Subangstrom crystallography reveals that short ionic hydrogen bonds, and not a His-Asp low-barrier hydrogen bond, stabilize the transition state in serine protease catalysis.
To address questions regarding the mechanism of serine protease catalysis, we have solved two X-ray crystal structures of alpha-lytic protease (alphaLP) that mimic aspects of the transition states: alphaLP at pH 5 (0.82 A resolution) and alphaLP bound to the peptidyl boronic acid inhibitor, MeOSuc-Ala-Ala-Pro-boroVal (0.90 A resolution). Based on these structures, there is no evidence of, or requirement for, histidine-flipping during the acylation step of the reaction. Rather, our data suggests that upon protonation of His57, Ser195 undergoes a conformational change that destabilizes the His57-Ser195 hydrogen bond, preventing the back-reaction. In both structures the His57-Asp102 hydrogen bond in the catalytic triad is a normal ionic hydrogen bond, and not a low-barrier hydrogen bond (LBHB) as previously hypothesized. We propose that the enzyme has evolved a network of relatively short hydrogen bonds that collectively stabilize the transition states. In particular, a short ionic hydrogen bond (SIHB) between His57 Nepsilon2 and the substrate's leaving group may promote forward progression of the TI1-to-acylenzyme reaction. We provide experimental evidence that refutes use of either a short donor-acceptor distance or a downfield 1H chemical shift as sole indicators of a LBHB.


Reducing artefacts in ambulatory urodynamics.
To compare the diagnoses derived from a retrospective analysis of 50 ambulatory urodynamic recordings, unaware of the final diagnosis, and to evaluate the importance of the symptom diary and the presence of two transducers in the bladder rather than one. Fifty women underwent ambulatory urodynamics (duration 4 h) after video cysto-urethrography. A single solid-state microtip pressure catheter was inserted with both transducers inside the bladder, and another was inserted in the rectum. The women were asked to complete a symptom diary and the results were analysed with the active participation of the patient. Detrusor 'instability' was diagnosed on ambulatory urodynamics if there was a simultaneous increase in detrusor pressure and in the 'urethral' line in the presence of symptoms (urgency or leakage). All 50 recordings were analysed retrospectively in four combinations, i.e. with and without the additional 'urethral' line displayed on the screen and with and without the diary information. The total number of detrusor contractions was then calculated for each reading and 'abnormal detrusor activity' diagnosed when a contraction occurred with or without symptoms as recorded in the diary. The final diagnosis for each reading was then compared with that made at the time of the test with the patient present. Using the information from the diary reduced the number of pressure rises classified as 'abnormal detrusor activity' by 58%; using a second bladder pressure transducer further reduced the number of pressure rises classified as 'abnormal' by 19%. Overall, using both techniques together reduced the number of spurious pressure rises misclassified as 'abnormal detrusor activity' by 64%. Both the symptom diary and the placement of two transducers in the bladder can decrease, by almost two-thirds, the diagnosis of pathological detrusor activity on ambulatory urodynamics.


Comprehensive geriatric assessment predicts azacitidine treatment duration and survival in older patients with myelodysplastic syndromes.
Treatment of older patients with myelodysplastic syndrome (MDS) is based on disease biology and performance status. Performance status, however, does not reflect increasing co-morbidities, functional dependence or psychosocial issues in older patients. This prospective study evaluated the burden of geriatric related health issues, assessed feasibility of "tailored" Comprehensive Geriatric Assessment (CGA), and compared treatment duration and survival in older patients with MDS and oligoblastic acute myeloid leukemia with and without deficits in CGA domains (n = 98). Although only 27 (28%) patients had an Eastern Cooperative Oncology Group score ≥2, 78% (n = 77) patients had deficits in at least one CGA domain. Deficits were spread across all CGA domains, including dependence for instrumental activity of daily living (iADL; n = 33, 34%). Importantly, patients who were dependent for iADL (3.7 ± 2.6 vs 12.1 ± 7.9; p = .009), had cognitive impairment (3.5 ± 2.1 vs. 10.9 ± 7.9; p = .034) or impaired mobility (3.8 ± 2.5 vs. 13.2 ± 7.6; p = .001) completed significantly less azacitidine cycles as compared to those without these deficits. Cox-proportional regression showed that iADL dependency (hazard ratio 3.37; p = .008) and higher comorbidities (hazard ratio 4.7; p < .001) were associated with poor prognosis independent of disease related factors. Poor survival of iADL dependent patients was seen in both azacitidine (6 vs 19 months; p < .001) and supportive care cohorts (26 vs 48 months; p = .01). CGA detected geriatric related health issues, predicted poor survival and identified patients less likely to continue and benefit from azacitidine. Hence, CGA should be included in the treatment decision algorithm of older patients with MDS.


Moral stress, moral climate and moral sensitivity among psychiatric professionals.
The aim of the present study was to investigate the association between work-related moral stress, moral climate and moral sensitivity in mental health nursing. By means of the three scales Hospital Ethical Climate Survey, Moral Sensitivity Questionnaire and Work-Related Moral Stress, 49 participants' experiences were assessed. The results of linear regression analysis indicated that moral stress was determined to a degree by the work place's moral climate as well as by two aspects of the mental health staff's moral sensitivity. The nurses' experience of 'moral burden' or 'moral support' increased or decreased their experience of moral stress. Their work-related moral stress was determined by the job-associated moral climate and two aspects of moral sensitivity. Our findings showed an association between three concepts: moral sensitivity, moral climate and moral stress. Despite being a small study, the findings seem relevant for future research leading to theory development and conceptual clarity. We suggest that more attention be given to methodological issues and developing designs that allow for comparative research in other disciplines, as well as in-depth knowledge of moral agency.


Reprogramming with defined factors: from induced pluripotency to induced transdifferentiation.
Ever since work on pluripotency induction was originally published, reporting the reprogramming of somatic cells to induced pluripotent stem cells (iPS cells) by the ectopic expression of the four transcription factors Oct4, Sox2, Klf4 and c-Myc, high expectations regarding their potential use for regenerative medicine have emerged. Very recently, the direct conversion of fibroblasts into functional neurons with no prior pluripotent stage has been described. Interconversion between adult cells from ontogenically different lineages by an induced transdifferentiation process based on the overexpression of a cocktail of transcription factors, while avoiding transition through an embryonic stem cell-like state, provides a new impetus in the field of regenerative medicine. Here, we review the induced reprogramming of somatic cells with defined factors and analyze their potential clinical use. Beginning with induced pluripotency, we summarize the initial objections including their extremely low efficiency and the risk of tumor generation. We also review recent reports describing iPS cells' capacity to generate viable offspring through tetraploid complementation, the most restrictive pluripotency criterion. Finally, we explore the available evidence for 'induced transdifferentiated cells' as a novel tool for adult cell fate modification.


[Antibacterial therapy of complicated urinary infections in outpatients].
The term complicated urinary infections (CUIs) includes infections developing in the presence of anatomic anomalies, metabolic or hormonal disorders, immunodeficiency or infection with atypical microorganisms. Complicating factors diminish efficiency of antibiotic treatment, raise probability of recurrence. CUIs account for 45.2% of all cases of outpatient urinary infections in adults in Russia. Nephroliths, diabetes mellitus and renal cysts are most prevalent complicating factors. CUIs causative agents' spectrum is wider and resistance bacteria isolation is more frequent compared to uncomplicated urinary infections. In addition to antibiotic therapy, CUIs treatment should be focused on detection and elimination of the complicating factor. If complicating factors are unremovable, antibiotic therapy should be directed to management of clinical symptoms of urinary infection, prevention of complications and damage to renal parenchyma. CUIs demand longer courses of antibiotics than uncomplicated urinary infections: 7-14 days in infection of the lower urinary tracts, at least 14 days in infection of the upper urinary tracts and 4-6 weeks in failure of the standard course. Fluoroquinolones are drugs of choice in adults.


Improving critical care discharge summaries: a collaborative quality improvement project using PDSA.
Around 110,000 people spend time in critical care units in England and Wales each year. The transition of care from the intensive care unit to the general ward exposes patients to potential harms from changes in healthcare providers and environment. Nurses working on general wards report anxiety and uncertainty when receiving patients from critical care. An innovative form of enhanced capability critical care outreach called 'iMobile' is being provided at King's College Hospital (KCH). Part of the remit of iMobile is to review patients who have been transferred from critical care to general wards. The iMobile team wished to improve the quality of critical care discharge summaries. A collaborative evidence-based quality improvement project was therefore undertaken by the iMobile team at KCH in conjunction with researchers from King's Improvement Science (KIS). Plan, Do, Study, Act (PDSA) methodology was used. Three PDSA cycles were undertaken. Methods adopted comprised: a scoping literature review to identify relevant guidelines and research evidence to inform all aspects of the quality improvement project; a process mapping exercise; informal focus groups / interviews with staff; patient story-telling work with people who had experienced critical care and subsequent discharge to a general ward; and regular audits of the quality of both medical and nursing critical care discharge summaries. The following behaviour change interventions were adopted, taking into account evidence of effectiveness from published systematic reviews and considering the local context: regular audit and feedback of the quality of discharge summaries, feedback of patient experience, and championing and education delivered by local opinion leaders. The audit results were mixed across the trajectory of the project, demonstrating the difficulty of sustaining positive change. This was particularly important as critical care bed occupancy and through-put fluctuates which then impacts on work-load, with new cohorts of staff regularly passing through critical care. In addition to presenting the results of this quality improvement project, we also reflect on the lessons learned and make suggestions for future projects.


Curve progression in idiopathic scoliosis.
One hundred and thirty-three curves in 102 patients who were followed for an average of 40.5 years were evaluated to quantitate curve progression after skeletal maturity and for prognostic factors leading to curve progression. Sixty-eight per cent of the curves progressed after skeletal maturity. In general, curves that were less than 30 degrees at skeletal maturity tended not to progress regardless of curve pattern. In thoracic curves the Cobb angle, apical vertebral rotation, and the Mehta angle were important prognostic factors. In lumbar curves the degree of apical vertebral rotation, the Cobb angle, the direction of the curve, and the relationship of the fifth lumbar vertebra to the intercrest line were of prognostic value. Translatory shifts played an important role in curve progression. Curves that measured between 50 and 75 degrees at skeletal maturity, particularly thoracic curves, progressed the most.


