articles+ search results

LOW-fat diet and BLOOD cholesterol

Examines the effect of dietary cholesterol on plasma cholesterol concentration in subjects following low fat diet in Great Britain. Ratio of polyunsaturated to saturated fatty acids; Comparison of the cholesterol concentration among subjects; Importance of dietary cholesterol for the reduction of saturated fats.

MEDICINE, FETAL tissue research, POPULATION & the environment, FETAL death, and POLITICAL science

Presents global developments on the political aspects of medicine as of March 1992. Progress on fetal tissue research and transplants in Australia, Europe, and the United States; Increase in human population; Disposal of fetuses and fetus remains.

ARCHAEOLOGICAL excavations, ARCHAEOLOGICAL surveying, ARCHAEOLOGY, INTERMENT, and IRON Age

Geophysical survey and excavation have demonstrated that iron age settlement features and early Anglo-Saxon burials discovered during road construction in 1983 were part o[ an extensive multi-period site, now a Scheduled Ancient Monument. This paper presents the results of the archaeological investigations. The bulk of the report is concerned with the early Anglo-Saxon burials, which included a grave containing a balance, weights and runic inscription. The evidence for late mesolithic, neolithic -- early bronze age, iron age and post-medieval activity is also discussed, and the site is considered in its regional and wider context. [ABSTRACT FROM AUTHOR]

BEER, INTERNATIONAL economic relations, and INTERNATIONAL trade

Demonstrates how United States and Canadian controls on the alcohol market affect public health. US-Canadian alcohol control; Public health implications; How the trade agreements (GATT, FTA, NAFTA) work; Trade disputes since 1985; The larger meaning of the disputes; Chronology of the US-Canada beer dispute; Glossary; Summary.

ALCOHOL drinking

In a national sample of 11 634 Canadians aged 15 years and above, risk curves for harm to six life-areas from one's own drinking and for assault by another drinker rose steadily with the respondent's volume of alcohol consumption. While drinking five or more drinks on an occasion at least once a month substantially raised the risk at a given volume of drinking, the risk rose with volume even among those not regularly drinking five or more drinks. These relationships remained in logistic regressions which controlled for gender, age and educational level. Younger respondents, those without higher education and men reported more harm for a given level of their own drinking although differences by gender disappeared above one-third of one drink per day. Three sets of guidelines for low-risk drinking-two from Canada, and one generally used in Britain-were compared in terms of the proportions of respondents reporting harm from their own drinking among those who had kept within the guideline in the previous 7 days' drinking. More restrictiveness in the guidelines was associated with substantial reductions in reported drinking-related harm. [ABSTRACT FROM AUTHOR]

TUBERCULOSIS prevention, MEDICAL care of HIV-positive persons, ISONIAZID, PTERIDINES, and DRUG efficacy

Studies the effectiveness of isoniazid versus rifampicin with pyrazinamide for prevention of tuberculosis in HIV-1 positive individuals. Methods for comparing efficacy of the chemoprophylaxis regimens; Findings; Interpretation. INSET: Disease categories.

PERSONALITY, ANGER, CITY traffic, AFRICAN Americans, AUTOMOBILE drivers, ATTITUDE (Psychology), and PSYCHOLOGICAL burnout

This study evaluates the psychosocial correlates of anger-related traits. Participants include New York City traffic enforcement agents (TEAs), who issue summonses for vehicular and parking violations and are frequently confronted by angry motorists. This sample of TEAs is 53% African American and 57% female. Participants completed surveys at 2 points, 4 months apart, which measured attitudinal, affective, and expressive components of hostility and anger, as well as dimensions of workplace psychosocial response. Results indicate that trait anger-in was positively associated with frequency of conflict, anger intensity, and burnout in cross-sectional analyses; and positively associated with frequency of conflict in prospective analyses. Trait anger was positively associated with an increase in burnout over a 4-month period. These findings provide support for the transactional model of hostility and health and have implications for worksite interventions promoting cardiovascular health. [ABSTRACT FROM AUTHOR]

