Implications for theory and clinical practice are discussed.


Dextran sulfate activates contact system and mediates arterial hypotension via B2 kinin receptors.
To define some of the mechanisms underlying dextran sulfate (DXS)-induced hypotension, we investigated the effects of either the plasma kallikrein inhibitor des-Pro2-[Arg15] aprotinin (BAY x 4620) or the specific bradykinin B2-receptor antagonist Hoe-140 on the hypotensive response to DXS. In the first study, anesthetized miniature pigs were given DXS alone, DXS plus BAY x 4620 in various doses, or saline. As expected, DXS alone produced a profound but transient systemic arterial hypotension with a concomitant reduction in kininogen. Circulating kinin levels, complement fragment des-Arg-C3a, and fibrin monomer were all increased. Treatment with BAY x 4620 produced a dose-dependent attenuation of these effects with complete blockade of the hypotension as well as the observed biochemical changes at the highest dose (360 mg). In a second study, two groups of pigs were given either DXS alone or DXS plus Hoe-140. DXS-induced hypotension was completely blocked by Hoe-140 pretreatment; however, kininogen was again depleted. We conclude, therefore, that DXS-induced hypotension is produced by activation of plasma kallikrein that results in the production of bradykinin and that liberation of bradykinin and its action on B2 receptors in the vasculature are both necessary and sufficient to produce the observed effects on circulatory pressure.