Response to intradermal injection of monosodium urate crystals in Behçet's syndrome.
The cutaneous response to intradermal injection of monosodium urate crystals was investigated in 97 patients with Behçet's syndrome in Turkey and 14 in the United Kingdom, and in 82 healthy and 88 diseased controls. Urate crystals produced an increased erythematous response in patients compared with controls in both countries. This response was different from that of the pathergy test performed at the same time. The systemic acute phase response, studied only in Turkey, showed no differences between patients and controls.


Interference with splicing of Presenilin transcripts has potent dominant negative effects on Presenilin activity.
Missense mutations in the PRESENILIN1 (PSEN1) gene frequently underlie familial Alzheimer's disease (FAD). Nonsense and most splicing mutations result in the synthesis of truncated peptides, and it has been assumed that truncated PSEN1 protein is functionless so that heterozygotes for these mutations are unaffected. Some FAD mutations affecting PSEN1 mRNA splicing cause loss of exon 8 or 9 sequences while maintaining the reading frame. We attempted to model these exon-loss mutations in zebrafish embryos by injecting morpholino antisense oligonucleotides (morpholinos) directed against splice acceptor sites in zebrafish psen1 transcripts. However, this produced cryptic changes in splicing potentially forming mRNAs encoding truncated presenilin proteins. Aberrant splicing in the region between exons 6 and 8 produces potent dominant negative effects on Psen1 protein activity, including Notch signalling, and causes a hydrocephalus phenotype. Reductions in Psen1 activity feedback positively to increase psen1 transcription through a mechanism apparently independent of gamma-secretase. We present evidence that the dominant negative effects are mediated through production of truncated Psen1 peptides that interfere with the normal activity of both Psen1 and Psen2. Mutations causing such truncations would be dominant lethal in embryo development. Somatic cellular changes in ageing cells that interfere with PSEN1 splicing, or otherwise cause protein truncation, might contribute to sporadic Alzheimer's disease, cancer and other diseases.


Perceptions of family-centred care among caregivers of children with cerebral palsy in South India: An exploratory study.
Parental views and expectations about family-centred care (FCC) need to be understood for its successful implementation. Knowledge of caregiver's perceptions and needs, within their social and cultural context, forms the basis for effective health care partnerships with families. The purpose of this study was to explore perceptions about FCC among caregivers of children with cerebral palsy (CP) in South India. Fourteen caregivers of children with CP (aged 4-12 years) living in rural areas of the coastal region of Karnataka, India, participated in this qualitative study. Face-to-face semi-structured interviews were recorded and transcribed for analysis using the framework and hybrid approaches. Thematic mapping of the categories and themes was done to explore relationships about perceptions of FCC. Caregiver's life emerged inductively as a new theme highlighting caregiver's own physical and mental health, family roles and well-being, integrating the onus of care with household responsibilities, limited participation in personal activities and social isolation. The qualitative findings revealed the ubiquity of respectful and trusting relationships with health professionals while expressing paucity of coordinated comprehensive care, sporadic partnerships and opportunities for shared decision-making; desire for receiving specific information related to child's progress and prognosis; and general information on community resources and the need of empowerment and support groups. Our study has practical implications for the implementation of FCC within the South Indian context, by recognizing unique caregiver needs and expectations in sync with cultural perspectives towards childhood disability such as societal stigma, values and traditional beliefs; attitudes towards medical professionals; and life stressors and gender responsibilities.


Oceanicola marinus sp. nov., a marine alphaproteobacterium isolated from seawater collected off Taiwan.
A short-rod-shaped, Gram-negative, non-motile bacterial strain, designated AZO-C(T), was isolated from a sample of seawater collected from the Eluanbi coast of Pingtung County in southern Taiwan and was characterized by using a polyphasic approach. Phylogenetic analyses based on 16S rRNA gene sequences showed that the strain formed a monophyletic branch at the periphery of the evolutionary radiation occupied by the genus Oceanicola in the order Rhodobacterales of the Alphaproteobacteria. The closest neighbours were Oceanicola batsensis HTCC2597(T) (95.6 % similarity), Oceanicola nanhaiensis SS011B1-20(T) (94.5 %) and Oceanicola granulosus HTCC2516(T) (94.0 %). The predominant fatty acid was 18 : 1 omega 7c (49.1 %), and significant amounts of 19 : 0 cyclo (24.6 %) and 16 : 0 (14.7 %) were present. The DNA-DNA relatedness of the strain with respect to recognized species of the genus Oceanicola was less than 70 %. The isolate was also distinguishable from members of the genus Oceanicola on the basis of phenotypic and biochemical characteristics. It is evident from the genotypic, chemotaxonomic and phenotypic data, therefore, that strain AZO-C(T) represents a novel species of the genus Oceanicola, for which the name Oceanicola marinus sp. nov. is proposed. The type strain is AZO-C(T) (=LMG 23705(T)=BCRC 17591(T)).


A brief measure for the assessment of coping self-efficacy among alcohol and other drug users.
To develop a reliable and valid brief measure of coping self-efficacy for substance users to serve the needs of clinicians and researchers who desire a global measure of a client's confidence across high-risk situations. The eight-item global measure of self-efficacy was derived from the Drug-Taking Confidence Questionnaire (DTCQ), a 50-item self-report measure of situation-specific coping self-efficacy applicable to alcohol and other drug users. The questionnaire was administered by trained staff to clients at intake to treatment. Items were selected using stepwise regression. Reliability and construct validity were assessed using alpha and correlation coefficients. An addiction treatment facility in Toronto, Ontario. Seven hundred and thirteen English-speaking adults presenting for treatment with an alcohol or other drug problem. The sample was comprised of alcohol (344), cocaine (253), heroin (53), cannabis (43), other drug (20) users. The DTCQ: perceived difficulty quitting, motivation to quit and confidence in quitting; depression score (SCL-90-R); and motivation scores (SOCRATES-revised). An eight-item version (DTCQ-8) accounted for 95% of the variance in the total DTCQ-50 scores and correlated 0.97 with the total DTCQ-50 score. Reliability and validity for the DTCQ-8 as a global indicator of coping self-efficacy was confirmed. Clinically, the DTCQ-8 is useful for the assessment and monitoring of confidence levels during treatment. The DTCQ-8 is a promising research tool for inclusion in outcome evaluation batteries that require a brief, reliable and valid measure of coping self-efficacy.


Effect of isoflurane on the canine hepatic circulation and hepatic oxygen balance.
We have studied the effects of increasing concentrations of isoflurane (1%, 1.5% and 2%) on the hepatic circulation and the oxygen supply and demand of the liver in six barbiturate-anaesthetized greyhounds. Following laparotomy, the hepatic arterial and portal venous blood flows were measured continuously using electromagnetic flow probes, and mean arterial pressure and cardiac output were measured as appropriate. Cardiac output was maintained while mean arterial pressure and systemic vascular resistance decreased in a dose dependent manner. Hepatic arterial and total liver blood flows and oxygen supplies decreased significantly at all isoflurane concentrations. Portal venous blood flow and portal venous oxygen supply did not decrease significantly until the concentration of isoflurane was increased to 2% and 1.5%, respectively. Hepatic oxygen consumption was reduced with 2% isoflurane (P less than 0.05), but this was insufficient to offset the reduction in hepatic oxygen supply and resulted in an increased extraction of oxygen by the liver.


Pre-hospital risk factors for inpatient death from severe febrile illness in Malian children.
Inpatient case fatality from severe malaria remains high in much of sub-Saharan Africa. The majority of these deaths occur within 24 hours of admission, suggesting that pre-hospital management may have an impact on the risk of case fatality. Prospective cohort study, including questionnaire about pre-hospital treatment, of all 437 patients admitted with severe febrile illness (presumed to be severe malaria) to the paediatric ward in Sikasso Regional Hospital, Mali, in a two-month period. The case fatality rate was 17.4%. Coma, hypoglycaemia and respiratory distress at admission were associated with significantly higher mortality. In multiple logistic regression models and in a survival analysis to examine pre-admission risk factors for case fatality, the only consistent and significant risk factor was sex. Girls were twice as likely to die as boys (AOR 2.00, 95% CI 1.08-3.70). There was a wide variety of pre-hospital treatments used, both modern and traditional. None had a consistent impact on the risk of death across different analyses. Reported use of traditional treatments was not associated with post-admission outcome. Aside from well-recognised markers of severity, the main risk factor for death in this study was female sex, but this study cannot determine the reason why. Differences in pre-hospital treatments were not associated with case fatality.


A Case of Lacrimal Sac Septum Presenting With Dacryocystocele.
Lacrimal sac septum is a rare structural abnormality of the lacrimal system. A 15-year-old patient presented with epiphora and a mass inferior to the left medial canthal tendon. Dacryocystography and CT-dacryocystography revealed a dilated lacrimal sac with complete obstruction. A horizontal lacrimal sac septum was found in the mid-sac region during endoscopic dacryocystorhinostomy. Histopathologic examination of the septum revealed chronic inflammation with stratified columnar epithelial cell lining consistent with the lacrimal sac.