COMMUNITY health services, NATIONAL health insurance, and MEDICAL care

A series of 12 studies (five historic cohort and seven randomized trials) examined clients in community settings in Southern Ontario suffering from a variety of chronic physical and mental health conditions. These studies are appraised using a framework for evaluating possible outcomes of economic evaluation. In the 12 studies, sample composition and size varied. Each study was designed to quantify the well-being outcomes and expenditures associated with different community-based approaches to care provided in the context of a system of national health insurance. As a collective, these studies represent increasing methodological rigour. Multiple-perspective client well-being outcome measures were used. In two studies, caregiver burden also was analysed. A common approach to quantification and evaluation of expenditures for service consumption was used in all 12 studies. The nature of community-based health services (health vs. disease care orientation) was found to have direct and measurable impact on total expenditures for health service utilization and client well-being outcomes. In most cases, a recurring pattern of equal or better client outcomes, yet lower expenditures for use of community based health services, was associated with well-integrated health oriented services. Integrated services aimed at factors which determine health are superior when compared to individual, fragmented, disease oriented, and focused approaches to care. The main lessons from the 12 studies are that it is as or more effective and as or less expensive to offer complete, proactive, community health services to persons living with chronic circumstance than to provide focused, on-demand, piecemeal services. Complete services would have a psychosocial and mental health focus included with the physical care approach. Furthermore, people with coexisting risk factors (age, living arrangements, mental distress and problem-solving ability) are the ones who most benefit at lower expense... [ABSTRACT FROM AUTHOR]

PERIODONTAL disease and KERATOSIS

Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7-9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between DllS4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers. [ABSTRACT FROM AUTHOR]

SUBSTANCE abuse prevention, ETHNICITY, MEDICAL communication, ETHNIC groups, PATHOLOGICAL psychology, and SOCIAL psychology

The rationale for targeted and tailored substance use prevention programs derives from essentially three observations: 1) differences in substance use prevalence rates across racial/ethnic groups; 2) differences in the prevalence of the risk factors for substance use across racial/ethnic groups; and 3) differences in the predictors of substance use across groups. This article provides a model for understanding cultural sensitivity as it pertains to substance use prevention. Cultural sensitivity is defined by two dimensions, surface and deep structure. Surface structure involves matching intervention materials and messages to observable, “superficial” characteristics of a target population. This may involve using people, places, language, product brands, music, food, locations, and clothing familiar to, and preferred by, the target audience. Surface structure refers to how well interventions fit within a specific culture. Deep structure involves incorporating the cultural, social, historical, environmental, and psychologic forces that influence the target health behavior in the proposed target population. For example, peer influences may exert a greater influence on substance use initiation among White and Hispanic than among African American youth, while parental influences may be stronger among African Americans. Whereas surface structure generally increases the "receptivity" or "acceptance" of messages, deep structure conveys salience. Techniques for developing culturally sensitive interventions, borrowed from social marketing and health communication theory, are described. © 2000 John Wiley & Sons, Inc. [ABSTRACT FROM AUTHOR]

GENETICS of multiple sclerosis, APOLIPOPROTEIN E, GENETIC polymorphisms, and GENETICS of disease susceptibility

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, with a complex etiology that includes a strong genetic component. The contribution of the major histocompatibility complex (MHC) has been established in numerous genetic linkage and association studies. In addition to the MHC, the chromosome 19q13 region surrounding the apolipoprotein E (APOE) gene has shown consistent evidence of involvement in MS when family-based analyses were conducted. Furthermore, several clinical reports have suggested that the APOE-4 allele may be associated with more-severe disease and faster progression of disability. To thoroughly examine the role of APOE in MS, we genotyped its functional alleles, as well as seven single-nucleotide polymorphisms (SNPs) located primarily within 13 kb of APOE, in a data set of 398 families. Using family-based association analysis, we found statistically significant evidence that an SNP haplotype near APOE is associated with MS susceptibility (P = .005 ). An analysis of disease progression in 614 patients with MS from 379 families indicated that APOE-4 carriers are more likely to be affected with severe disease (P = .03 ), whereas a higher proportion of APOE-2 carriers exhibit a mild disease course (P = .02 ). [ABSTRACT FROM AUTHOR]

RELAXIN, RAT physiology, RENAL artery, MYOGENESIS, and MESENTERIC artery

Presents information on a study which investigated whether myogenic reactivity of small renal and mesenteric arteries is reduced in relaxin-treated rats. Methodology; Impact of relaxin on myogenic reactivity; Link between denudation of endothelium and myogenic reactivity; Role of nitric oxide in the reduction of myogenic activity.

CONDENSATION, PYRYLIUM compounds, and CARBANIONS

The condensation reaction between γ-unsubstituted pyrylium salts and carbanions of Fischer-type carbene complexes allowed the synthesis of new γ-methylenepyran carbene complexes. NMR data, single crystal X-ray analysis, and DFT calculations suggest that these complexes have a partial pyrylium character due to the π electron-accepting ability of the carbenic fragment and to the electron-releasing properties of the methylenepyran part. [Copyright &y& Elsevier]

XYLANASES and ASPERGILLUS

The heterologous production of Arthromyces ramosus peroxidase (ARP) was analysed in the filamentous fungus Aspergillus awamori under control of the inducible endoxylanase promoter. Secretion of active ARP was achieved up to 800 mg l−1 in shake flask cultures. Western blot analysis showed that an rARP product of the correct molecular weight was produced. In contrast to several other studies about heterologous production of heme containing peroxidases, our results suggest that in A. awamori no heme limitation exists during overproduction of ARP. [Copyright &y& Elsevier]

CELL differentiation, APOPTOSIS, FATTY acids, and PROTEINS

We previously reported that the enterocytic differentiation of human colonic Caco-2 cells correlated with alterations in integrin signaling. We now investigated whether differentiation and apoptosis of Caco-2 cells induced by the short-chain fatty acid butyrate (NaBT) was associated with alterations in the integrin-mediated signaling pathway with special interest in the expression and activity of focal adhesion kinase (FAK), of the downstream phosphatidylinositol 3'-kinase (PI 3-kinase)Akt pathway and in the role of the nuclear factor κB (NF-κB). NaBT increased the level of sucrase. It induced apoptosis as shown by: (1) decreased Bcl-2 and Bcl-XL proteins and increased Bax protein; (2) activation of caspase-3; and (3) increased shedding of apoptotic cells in the medium. This effect was associated with defective integrin-mediated signaling as shown by: (1) down-regulation of β1 integrin expression; 2) decreased FAK expression and tyrosine phosphorylation; (3) concerted alterations in cytoskeletal and structural focal adhesions proteins (talin, ezrin); and (4) decreased FAK ability to associate with PI 3-kinase. However, in Caco-2 cells, β1-mediated signaling failed to be activated downstream of FAK and PI 3-kinase at the level of Akt. Transfection studies show that NaBT treatment of Caco-2 cells promoted a significant activation of the NF-κB which was probably involved in the NaBT-induced apoptosis. Our results indicate that the prodifferentiating agent NaBT induced apoptosis of Caco-2 cells probably through NF-κB activation together with a defective β1 integrin-FAK-PI 3-kinase pathways signaling. J. Cell. Physiol. 197: 336347, 2003© 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

NEURONS, ELECTROPHYSIOLOGY, SENSORY receptors, HAIR cells, and COCHLEA

Type I and type II spiral ganglion neurons convey auditory information from the sensory receptors in the cochlea to the CNS. The numerous type I neurons have been extensively characterized, but the small population of type II neurons with their unmyelinated axons are undetectable with most recording methods. Despite the paucity of information about the type II neurons, it is clear that they must have a significant role in sound processing because they innervate the large number of outer hair cells that are critical for maintaining normal responses to stimuli. To elucidate the function of type II neurons, we have developed an approach for studying their electrophysiological features in vitro. Type II neurons obtained from postnatal day 6-7 mice displayed distinctly different firing properties than type I neurons. They showed slower accommodation, lower action potential thresholds, and more prolonged responses to depolarizing current injection than the type I neurons. These differences were most evident in neurons from the basal, high-frequency region of the cochlea. The basal type I neurons displayed uniformly fast firing features, whereas the basal type II neurons showed particularly slow accommodation and responses to depolarization. Interestingly, neurons from the apical, low-frequency region of the cochlea showed the opposite trend. These data suggest that the type I and type II neurons have specialized electrophysiological characteristics tailored to their different roles in auditory signal processing. In particular, the type II neuron properties are consistent with cells in other sensory systems that receive convergent synaptic input for high-sensitivity stimulus detection. [ABSTRACT FROM AUTHOR]

HABITAT selection, GLOBAL Positioning System, HABITATS, VEGETATION & climate, RADIO telemetry, and ANIMAL radio tracking

Journal of Applied Ecology (2004) 41, 201–212 [ABSTRACT FROM AUTHOR]

Objectives: To compare the effects of low vs. high tidal volume (Vt) with three positive end-expiratory pressure (PEEP) strategies on activated neutrophil influx into the lung.Design: Prospective, randomized controlled animal study.Setting: Animal laboratory in a university hospital.Subjects: Newborn piglets.Interventions: Surfactant-depleted piglets were randomized in littermate pairs; to PEEP of either 0 (zero end-expiratory pressure [ZEEP]; n = 6), 8 cm H2O (PEEP 8; n = 5), or 1 cm H2O above the lower inflection point (LIP) (PEEP>LIP; n = 6). Within each pair piglets were randomized to a low VT (5-7 mL/kg) or high VT strategy (17-19 mL/kg). After 4 hrs of mechanical ventilation, 18-fluorodeoxyglucose (18FDG) was injected and positron emission tomography scanning was performed.Measurements and Main Results: VT and PEEP changes on influx constants of 18FDG were assessed by analysis of variance. A within-litter comparison of Vt was nonsignificant (p = .50). A between-litter comparison, ordered in linear trend rank, from ZEEP, to PEEP 8, to PEEP>LIP, showed a strong effect of PEEP on influx constant (p = .019).Conclusions: PEEP set above the LIP on the inspiratory limb of the pressure-volume curve affords a stronger lung protection than VT strategy. [ABSTRACT FROM AUTHOR]

MENTAL depression, QUALITY of life, PSYCHOLOGICAL adaptation, HIV-positive persons, AIDS patients, and SOCIAL services

Examines the prevalence of depression, and its association with quality–of–life, coping strategies, social support, and use of health and social services among people living with HIV and AIDS in Ontario. Indication of the prevalence of depression; Increase of the use of crisis health care and related services among subjects; Improvement of the quality of life through expanding the capacity of medical workers to recognize and address depression.