Respiratory muscle function in health.
Normally both quiet breathing and augmented ventilation during physical exercise are sustained by the inspiratory muscles around the chest wall. Among these, the diaphragm is most important. The inspiratory muscles of the upper airways must also contract to permit inspiration to occur. The expiratory muscles of the chest wall and abdomen do not normally participate in breathing per se, but are critically important for coughing. The strength of respiratory muscle contraction, as estimated from maximum static inspiratory and expiratory pressures, depends on neural drive, the length at which the muscles contract, and the velocity with which they shorten during contraction. The intrinsic strength of the respiratory muscles also depends on whether they are hypertrophied, or atrophied consequent to weight loss. As a result of the structural and biochemical properties of their muscle fibers and their blood supply, normal respiratory muscles have a high level of endurance. However, even well-trained normal subjects may develop inspiratory muscle fatigue if they are subjected to severe inspiratory resistive loads, hypoxia, high levels of physical exercise at normal atmospheric pressure, or work under hyperbaric conditions. The respiratory muscles of normal subjects respond to training. Strength training regimens enhance respiratory muscle but not ventilatory endurance, and vice versa.(ABSTRACT TRUNCATED AT 250 WORDS)


Homicide or suicide? A probabilistic approach for the evaluation of the manner of death in sharp force fatalities.
The role of forensic science can be defined as providing relevant opinions to assist investigators and courts of law in answering questions. The Likelihood Ratio (LR) provides a quantitative and logical approach to communicating the strength of expert evidence. We reviewed existing forensic literature on sharp force fatalities, focusing on studies reporting the manner of death and the frequency of some characteristics that are traditionally assessed. Four studies were included, resulting in a database of 173 suicides and 354 homicides. The LR of each of the characteristic under both hypotheses (suicide and homicide) was obtained. Subsequently, the LR was computed in six fatalities with known manner of death, three suicides and three homicides, by multiplying the corresponding LR of each individual characteristic. LR ranged from 115 to 140,250 in suicidal cases and from 9 to 2728 in homicidal cases. Compared to other fields of forensic science where LR is used extensively, the values obtained in our cases of sharp force fatalities is low. However, in forensic pathology there is evidence that is outside the expert's opinion, and it is for the trier of fact, such as the judge or jury, to draw conclusions. Nevertheless, the LR serves as a tool for interpreting and weighing evidence while maintaining the distinct roles of the trier of fact and the expert. To comprehensively apply the LR in the field of sharp force deaths, it will be necessary to standardize the methodology of investigation and data collection in descriptive studies.


Enzymatic synthesis of chiral organophosphothioates from prochiral precursors.
The phosphotriesterase from Pseudomonas diminuta has been shown to selectively cleave the pro-R p-nitrophenolate substituent from bis-p-nitrophenyl alkyl phosphothioate esters. When the alkyl substituent is methyl, ethyl, or isopropyl the enantiomeric excess of the product is >/=99%. Manipulation of the active site through mutagenesis has enabled the preparation of protein variants that preferentially hydrolyze the pro-S substituent of the target substrates. This methodology thus permits the preparation of chiral products from prochiral precursors.


[Titration of the level of effective positive pressure in the treatment of obstructive sleep apnea syndromes with continuous positive pressure].
The efficacy of continuous airway positive pressure ventilation with a nasal mask mainly depends on the appropriateness of the effective positive pressure level. Conventionally, this level is determined from polysomnographic recordings using progressively increasing pressure levels to determine, the point where episodes of apnea, hypopnea and snoring regress in all sleep phases and in all body positions. Since the first description of this method, many other titration methods have been proposed. Some use sophisticated signals such as the analysis of respiratory exertion level or limitation of inspiratory flow to provide a more precise titration which is particularly useful in cases where the classical titration method is insufficiently effective. Inversely, simplified methods have been examined from an economic point of view. These methods do not require the presence of a technician in a specialized laboratory where the waiting list for diagnostic tests is often long. Recordings during naps or short nights have been proposed for the more severe cases. Likewise titrations during simple polygraphy recordings or with an autoCPAP device have been shown to be effective in one-night laboratory recordings. Much work remains to be done to determine the effectiveness of these methods when used in the patient's home as well the long-term effects.


Defining the construct of reactive aggression in borderline personality disorder: Commentary on "Aggression in borderline personality disorder--A multidimensional model".
Comments on the article by F. Mancke et al. (see record 2015-31349-001). The article presents a multidimensional model of aggression in the context of borderline personality disorder (BPD), with a selective review of the research literature. BPD is arguably the most widely researched personality disorder, and the review suggests that there has been extensive progress in characterizing behavioral and biological correlates of aggression. What is not clear from the review, and indeed, the broader literature, is whether the research cited in this review is specific to BPD or can generally be applied to reactive aggression in the context of other disorders (or by extension into the normative range of the behavior). The review by Mancke et al. also highlights the fact that there is a general lack of research establishing predictive validity of aggression in BPD, with most research comparing two groups sampled at one time point.


The metabolic syndrome as a predictor of incident diabetes mellitus in Mauritius.
To assess the utility of the metabolic syndrome (MetS) and a Diabetes Predicting Model as predictors of incident diabetes. A longitudinal survey was conducted in Mauritius in 1987 (n = 4972; response 80%) and 1992 (n = 3685; follow-up 74.2%). Diabetes status was retrospectively determined using 1999 World Health Organization (WHO) criteria. MetS was determined according to four definitions and sensitivity, positive predictive value (PPV), specificity and the association with incident diabetes before and after adjustment for MetS components calculated. Of the 3198 at risk, 297 (9.2%) developed diabetes between 1987 and 1992. The WHO MetS definition had the highest prevalence (20.3%), sensitivity (42.1%) and PPV (26.8%) for prediction of incident diabetes, the strongest association with incident diabetes after adjustment for age and sex [odds ratio 4.6 (3.5-6.0)] and was the only definition to show a significant association after adjustment for its component parts (in men only). The low prevalence and sensitivity of the International Diabetes Federation (IDF) and ATPIII MetS definitions resulted from waist circumference cut-points that were high for this population, particularly in men, and both were not superior to a diabetes predicting model on receiver operating characteristic analysis. Of the MetS definitions tested, the WHO definition best identifies those who go on to develop diabetes, but is not often used in clinical practice. If cut-points or measures of obesity appropriate for this population were used, the IDF and ATPIII MetS definitions could be recommended as useful tools for prediction of diabetes, given their relative simplicity.


Microbiota that affect risk for shigellosis in children in low-income countries.
Pathogens in the gastrointestinal tract exist within a vast population of microbes. We examined associations between pathogens and composition of gut microbiota as they relate to Shigella spp./enteroinvasive Escherichia coli infection. We analyzed 3,035 stool specimens (1,735 nondiarrheal and 1,300 moderate-to-severe diarrheal) from the Global Enteric Multicenter Study for 9 enteropathogens. Diarrheal specimens had a higher number of enteropathogens (diarrheal mean 1.4, nondiarrheal mean 0.95; p<0.0001). Rotavirus showed a negative association with Shigella spp. in cases of diarrhea (odds ratio 0.31, 95% CI 0.17-0.55) and had a large combined effect on moderate-to-severe diarrhea (odds ratio 29, 95% CI 3.8-220). In 4 Lactobacillus taxa identified by 16S rRNA gene sequencing, the association between pathogen and disease was decreased, which is consistent with the possibility that Lactobacillus spp. are protective against Shigella spp.-induced diarrhea. Bacterial diversity of gut microbiota was associated with diarrhea status, not high levels of the Shigella spp. ipaH gene.


Polydrug use typologies and childhood maltreatment in a nationally representative survey of Danish young adults.
Substance use and childhood maltreatment experience are linked, but little is known about the association with polydrug use patterns. Latent class analyses (LCA) were performed on eight illicit drugs in a random population sample of young Danes separated by sex (males: n = 1,555; females: n = 1,425). Logistic regressions explored associations of polydrug use patterns and childhood maltreatment. A three-class solution best described patterns of polydrug use in both the male and female samples. Across all LCA models, Class 1 was characterized by individuals who represented wide-range polydrug users, endorsing many of the drug types (males = 8%; females = 2%). Class 2 was characterized by amphetamine, cannabis, cocaine, and amyl nitrate users (males = 18%; females = 7%). Class 3 was characterized by individuals who endorsed either low-level use of cannabis only or no drug use (males = 74%; females = 91 %). For males, having been a child-protection case was associated with Classes 1 and 2 and for females with Class 2, compared with Class 3. Alcohol problems were associated with Classes 1 and 2 for both sexes. Sexual abuse was associated with Classes 1 and 2 for females but not males, whereas physical abuse was associated with Classes 1 and 2 for males but not females, as compared with Class 3. Separate sex analyses are important; although patterns of polydrug use are broadly similar, females are less frequently polydrug users. In addition, different relationships exist for the sexes, such that polydrug use patterns are associated with sexual abuse in females, whereas such patterns are associated with physical abuse in young males.


Incidence of squamous cell carcinoma of the head and neck: report of 1,000 cases.
The purpose of this paper is to define the incidence of squamous cell carcinoma (SCC) of the head and neck as seen at the Free University Hospital, Amsterdam, the Netherlands, in the last six years, according to the latest revised classification system of the International Union against Cancer (UICC, 1982). In addition, male to female ratios, relative frequencies at the various sites, age distribution, incidence of second or third primary and the relationship of distant metastases to the nodal metastases and the T-stage of the primary lesion are reported. These incidences are compared with those in other countries and the major differences are discussed.


The status of clinical trials: cause for concern.
Americans see clinical research as important, with over 15 million American residents participating in NIH-sponsored studies in 2008 and growing yearly. Documents reporting NIH supported Clinical Research projects were reviewed. When compared with other studies, the number of interventional Phase III and Phase IV trials have decreased from 20% to 4.4% from 1994-2008. This finding most likely has occurred for several reasons. One reason is that the physician lacks an infrastructure for designing and carrying out trials. This lack is because of an absence of a coordinated effort to train clinical trialists. It is clear that the Nation needs a more purposeful approach to developing and maintaining the infrastructure for designing and conducting clinical trials. Building it de novo trial by trial is profoundly inefficient, to say nothing about time consuming and error prone.


Health-related quality of life and gastrointestinal disease.
Society is changing rapidly, and new aspects need to be considered when evaluating treatment of disease. Health-related quality of life (HRQL) is a relatively new addition to the tools clinicians use to gain a better understanding of the impact of disease and its treatment. The questions 'What is it?', 'How it is measured?' and 'How can the information be used?' are now better understood than a few years ago. Generic instruments to capture HRQL enable a broad assessment of a range of aspects and can be used to make comparisons between different patient populations. Irrespective of the choice of instrument, they can classify the influence of different factors, such as gender, age, general health status and disease severity. Health-related quality of life assessments have been made in many areas of gastroenterology, such as reflux disease, inflammatory bowel disease and irritable bowel syndrome, to describe the burden of illness and the impact of treatment. Health-related quality of life as a prediction of treatment response is another interesting option. Its ability in the context of surgical intervention and outcomes is also emerging even though more work must be done in this area. Health-related quality of life evaluations, as an additional tool in the management of patients, are here to stay.


On the functional relevance of frontal cortex for passive and voluntarily controlled bistable vision.
In bistable vision, one constant ambiguous stimulus leads to 2 alternating conscious percepts. This perceptual switching occurs spontaneously but can also be influenced through voluntary control. Neuroimaging studies have reported that frontal regions are activated during spontaneous perceptual switches, leading some researchers to suggest that frontal regions causally induce perceptual switches. But the opposite also seems possible: frontal activations may themselves be caused by spontaneous switches. Classically implicated in attentional processes, these same regions are also candidates for the origins of voluntary control over bistable vision. Here too, it remains unknown whether frontal cortex is actually functionally relevant. It is even possible that spontaneous perceptual switches and voluntarily induced switches are mediated by the same top-down mechanisms. To directly address these issues, we here induced "virtual lesions," with transcranial magnetic stimulation, in frontal, parietal, and 2 lower level visual cortices using an established ambiguous structure-from-motion stimulus. We found that dorsolateral prefrontal cortex was causally relevant for voluntary control over perceptual switches. In contrast, we failed to find any evidence for an active role of frontal cortex in passive bistable vision. Thus, it seems the same pathway used for willed top-down modulation of bistable vision is not used during passive bistable viewing.


Effect of bilirubin on the activity and thermokinetic characteristics of brain (synaptosomal) membrane NO synthase.
NO synthase activity was found in the plasma (synaptosomal) membrane particles isolated from the homogenate of adult rat brain (without cerebellum) under conditions preventing the protease attack and formation of reactive oxygen species. The NO synthase discovered exhibited some properties of a neuronal constitutive integral membrane enzyme and was inhibited by N-nitro-L-arginine. NO synthase activity decreased when bilirubin entered the synaptosomal membrane in vitro. Bilirubin caused the shift of the transition temperature in the temperature dependence of NO synthase activity in Arrhenius plots. The incorporation of bilirubin into synaptosomal membranes resulted in an increase in the apparent activation energy for NO synthase within a temperature range of 10-30 degrees C. The membrane NO synthase was susceptible to the photodynamic effect of membrane-bound bilirubin molecules. Monomeric human serum albumin without organophilic ligands exerted a protective effect on NO synthase in bilirubin-containing membrane particles.


[Effect of the meat of farm animals fed new nitrogen-containing food additives on the morphologic features of the internal organs in the rat].
A study was made of the internal organs of rats fed the meat of agricultural animals whose diet included non-protein nitrogen-containing compounds--urea, isobutylidene diurea and a polymer, carbamide with polyacrylamide. Morphological studies have demonstrated that inclusion into the diet of experimental rats of the meat of young bulls given isobutylidene diurea and urea leads to structural alterations in the internal organs of rats, the most pronounced alterations being detected in experiments with the use of the meat of young bulls given isobutylidene diurea. The feeding of experimental rats with the meat of animals grown with the use of the polymer did not affect the morphofunctional status of their organs.


Surface characterization of Streptococcus mutans biofilms grown on polyethylene and beta-titanium.
In this study, we considered the biofilms as a surface, characterizing them using instruments for surface analyses, environmental microscopy, IR-spectroscopy (ATR-mode) and goniometry of the contact angle. The bacteria that formed the biofilms were grown on two different supports: beta-titanium alloy (beta-Ti) and polyethylene (PE). Environmental microscopy allowed the observation of biofilms in situ and in their hydrated state. On the metallic support, the biofilm quickly adhered and formed a dense structure with micro-colonies, but on the PE a thinner biofilm layer was observed covering a large surface area of the support. IR-spectroscopy is another effective method to detect the biofilm quickly and in situ, without pre-treating the sur-face. Nevertheless, problems with the overlapping of the characteristic bands on the spectra are frequent between the biofilm and PE. Finally, we compared the surface energy (SE) of the supports before and after biofilm formation. Our results indicate that the SE of the supports depends on the sterilization method, and that the SE of the biofilms varies depending on the support and the sterilization method. The biofilm on the beta-Ti had the highest SE, and as mentioned above, microscopic images showed a higher roughness on its surface.


Role of the clotting system in the pathogenesis of neuroimmunologic disease.
Experimental allergic encephalomyelitis (EAE) is a prototypic neuroautoimmune disease involving sensitization to central nervous system myelin basic protein (MBP). Our studies of the clotting system and ensuing fibrinolysis implicate coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature as events initiating the inflammation characterizing EAE. Among recipient rats injected with MPB-primed, cultured-activated lymph node cells, opening of the blood-brain barrier (BBB) and deposition of perivascular fibrin within the spinal cord occur in parallel 1 day before onset of clinical signs of EAE. Daily treatment of recipient rats with trans-4-(aminomethyl)cyclohexanecarboxylic acid, a synthetic product that specifically inhibits plasminogen activator derived from endothelial cells, results in marked reduction of increased permeability of the BBB and suppression of clinical signs of EAE. We postulate that the critical event precipitating EAE is binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of cerebrovascular endothelial cells. Coagulation and ensuing fibrinolysis occur at sites of binding of effector cells to cerebrovascular endothelium. Release of biologically active peptides cleaved from fibrin open the BBB, thereby setting the stage for the cascade of inflammatory events culminating in clinical manifestations of EAE.


AIM1 is an actin-binding protein that suppresses cell migration and micrometastatic dissemination.
A defining hallmark of primary and metastatic cancers is the migration and invasion of malignant cells. These invasive properties involve altered dynamics of the cytoskeleton and one of its major structural components β-actin. Here we identify AIM1 (absent in melanoma 1) as an actin-binding protein that suppresses pro-invasive properties in benign prostate epithelium. Depletion of AIM1 in prostate epithelial cells increases cytoskeletal remodeling, intracellular traction forces, cell migration and invasion, and anchorage-independent growth. In addition, decreased AIM1 expression results in increased metastatic dissemination in vivo. AIM1 strongly associates with the actin cytoskeleton in prostate epithelial cells in normal tissues, but not in prostate cancers. In addition to a mislocalization of AIM1 from the actin cytoskeleton in invasive cancers, advanced prostate cancers often harbor AIM1 deletion and reduced expression. These findings implicate AIM1 as a key suppressor of invasive phenotypes that becomes dysregulated in primary and metastatic prostate cancer.


Synergistic ELCA-aspiration-DES thrombus removal strategy-embolus impact in high-risk plaque: A case report.
Thin-cap fibroatheroma (TCFA) and red thrombus are suggested as a high-risk of embolic complications during percutaneous coronary intervention (PCI). Intracoronary aspiration procedures occasionally result in either an insufficient thrombus removal or provide no significant effects on TCFA. A 76-year-old male underwent coronary angiography for chest pain. Coronary angiography revealed a tight stenosis at the right coronary artery which resulted in treatment by PCI. Optical frequency domain imaging (OFDI) delineated a red thrombus with TCFA. To avoid embolic complications, excimer laser coronary angioplasty (ELCA) was applied with intracoronary aspiration before drug-eluting stent (DES) implantation. The red thrombus was vaporized by ELCA in an energy-intensity dependent manner and subsequently removed by intracoronary aspiration. The fibrous cap of TCFA was dissected with the material beneath the cap ablated by ELCA and extensively removed by intracoronary aspiration. DES implantation and postdilatation achieved an optimal result without flow compromise. This combined synergistic strategy of ELCA-aspiration-DES yielded a successful outcome. A synergistic embolus removal strategy combining ELCA, aspiration and DES implantation is a promising option for the treatment of high-risk plaque with potential embolic complications.


MATCHER: manifold alignment reveals correspondence between single cell transcriptome and epigenome dynamics.
Single cell experimental techniques reveal transcriptomic and epigenetic heterogeneity among cells, but how these are related is unclear. We present MATCHER, an approach for integrating multiple types of single cell measurements. MATCHER uses manifold alignment to infer single cell multi-omic profiles from transcriptomic and epigenetic measurements performed on different cells of the same type. Using scM&T-seq and sc-GEM data, we confirm that MATCHER accurately predicts true single cell correlations between DNA methylation and gene expression without using known cell correspondences. MATCHER also reveals new insights into the dynamic interplay between the transcriptome and epigenome in single embryonic stem cells and induced pluripotent stem cells.


[Analysis of the role of DNA repair, regulation of cell cycle and apoptosis in the radiation-induced adaptive response of mammalian cells].
In according with the mechanism for an adaptive response (AR) offered in [Bodnarchuk I.A.//Radiat. biologiya. Radioecologiya. 2002. V. 42. No. 1. P. 36-43], the low-dose irradiation of mammalian cells leads to the activation of such enzymes as Ras, ceramid-activated protein kinase, phospholipase C (PL C) and phosphatidilinostol 3-kinase (PI 3-K). All of them initiate apoptosis and eliminate the most radiosensitive cells form the population before the damaging irradiation. The function of PL C and PI 3-K accompanied by protein kinase C (PK C) activation. PK C activates transcription of the poly(ADP-ribose)polymerase (PARP) gene and DNA polymerase beta gene, and makes posttranslation activation of apurinic/apyrimidinic endonuclease APE, which are participating in the base excision repair (BER). PK C, APE and PARP activate the transcription factor p53, PK C and APE also activate the transcription factor AP-1, AP-1 and p53 take part in the initiation of nucleotide excision reapir (NER). The function of BER, NER and p53 after the damaging irradiation is accompanied by the G1-arrest of cell cycle progression. During G1-arrest there is p53-dependent activation of nonhomologous ends joining (NHEJ) and the inhibition of homologous recombination repair (HRR) of the DNA double-strand breaks takes place. Passing through the NHEJ the cells will outgo from G1-arrest and follow by HRR. AP-1 takes part in outgoing of cells from G1-arrest. So, the preliminary low-dose irradiation causes the decrease of quantity of cells died apoptotically after damaging irradiation as a result of inability to overcome G1-arrest. Thus, AR is the combination of processes: the removal of radiosensitive subpopulation of cells, and/or the activation of DNA repair, and/or the increase of cells ability to overcome the cell cycle delay.


Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial.
Patients with high Gleason score, elevated prostate specific antigen (PSA) level, and advanced clinical stage are at increased risk for both local and systemic relapse. Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical, metastasis-free and disease-specific survival. No randomized data is available on the benefits of long-term hormonal therapy (HT) in these patients. A prospective study on the efficacy and safety of trimodality treatment consisting of HT, external beam radiation therapy (EBRT), and brachytherapy (BT) for high-risk prostate cancer (PCa) is strongly required. This is a phase III, multicenter, randomized controlled trial (RCT) of trimodality with BT, EBRT, and HT for high-risk PCa (TRIP) that will investigate the impact of adjuvant HT following BT using iodine-125 ((125)I-BT) and supplemental EBRT with neoadjuvant and concurrent HT. Prior to the end of September 2012, a total of 340 patients with high-risk PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from more than 41 institutions, all of which have broad experience with (125)I-BT. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will commonly undergo 6-month HT with combined androgen blockade (CAB) before and during (125)I-BT and supplemental EBRT. Those randomly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist. All participants will be assessed at baseline and every 3 months for the first 30 months, then every 6 months until 84 months from the beginning of CAB.The primary endpoint is biochemical progression-free survival. Secondary endpoints are overall survival, clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, and adverse events. To our knowledge, there have been no prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa. The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach, and to establish an appropriate treatment strategy for high-risk PCa. UMIN000003992.


The spatial patterns of Pick bodies, Pick cells and Alzheimer's disease pathology in Pick's disease.
The spatial patterns of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) were studied in the frontal and temporal lobe in nine cases of Pick's disease (PD). Pick bodies exhibited clustering in 41/44 (93%) of analyses and clusters of PB were regularly distributed parallel to the tissue boundary in 24/41 (58%) of analyses. Pick cells exhibited clustering with regular periodicity of clusters in 14/16 (88%) analyses, SP in three out of four (75%) analyses and NFT in 21/27 (78%) analyses. The largest clusters of PB were observed in the dentate gyrus and PC in the frontal cortex. In 10/17 (59%) brain areas studied, a positive or negative correlation was observed between the densities of PB and PC. The densities of PB and NFT were not significantly correlated in the majority of brain areas but a negative correlation was observed in seven of 29 (24%) brain areas. The data suggest that PB and PC in patients with PD exhibit essentially the same spatial patterns as SP and NFT in Alzheimer's disease (AD) and Lewy bodies (LB) in dementia with Lewy bodies (DLB). In addition, there was a spatial correlation between the clusters of PB and PC, suggesting a pathogenic relationship between the two lesions. However, in the majority of tissues examined there was no spatial correlation between the clusters of PB and NFT, suggesting that the two lesions develop in association with different populations of neurons.


Patients with liver cirrhosis due to nonalcoholic steatohepatitis have lesser chances for liver transplantation.
The main causes of liver cirrhosis have changed over the past decade. In Japan, the number of deceased donors is increasing but is still insufficient relative to the number of patients awaiting a liver transplant. In the present study we aimed to assess the outcomes of candidates for liver transplantation. This was a retrospective study of adult patients who visited our department for consultation regarding liver transplantation from January 2009 to December 2020. Of a total of 601 patients, 336 were followed-up. The following data were collected and analyzed: patient's characteristics, liver etiology, Child-Pugh and MELD scores, and the eventual outcome, that is, whether liver transplantation was performed. Only 153 of 336 (45.5%) patients underwent liver transplantation, of which 42 (27.5%) received deceased donor liver transplantation, and 129 (38.4%) died without transplantation. The proportion of patients who underwent liver transplantation was low among patients with nonalcoholic steatohepatitis (NASH) (10.7%) (P < .001). The rate of qualified living donors was the lowest for patients with NASH (28.6%) and that for the other etiologies ranged from 55.6% to 67.4% (P = .050). Patients with liver cirrhosis due to NASH may have a lesser chance of undergoing liver transplantation from both living and deceased donors.


Osteopathic manipulative treatment to resolve head and neck pain after tooth extraction.
Pain is a common occurrence after tooth extraction and is usually localized to the extraction site. However, clinical experience shows that patients may also have pain in the head or neck in the weeks after this procedure. The authors present a case representative of these findings. In the case, cranial and cervical somatic dysfunction in a patient who had undergone tooth extraction was resolved through the use of osteopathic manipulative treatment. This case emphasizes the need to include a dental history when evaluating head and neck pain as part of comprehensive osteopathic medical care. The case can also serve as a foundation for a detailed discussion regarding how to effectively incorporate osteopathic manipulative treatment into primary care practice for patients who present with head or neck pain after tooth extraction.


Out of the quagmire of plant defense hypotheses.
Several hypotheses, mainly Optimal Defense (OD), Carbon: Nutrient Balance (CNB), Growth Rate (GR), and Growth-Differentiation Balance (GDB), have individually served as frameworks for investigating the patterns of plant defense against herbivores, in particular the pattern of constitutive defense. The predictions and tests of these hypotheses have been problematic for a variety of reasons and have led to considerable confusion about the state of the "theory of plant defense." The primary contribution of the OD hypothesis is that it has served as the main framework for investigation of genotypic expression of plant defense, with the emphasis on allocation cost of defense. The primary contribution of the CNB hypothesis is that it has served as the main framework for investigation of how resources affect phenotypic expression of plant defense, often with studies concerned about allocation cost of defense. The primary contribution of the GR hypothesis is that it explains how intrinsic growth rate of plants shaped evolutionarily by resource availability affects defensive patterns. The primary contribution of the expanded GDB hypothesis is that it recognizes the constant physiological tradeoff between growth and differentiation at the cellular and tissue levels relative to the selective pressures of resource availability, including explicitly taking into account plant tolerance of damage by enemies. A clearer understanding of these hypotheses and what we have learned from investigations that use them can facilitate development of well-designed experiments that address the gaps in our knowledge of plant defense.


Gravid uterus in an umbilical hernia.
Umbilical hernias large enough to contain a gravid uterus are rare. We report a case of a woman with prolapse of a gravid uterus through a previously repaired umbilical hernia. Our plans for elective surgery with caesarean section and hernia repair were foiled by poor compliance. The hernia was repaired during an emergency caesarean section. We provide details of her management and briefly review the literature on umbilical hernias and pregnancy. Surgical management offers an opportunity for hernia repair and can ensure a safe delivery for the mother and child.


NuRD-ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination.
Alternative lengthening of telomeres (ALT) is a homologous recombination (HR)-dependent mechanism for de novo synthesis of telomeric DNA in mammalian cells. Nuclear receptors are bound to the telomeres of cells that use ALT. Here we demonstrate that nuclear receptors recruit ZNF827, a zinc-finger protein of unknown function, which recruits the nucleosome remodeling and histone deacetylation (NuRD) complex via binding to an N-terminal RRK motif within ZNF827. This results in decreased shelterin binding, hypoacetylation of telomeric chromatin, enhanced telomere-telomere interactions and recruitment of HR proteins, and it is critically important for cell viability and proliferation. We propose that NuRD-ZNF827 recruitment to human telomeres causes remodeling of telomeric chromatin and creates an environment that promotes telomere-telomere recombination and integrates and controls multiple mechanistic elements of ALT activity.


Imaging of actinomycosis in various organs: a comprehensive review.
Actinomycosis is a chronic suppurative bacterial infection caused by Actinomyces species. Actinomyces israelii is the organism most commonly found in human disease. Actinomycosis usually manifests with abscess formation, dense fibrosis, and draining sinuses. The disease is further characterized by the tendency to extensively spread beyond normal fascial and connective tissue planes. Actinomycosis occurs most commonly in the cervicofacial region (50%-65%), followed by the thoracic (15%-30%) and abdominopelvic (20%) regions, but rarely involves the central nervous system. Most cases of cervicofacial actinomycosis are odontogenic in origin. In the acute form, cervicofacial disease can manifest with soft-tissue swelling, a painful pyogenic abscess, or a mass lesion. In the subacute to chronic form, a painless indurated mass can spread to the skin, leading to draining sinus tracts. Thoracic manifestations include parenchymal, bronchiectatic, and endobronchial actinomycosis. At computed tomography, pulmonary actinomycosis usually appears as chronic segmental airspace consolidation containing necrotic low-attenuation areas with peripheral enhancement. Abdominopelvic actinomycosis preferentially involves the ileocecal region, ovary, and fallopian tube. The imaging findings favoring abdominopelvic actinomycosis include strong enhancement in the solid portion of the mass after contrast material administration, small rim-enhancing abscesses within the mass, and extensive inflammatory extensions. Actinomycosis in the central nervous system may produce brain abscess, meningitis, subdural empyema, actinomycetoma, and spinal and cranial epidural abscess. In general, actinomycosis responds well to antibiotic therapy, but long-term follow-up after treatment is needed because of frequent relapses.


Intercountry Transfer of Triazole-Resistant Aspergillus fumigatus on Plant Bulbs.
We investigated whether plants imported to Ireland from the Netherlands might harbor triazole-resistant Aspergillus fumigatus. Samples of plant bulbs were positive for triazole-resistant A. fumigatus with CYP51A mutations. We hypothesize that this represents a route for intercountry transfer of an emerging resistance mechanism in a major opportunistic mold pathogen.


Frequency of adhesive factors and enterotoxins in strains of Escherichia coli isolated from piglets with diarrhea.
Neonatal colibacillosis is one of the most prevalent illnesses in pig farms. In order to examine the frequency of adherence factors and the production of enterotoxins in strains of E. coli, we collected stool specimens from 500 piglets between 1 and 10 days of age with diarrhea, including piglets from several different farms on the periphery of Mérida, Yucatán. One thousand and eighty (1080) strains of E. coli were isolated, of which 127 (11.76%) produced STa, and 62 (5.74%) produced adherence factors. Of these, 30 (48.39%) produced factor K88, 18 (29.03%) produced factor 987P, 12 (19.35%) produced K99, and 2 (3.23%) produced F41. Of the 62 strains which produced adherence factors, 42 (67.74%) also produced STa, and of these, 17 (40.84%) produced factor K88, 13 (30.95%) produced 987P, 10 (23.81%) produced K99, and 2 (4.76%) produced F41. In summary, of the 1080 strains isolated, 42 (3.89%) produced both STa toxin and adherence factors, 85 (7.87%) produced STa but did not produce adherence factors, and 933 (86.39%) produced neither STa or adherence factors. No LT-producing E. coli was detected in this study.


Highly convergent synthesis of a β-mannuronic acid alginate hexadecasaccharide.
Solution-phase synthesis of poly-β-mannuronic acids still remains unexplored. We report the first synthesis of a β-mannuronic acid alginate hexadecasaccharide representing the longest synthetic polymannuronic acid so far. The highly convergent synthetic approach provides a new avenue to access poly-β-mannuronic acids that can enable the biological evaluation of poly-β-mannuronic acids as potential therapeutics and vaccines.


Constitutive activation of myosin-dependent contractility sensitizes glioma tumor-initiating cells to mechanical inputs and reduces tissue invasion.
Tumor-initiating cells (TIC) perpetuate tumor growth, enable therapeutic resistance, and drive initiation of successive tumors. Virtually nothing is known about the role of mechanotransductive signaling in controlling TIC tumorigenesis, despite the recognized importance of altered mechanics in tissue dysplasia and the common observation that extracellular matrix (ECM) stiffness strongly regulates cell behavior. To address this open question, we cultured primary human glioblastoma (GBM) TICs on laminin-functionalized ECMs spanning a range of stiffnesses. Surprisingly, we found that these cells were largely insensitive to ECM stiffness cues, evading the inhibition of spreading, migration, and proliferation typically imposed by compliant ECMs. We hypothesized that this insensitivity may result from insufficient generation of myosin-dependent contractile force. Indeed, we found that both pharmacologic and genetic activation of cell contractility through RhoA GTPase, Rho-associated kinase, or myosin light chain kinase restored stiffness-dependent spreading and motility, with TICs adopting the expected rounded and nonmotile phenotype on soft ECMs. Moreover, constitutive activation of RhoA restricted three-dimensional invasion in both spheroid implantation and Transwell paradigms. Orthotopic xenotransplantation studies revealed that control TICs formed tumors with classical GBM histopathology including diffuse infiltration and secondary foci, whereas TICs expressing a constitutively active mutant of RhoA produced circumscribed masses and yielded a 30% enhancement in mean survival time. This is the first direct evidence that manipulation of mechanotransductive signaling can alter the tumor-initiating capacity of GBM TICs, supporting further exploration of these signals as potential therapeutic targets and predictors of tumor-initiating capacity within heterogeneous tumor cell populations.


Metformin treatment status and abdominal aortic aneurysm disease progression.
In population-based studies performed on multiple continents during the past two decades, diabetes mellitus has been negatively associated with the prevalence and progression of abdominal aortic aneurysm (AAA) disease. We investigated the possibility that metformin, the primary oral hypoglycemic agent in use worldwide, may influence the progression of AAA disease. Preoperative AAA patients with diabetes were identified from an institutional database. After tabulation of individual cardiovascular and demographic risk factors and prescription drug regimens, odds ratios for categorical influences on annual AAA enlargement were calculated through nominal logistical regression. Experimental AAA modeling experiments were subsequently performed in normoglycemic mice to validate the database-derived observations as well as to suggest potential mechanisms of metformin-mediated aneurysm suppression. Fifty-eight patients met criteria for study inclusion. Of 11 distinct classes of medication considered, only metformin use was negatively associated with AAA enlargement. This association remained significant after controlling for gender, age, cigarette smoking status, and obesity. The median enlargement rate in AAA patients not taking oral diabetic medication was 1.5 mm/y; by nominal logistic regression, metformin, hyperlipidemia, and age ≥70 years were associated with below-median enlargement, whereas sulfonylurea therapy, initial aortic diameter ≥40 mm, and statin use were associated with above-median enlargement. In experimental modeling, metformin dramatically suppressed the formation and progression, with medial elastin and smooth muscle preservation and reduced aortic mural macrophage, CD8 T cell, and neovessel density. Epidemiologic evidence of AAA suppression in diabetes may be attributable to concurrent therapy with the oral hypoglycemic agent metformin.


Methods for in vitro characterization of multichannel nerve tubes.
Multichannel conduits have been developed for experimental peripheral nerve and spinal cord repair. We present a series of methods to characterize multichannel nerve tubes for properties of bending, deformation, swelling, and degradation and introduce a new method to test the permeability of multichannel nerve tubes from the rate of diffusion of different-sized fluorescent dextran molecules (10, 40, and 70 kDa). First, single-lumen nerve tubes made with different poly(lactic-co-glycolic acid) (PLGA) ratios (50:50, 75:25, and 85:15) were compared. One ratio (75:25 PLGA) was subsequently used to compare single-lumen and multichannel nerve tubes. Nerve tubes made with lower PLGA ratios were found to be more flexible than nerve tubes made with a higher PLGA ratio. For low ratios, however, swelling was also greater as a result of a faster rate of degradation. Multichannel structure did not interfere with the permeability of the tube; the rate of diffusion into multichannel 75:25 PLGA nerve tubes appeared to be even higher than that into single-lumen ones, but this was only significant for 70-kDa molecules. Also, multichannel 75:25 PLGA nerve tubes were more flexible and, at the same time, more resistant to deformation. However, swelling significantly decreased the total cross-sectional lumen area, especially in multichannel 75:25 PLGA nerve tubes. Permeability, bending, deformation, swelling, and degradation are important properties to characterize in the development of multichannel nerve tubes. The methods presented in this study can be used as a basis for optimizing these properties for future, possibly clinical, application.


Adolescent vegetarians: how well do their dietary patterns meet the healthy people 2010 objectives?
To examine whether adolescent vegetarians were more likely than nonvegetarian peers to meet the dietary recommendations of the Healthy People 2010 objectives and to examine differences in other nutrients between these 2 groups. A total of 4746 adolescents from 31 middle and high schools in the Twin Cities area of Minnesota. Data were collected via self-report surveys, with a student response rate of 81.5%. Urban secondary schools. Participants were equally divided by sex. The mean age was 14.9 years; 34.3% were in junior high school and 65.7% in high school. The racial/ethnic distribution was 48.5% white, 19.0% African American, 19.2% Asian American, 5.8% Hispanic, 3.5% American Indian, and 3.9% mixed or other. Questions on vegetarian status and whether particular foods (eggs, dairy foods, chicken, fish) were excluded. Dietary intake was assessed using the Youth and Adolescent Food Frequency Questionnaire. Vegetarian adolescents were significantly more likely than nonvegetarian adolescents to meet the Healthy People 2010 objectives. This was particularly noteworthy for total fat (70% vs 48%), saturated fat (65% vs 39%), daily servings of vegetables (26% vs 14%), and 5 or more servings of fruits and vegetables (39% vs 28%). Vegetarians were also less likely to eat fast food or drink regular soda and fruit drinks. Vegetarians consumed less vitamin B(12), more diet soda, more caffeine, and more iron. Adolescent vegetarians have a dietary pattern that is more likely than nonvegetarians to meet the Healthy People 2010 objectives.


Identification and Prioritization of Relationships between Environmental Stressors and Adverse Human Health Impacts.
There are > 80,000 chemicals in commerce with few data available describing their impacts on human health. Biomonitoring surveys, such as the NHANES (National Health and Nutrition Examination Survey), offer one route to identifying possible relationships between environmental chemicals and health impacts, but sparse data and the complexity of traditional models make it difficult to leverage effectively. We describe a workflow to efficiently and comprehensively evaluate and prioritize chemical-health impact relationships from the NHANES biomonitoring survey studies. Using a frequent itemset mining (FIM) approach, we identified relationships between chemicals and health biomarkers and diseases. The FIM method identified 7,848 relationships between 219 chemicals and 93 health outcomes/biomarkers. Two case studies used to evaluate the FIM rankings demonstrate that the FIM approach is able to identify published relationships. Because the relationships are derived from the vast majority of the chemicals monitored by NHANES, the resulting list of associations is appropriate for evaluating results from targeted data mining or identifying novel candidate relationships for more detailed investigation. Because of the computational efficiency of the FIM method, all chemicals and health effects can be considered in a single analysis. The resulting list provides a comprehensive summary of the chemical/health co-occurrences from NHANES that are higher than expected by chance. This information enables ranking and prioritization on chemicals or health effects of interest for evaluation of published results and design of future studies. Bell SM, Edwards SW. 2015. Identification and prioritization of relationships between environmental stressors and adverse human health impacts. Environ Health Perspect 123:1193-1199; http://dx.doi.org/10.1289/ehp.1409138.


Long-term duct-occluded segmental pancreatic autografts: absence of microvascular diabetic complications.
Current insulin therapies for control of glucose metabolism in patients with type I diabetes mellitus prevent major metabolic consequences of insulin deficiency, but none prevents or arrests long-term complications. In experimental models of canine diabetes, retinopathy, neuropathy, and nephropathy have been shown to develop within 5 years. The aim of this study was to determine in a canine model whether glucose control provided by segmental duct-occluded pancreas autografts could prevent the long-term complications of diabetes. Thirty-five outbred mongrel dogs underwent segmental pancreas autotransplantation with residual pancreatectomy. Follow-up over 5 years included endocrine, retinal fundus photography, fluorescein angiography, and nerve conduction studies. At endpoint, analysis of organ specific changes was undertaken. Long-term survival was achieved in 14 dogs for 4 to 5 years and in 3 dogs for 3 to 5 years. Glycosylated hemoglobin levels remained within normal limits, although response to glucose challenge was suboptimal. Fundus photography and fluorescein angiography demonstrated the absence of retinal vascular aneurisms, capillary leakage, and obliteration. Retinal digest showed no vascular changes and normal endothelial/pericyte ratios. Nerve conduction was normal, and histology of nerves revealed normal density of myelinated fibers and absence of intrafascicular vessels and glycogen deposits, with no change in spectrum of fiber diameters and ovoids. Renal histology revealed no evidence of nephropathy with normal glomerular basement membranes. We have demonstrated that duct-occluded segmental pancreatic autografts are capable of providing satisfactory metabolic control for up to 5 years, thereby preventing development of the long-term microvascular complications of diabetes.


Investigation of immunoperoxidase-labelled rotavirus in tissue culture by light and electron microscopy.
A tissue culture-adapted strain of bovine rotavirus, grown in calf kidney monolayers, has been examined by light and electron microscopy after immunoperoxidase labelling. Some of the characteristic problems associated with pre-embedding methods have been demonstrated. Preparative techniques involving pretreatment of infected cells with a detergent followed by a detergent/fixative combination have enabled virus antigen to be labelled while maintaining satisfactory ultrastructural preservation.


A study of the anti-inflammatory effect of the leaves of Psidium guajava Linn. on experimental animal models.
The aim is to study the anti-inflammatory effect of the ethanolic extract of the leaves of Psidium guajava(PGE) on experimental animal models. Fresh leaves were collected, air-dried, powdered, and percolated in 95% ethanol. Acute toxicity test was done according to OECD guidelines. Four groups of animals of either sex, weighing 150-200g of the species Rattus norvegicus were taken for the study (n = 6). Group A was taken as control (3% gum acacia in 10 mL/kg body weight), Group B as test group (PGE 250 mg/kg body weight), Group C as test group (PGE 500 mg/kg body weight), and Group D as standard (Aspirin 100 mg/kg body weight). The animals were studied for acute inflammation by Carrageenan-induced rat paw edema, subacute inflammation by Granuloma pouch method, and chronic inflammation by Freund's adjuvant-induced arthritis method. Statistical analysis was done by one-way analysis of variance followed by multiple comparison tests. In acute inflammation, there was significant inhibition of paw edema in Groups B, C, and D in comparison with Group A (P < 0.05). In subacute inflammation, there was significant inhibition of exudate formation in Groups B, C, and D in comparison to Group A (P < 0.05). In chronic inflammation, there was significant inhibition of paw edema and inhibition of weight reduction in Groups B, C, and D compared with Group A. Downregulation of arthritis index was also significant in Groups B, C, and D in comparison with Group A (P < 0.05). The ethanolic extract of PGE has significant anti-inflammatory activity.


Regulation of Clinical Xenotransplantation-Time for a Reappraisal.
The continual critical shortage of organs and cells from deceased human donors has stimulated research in the field of cross-species transplantation (xenotransplantation), with the pig selected as the most suitable potential source of organs. Since the US Food and Drug Administration concluded a comprehensive review of xenotransplantation in 2003, considerable progress has been made in the experimental laboratory to improve cell and organ xenograft survival in several pig-to-nonhuman primate systems that offer the best available models to predict clinical outcomes. Survival of heart, kidney, and islet grafts in nonhuman primates is now being measured in months or even years. The potential risks associated with xenotransplantation, for example, the transfer of an infectious microorganism, that were highlighted in the 2003 Food and Drug Administration guidance and subsequent World Health Organization consensus documents have been carefully studied and shown to be either less likely than previously thought or readily manageable by donor selection or recipient management strategies. In this context, we suggest that the national regulatory authorities worldwide should re-examine their guidelines and regulations regarding xenotransplantation, so as to better enable design and conduct of safe and informative clinical trials of cell and organ xenotransplantation when and as supported by the preclinical data. We identify specific topics that we suggest require reconsideration.


EGR1 regulates radiation-induced apoptosis in head and neck squamous cell carcinoma.
The transcription factor, early growth response 1 (EGR1) belongs to the early growth response family. EGR1 regulates the transactivation of genes involved in growth inhibition and apoptosis by ionizing radiation. The aims of the present study were to evaluate the expression of EGR1, and its relationship to prognosis, in patients with advanced laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) receiving chemoradiation therapy, and to observe the effect of EGR1 on the apoptosis of head and neck squamous cell carcinoma (HNSCC) cells treated with ionizing radiation. Expression of the EGR1 protein in tissue samples from patients with LHSCC was detected by immunohistochemistry. A high expression of the EGR1 protein was observed in 37 (67.3%) of the 55 LHSCC tissue samples examined. A high EGR1 protein expression in patients with LHSCC who were treated with chemoradiation was significantly associated with improved larynx-preservation survival (p=0.04). The 5-year disease-specific survival rate with larynx preservation was 59% in patients with a high EGR1 protein expression vs. 30% in those with a low EGR1 protein expression. In the human HNSCC cell line, PCI50, EGR1 mRNA expression was induced at 30-60 min, and EGR1 protein expression was induced at 60-120 min, after exposure to a 5 Gy dose of ionizing radiation. To evaluate the impact of EGR1 on radiation-induced apoptosis, we used small‑interfering RNA to knock down endogenous EGR1 gene expression. Cleaved caspase 3, cleaved caspase 7, and cleaved PARP were decreased, while XIAP was increased, in EGR1-knockdown PCI50 cells compared to negative control PCI50 cells, at all observed post-irradiation time points. These findings suggested that EGR1 knockdown inhibits radiation-induced apoptosis. In conclusion, EGR1 may be associated with larynx-preservation survival, through the regulation of radiation-induced apoptosis in patients with LHSCC treated with chemoradiation. Although further investigations are required to support the present study, EGR1 serves as a favorable biomarker of radiosensitivity in the treatment of LHSCC.


The Concord Centre for Mental Health's new 'phase of illness' model of care: are we on the right track?
The aim of this study was to provide an overview of a new 'phase of illness' model of care after relocation of Rozelle Hospital to the new purpose built Concord Centre for Mental Health and discuss its implementation and progress thus far. One year after relocation, staff were asked to provide feedback of their views of the new model of care in order to identify implementation barriers and ways forward. The new model has clear benefits for the consumer, but there are a number of practical challenges and dilemmas emerging that necessitate some refinement and evaluation. Feedback from staff provided a wide range of opinions indicating that some were quite cynical of the new model while others were very supportive and thought that patient care was enhanced. Further development and consolidation of the model is required, including more education sessions and a clear mission statement at unit, hospital and community levels. Further research is also required to assess the impact and ability of the new model to deliver better patient outcomes, especially in regard to continuity of care.


Pharmacokinetics of 1,25(OH)(2)D(3) and 1alpha(OH)D(3) in normal and uraemic men.
The therapeutic equivalence of 1,25(OH)(2)D(3) and 1alpha(OH)D(3) on the suppression of PTH synthesis and secretion has not clearly been established. The aim of the present study was to evaluate the pharmacokinetics of 1,25(OH)(2)D(3) and 1alpha(OH)D(3) after oral and i.v. administration in healthy volunteers and uraemic patients. Six healthy volunteers and 12 uraemic patients were included in the study. With an interval of 2 weeks, 4 microg of 1,25(OH)(2)D(3) i.v., 4 microg of 1,25(OH)(2)D(3) orally, 4 microg of 1alpha(OH)D(3) i.v. and 4 microg of 1alpha(OH)D(3) orally were administered. Blood samples for analysis of plasma-Ca(2+), plasma-1,25(OH)(2)D(3), and plasma-PTH were drawn at time 0, 0.25, 0.5, 1, 2, 4, 6, 9, 12, 24, 48, and 72 h. The healthy volunteers were studied in all four protocols and the uraemic patients in either the 1alpha(OH)D(3) (n=6) or the 1,25(OH)(2)D(3) (n=6) protocol. After oral administration of 1,25(OH)(2)D(3) the bioavailability of 1,25(OH)(2)D(3) was 70.6+/-5.8/72.2+/-4.8% in healthy volunteers/uraemic patients (n.s.). After i.v. administration the volume of distribution of 1,25(OH)(2)D(3) was similar, 0.49+/-0.14 vs 0.27+/-0.06 l/kg in healthy volunteers vs uraemic patients (n.s.), while the metabolic clearance rate of 1,25(OH)(2)D(3) was 57% lower in the uraemic patients, 23.5+/-4.34 vs 10.1+/-1.35 ml/min in healthy volunteers vs uraemic patients, respectively (P<0.03). The bioavailability of 1,25(OH)(2)D(3) after i.v. administration of 1alpha(OH)D(3) was 42.4+/-11.0/42.0+/-2.0% in healthy volunteers/uraemic patients (n.s.); and after oral administration of 1alpha(OH)D(3) 42.0+/-2.0/29.8+/-3.1% in healthy volunteers/uraemic patients (n.s.). A small, but significant increase in plasma-Ca(2+) was seen after administration of 1,25(OH)(2)D(3) to the uraemic patients, while no increase was seen after administration of 1alpha(OH)D(3). PTH levels were significantly suppressed in the healthy volunteers 24 h after administration of 4 microg of 1,25(OH)(2)D(3) i.v., 4 microg of 1,25(OH)(2)D(3) orally, and 4 microg of 1alpha(OH)D(3) orally by 35+/-7, 30+/-8, and 35+/-4%, respectively (all P<0.03). In the uraemic patients, PTH levels were significantly suppressed after administration of 4 microg of 1,25(OH)(2)D(3) i.v., 4 microg of 1,25(OH)(2)D(3) orally, and 4 microg of 1alpha(OH)D(3) i.v. by 30+/-10, 45+/-7, and 40+/-7%, respectively (all P<0.04). The effect was transitory in the healthy volunteers and lasted for at least 72 h in the uraemic patients. The present study found a 57% lower metabolic clearance rate of 1,25(OH)(2)D(3) in uraemic patients, as compared with that of healthy volunteers (P<0.03). The bioavailability of 1,25(OH)(2)D(3) following administration of 1alpha(OH)D(3) i.v. and orally in both healthy volunteers and uraemic patients was markedly lower than after administration of oral 1,25(OH)(2)D(3) (P<0.03). In spite of lower plasma-1,25(OH)(2)D(3) levels after administration of 1alpha(OH)D(3), no significant difference was observed on the suppressive effect of 4 microg i.v. of either 1,25(OH)(2)D(3) or 1alpha(OH)D(3) on the plasma-PTH levels in the uraemic patients. This might suggest the existence of an effect of 1alpha(OH)D(3) on the parathyroid glands which is independent of the plasma-1,25(OH)(2)D(3) levels, that are achieved after oral or i.v. administration of 1alpha(OH)D(3).


Climate-driven uncertainties in modeling terrestrial energy and water fluxes: a site-level to global-scale analysis.
We used a land surface model constrained using data from flux tower sites, to analyze the biases in ecosystem energy and water fluxes arising due to the use of meteorological reanalysis datasets. Following site-level model calibration encompassing major vegetation types from the tropics to the northern high-latitudes, we repeated the site and global simulations using two reanalysis datasets: the NCEP/NCAR and the CRUNCEP. In comparison with the model simulations using observed meteorology from sites, the reanalysis-driven simulations produced several systematic biases in net radiation (Rn ), latent heat (LE), and sensible heat (H) fluxes. These include: (i) persistently positive tropical/subtropical biases in Rn using the NCEP/NCAR, and gradually transitioning to negative Rn biases in the higher latitudes; (ii) large positive H biases in the tropics/subtropics using the NCEP/NCAR; (iii) negative LE biases using the NCEP/NCAR above 40°N; (iv) high tropical LE using the CRUNCEP in comparison with observationally derived global estimates; and (v) flux-partitioning biases from canopy and ground components. Across vegetation types, we investigated the role of the meteorological drivers (shortwave and longwave radiation, atmospheric humidity, temperature, precipitation) and their seasonal biases in controlling these reanalysis-driven uncertainties. At the global scale, our site-level analysis explains several model-data differences in the LE and H fluxes when compared with observationally derived global estimates of these fluxes. Using our results, we discuss the implications of site-level model calibration on subsequent regional/global applications to study energy and hydrological processes. The flux-partitioning biases presented in this study have potential implications on the couplings among terrestrial carbon, energy, and water fluxes, and for the calibration of land-atmosphere parameterizations that are dependent on LE/H partitioning.


Anaplastic lymphoma kinase aberrations in rhabdomyosarcoma: clinical and prognostic implications.
The aim of this study is to investigate anaplastic lymphoma kinase (ALK) protein expression and underlying genetic aberrations in rhabdomyosarcoma (RMS), with special attention to clinical and prognostic implications. A total of 189 paraffin-embedded RMS tumor specimens from 145 patients were collected on tissue microarray. ALK protein expression was evaluated by immunohistochemistry. ALK gene (2p23) copy number and translocations were determined by in situ hybridization. cDNA sequencing of the receptor tyrosine kinase domain of the ALK gene was assessed in 43 samples. Strong cytoplasmic ALK protein expression was more frequently observed in alveolar RMS (ARMS) than in embryonal RMS (ERMS) (81% v 32%, respectively; P < .001). ALK gene copy number gain was detected in the vast majority of ARMS (88%), compared with 52% of ERMS (P < .001). ALK copy number correlated with protein expression in primary tumors (n = 107). We identified one point mutation (2%) and seven tumors harboring whole exon deletions (16%). In ERMS, specific ALK gain in the primary tumor correlated with metastatic disease (100% in metastatic disease v 29% in nonmetastatic disease; P = .004) and poor disease-specific survival (5-year disease-specific survival: 62% v 82% for nonspecific or no gain; P = .046). Because ALK aberrations on genomic and protein levels are frequently found in RMSs, in particular ARMS, and are associated with disease progression and outcome in ERMS, ALK may play a role in tumor biology and may provide a potential therapeutic target for these tumors. Future research should aim at the oncogenic role of ALK and the potential effect of ALK inhibitors in RMS.


Mutagenic and recombinogenic effects of the antitumor antibiotic anthramycin.
Anthramycin, one of the pyrrolo(1,4)benzodiazepine antibiotics with potent antitumor activity, was tested for its effects on a number of genetic parameters. The results show that this antibiotic is nonmutagenic in the Ames strains of Salmonella typhimurium while mutagenic in only one and antimutagenic in the rest of the genes tested in the eukaryotic organism Saccharomyces cerevisiae. The antibiotic is, however, a potent recombinogen inasmuch as it induced mitotic crossing over, mitotic gene conversion, and possibly other chromosomal alterations in a diploid strain of S. cerevisiae. These studies emphasize the need for a battery of test systems including eukaryotic organisms to detect the genetic activity of certain antitumor drugs. The importance of considering data distinguishing between highly mutagenic and poorly mutagenic cancer chemotherapeutic agents is also discussed.


Natural infection with highly pathogenic avian influenza virus H5N1 in domestic pigeons (Columba livia) in Egypt.
The highly pathogenic avian influenza virus (HPAIV) subtype H5N1 threatens animal and human health worldwide. Susceptibility of pigeons to HPAIV (H5N1) and their role in avian influenza virus transmission to domestic birds and humans remain questionable. In this study, an outbreak in domestic pigeons (1 to 18 months old) with 50% mortality was investigated. Pigeons exhibited nervous manifestations and greenish diarrhoea. Necropsy of the naturally infected pigeons revealed congestion of the internal organs, particularly the lungs and brain. The HPAIV subtype H5N1 designated A/Pigeon/Egypt/SHAH-5803/2011 was isolated from a 40-day-old pigeon. Sequencing of the haemagglutinin gene showed it to be closely related to viruses in group 2.2.1/C. Intravenous inoculation of the isolate in chickens induced 100% mortality within 2 days post inoculation and the intravenous pathogenicity index was 2.7. Virus pathogenicity and transmissibility was determined experimentally in 6-week-old domestic pigeons. Thirty per cent of pigeons inoculated oronasally with 10(6) median embryo infective dose showed congested beak, conjunctivitis, depression, and greenish diarrhoea. A mortality rate of 10% was recorded preceded by severe neurologic signs consisting of torticollis, incoordination, tremors, and wing paralysis. Pathological examination revealed a friable brain tissue and congested meningeal blood vessels. The lungs appeared oedematous and severely haemorrhagic. Subepicardial and petechial haemorrhages on the coronary fat were observed. Both infected and contact pigeons shed virus via the oropharynx and cloaca. To our knowledge, this is the first description and characterization of HPAIV in naturally infected pigeons in Egypt. Our findings reveal that pigeons can indeed be susceptible to H5N1 HPAIVs and could be a source of infection to other birds and humans.


Microsecond simulations indicate that ethanol binds between subunits and could stabilize an open-state model of a glycine receptor.
Cys-loop receptors constitute a superfamily of ion channels gated by ligands such as acetylcholine, serotonin, glycine, and γ-aminobutyric acid. All of these receptors are thought to share structural characteristics, but due to high sequence variation and limited structure availability, our knowledge about allosteric binding sites is still limited. These sites are frequent targets of anesthetic and alcohol molecules, and are of high pharmacological importance. We used molecular simulations to study ethanol binding and equilibrium exchange for the homomeric α1 glycine receptor (GlyRα1), modeled on the structure of the Gloeobacter violaceus pentameric ligand-gated channel. Ethanol has a well-known potentiating effect and can be used in high concentrations. By performing two microsecond-scale simulations of GlyR with/without ethanol, we were able to observe spontaneous binding in cavities and equilibrium ligand exchange. Of interest, it appears that there are ethanol-binding sites both between and within the GlyR transmembrane subunits, with the intersubunit site having the highest occupancy and slowest exchange (∼200 ns). This model site involves several residues that were previously identified via mutations as being crucial for potentiation. Finally, ethanol appears to stabilize the GlyR model built on a presumably open form of the ligand-gated channel. This stabilization could help explain the effects of allosteric ligand binding in Cys-loop receptors.


Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis.
The chronic inflammatory bowel diseases are characterized by aberrant innate and adaptive immune responses to commensal luminal bacteria. In both human inflammatory bowel disease and in experimental models of colitis, there is an increased expression of the enzyme IDO. IDO expression has the capacity to exert antimicrobial effects and dampen adaptive immune responses. In the murine trinitrobenzene sulfonic acid model of colitis, inhibition of this enzyme leads to worsened disease severity, suggesting that IDO acts as a natural break in limiting colitis. In this investigation, we show that induction of IDO-1 by a TLR-9 agonist, immunostimulatory (ISS) DNA, critically contributes to its colitis limiting capacities. ISS DNA induces intestinal expression of IDO-1 but not the recently described paralog enzyme IDO-2. This induction occurred in both epithelial cells and in subsets of CD11c(+) and CD11b(+) cells of the lamina propria, which also increase after ISS-oligodeoxynucleotide. Signaling required for intestinal IDO-1 induction involves IFN-dependent pathways, as IDO-1 was not induced in STAT-1 knockout mice. Using both the trinitrobenzene sulfonic acid and dextran sodium sulfate models of colitis, we show the importance of IDO-1s induction in limiting colitis severity. The clinical parameters and histological correlates of colitis in these models were improved by administration of the TLR-9 agonist; however, when the function of IDO is inhibited, the colitis limiting effects of ISS-oligodeoxynucleotide were abrogated. These findings support the possibility that targeted induction of IDO-1 is an approach deserving further investigation as a therapeutic strategy for diseases of intestinal inflammation.


Comparison of the ANSI, RSD, KKH, and BRMD thyroid-neck phantoms for 125I thyroid monitoring.
The Human Monitoring Laboratory, which acts as the Canadian National Calibration Reference Centre for In Vivo Monitoring, has determined the performance characteristics of four thyroid phantoms for 125I thyroid monitoring. The phantoms were a phantom built to the specifications of the American National Standards Institute Standard N44.3; the phantom available from Radiology Support Devices; the phantom available from Kyoto Kagaku Hyohon; the phantom manufactured by the Human Monitoring Laboratory and known as the BRMD phantom. The counting efficiencies of the phantoms for 125I were measured at different phantom-to-detector distances. The anthropomorphic characteristics of the phantoms have been compared with the average man parameters. It was concluded that the BRMD, American National Standards Institute, and Radiology Support Devices phantoms have the same performance characteristics when the neck-to-detector distances are greater than 12 cm and all phantoms are essentially equivalent at 30 cm or more. The Kyoto Kagaku Hyohon phantom showed lower counting efficiencies at phantom-to-detector distances less than 30 cm. This was attributed to the design of the phantom. This study has also shown that the phantom need not be highly anthropomorphic provided the calibration is not performed at short neck-detector distances. Indeed, it might be possible to use t simple point source of 125I placed behind a 1.5 cm block of lucite at neck detector distances of 12 cm or more.


Excess black mortality in the United States and in selected black and white high-poverty areas, 1980-2000.
Black working-aged residents of urban high-poverty areas suffered severe excess mortality in 1980 and 1990. Our goal in this study was to determine whether this trend persisted in 2000. We analyzed death certificate and census data to estimate age-standardized all-cause and cause-specific mortality among 16- to 64-year-old Blacks and Whites nationwide and in selected urban and rural high-poverty areas. Urban men's mortality rate estimates peaked in 1990 and declined between 1990 and 2000 back to or below 1980 levels. Evidence of excess mortality declines among urban or rural women and among rural men was modest, with some increases. Between 1980 and 2000, there was little decline in chronic disease mortality among men and women in most areas, and in some instances there were increases. In 2000, despite improved economic conditions, working-age residents of the study areas still died disproportionately of early onset of chronic disease, suggesting an entrenched burden of disease and unmet health care needs. The lack of consistent improvement in death rates among working-age residents of high-poverty areas since 1980 necessitates reflection and concerted action given that sustainable progress has been elusive for this age group.