BOOKS, LIBRARIES, INFORMATION science, HEALTH services administration, HEALTH of physicians, and MEDICAL care

The article presents a special report on the book "Standards for Hospital Libraries 2002." The 2004 revisions of the book include an expansion of standard 6, which is a glossary definition of "library," and updates to the bibliography. The expanded standard 6 defines appropriate resources, technology, and services that must be provided. The updates to the bibliography include the latest edition of the Joint Commission on Accreditation of Healthcare Organizations Comprehensive Accreditation Manual for Hospitals, the Medical Library Association policy statement on the role of expert searching in health sciences libraries, and updates of some Website addresses. The librarian uses a variety of tools and techniques, both formal and informal, to assess the knowledge-based information needs of the hospital and medical staff. The needs assessment should address the timeliness of information services and document delivery. In response, resources and services are made available to meet those identified needs.

SHEEHAN'S syndrome, SOMATOTROPIN, INTELLECTUAL disabilities, ETIOLOGY of diseases, TRANSCRIPTION factors, and PATHOLOGICAL psychology

Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR. [ABSTRACT FROM AUTHOR]

SCHIZOPHRENIA, PSYCHOSES, DELUSIONS, HALLUCINATIONS, DIAGNOSIS of schizophrenia, SIBLINGS, CHI-squared test, COMPARATIVE studies, DEMOGRAPHY, FACTOR analysis, FAMILY health, RESEARCH methodology, MEDICAL cooperation, PSYCHOLOGICAL tests, PSYCHOLOGY, RESEARCH, EVALUATION research, and SEVERITY of illness index

Abstract: Careful phenotyping and the identification of subtypes of schizophrenia can contribute significantly to the success of genetic studies in schizophrenia. The phenomenology of schizophrenia in affected sib pairs has been well-described in Caucasian populations, however a paucity of data exists for African populations. This study therefore investigated symptom dimensions in a sizeable group of affected Xhosa sib pairs as a means of evaluating the role of shared familial factors in the psychosis of schizophrenia. Five hundred and thirteen participants were interviewed with the Diagnostic Interview for Genetic Studies (DIGS), which included the Schedules for the Assessment of Negative and Positive symptoms (SANS/SAPS). One hundred and four sib pairs were then extracted (N =208) for analysis of concordance for lifetime psychotic symptoms and an exploratory factor analysis of the SANS/SAPS. Concordance analysis of life-time symptoms indicated a significant concordance for olfactory hallucinations, persecutory delusions, jealousy, somatic, reference and control delusions as well as thought insertion and withdrawal. The factor analysis of the global scores of the SAPS and SANS revealed a five factor best-fit model and accounted for 92.5% of variance. The factors included a negative symptom factor, a positive symptom factor, a positive thought disorder and a bizarre behaviour component. The core symptomatology of schizophrenia in this sib pair sample was similar to that reported in Caucasian populations with the exception of higher rates of auditory hallucinations and delusions of persecution. In summary therefore; although the factor analysis only supported the concept of the universality of psychotic symptoms in schizophrenia, the concordance analysis of these symptoms did reveal hallucinations as well as delusions of control as possible candidates relevant for future research into genotype–phenotype relationships. [Copyright &y& Elsevier]

AZEPINES, HETEROCYCLIC compounds, EPIDERMAL growth factor, and PROTEIN-tyrosine kinase inhibitors

Abstract: A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1μM in cellular phosphorylation assays (IC50 0.47–0.69μM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile. [Copyright &y& Elsevier]

SEPTEMBER 11 Terrorist Attacks, 2001, PARTICLES, TOXINS, GLASS fibers, POLYCYCLIC aromatic hydrocarbons, DIOXINS, and PUBLIC health

In the aftermath of the September 11 World Trade Center (WTC) attack, a large number of people sustained potential exposures to smoke, dust, particulate matter, and a variety of toxins, including asbestos, pulverized concrete, glass fibers, polycyclic aromatic hydrocarbons (PAHs), and polychlorinated furans and dioxins. Additionally, many had exposure to psychological traumatogens. The most common effects seen to date are respiratory and mental health consequences. The long-term consequences of exposures are not yet known, and there remains concern about the potential for late-emerging diseases such as cancers. This article reviews WTC-related health effects, the spectrum of exposures and how they were documented, and discusses future preventive efforts. [ABSTRACT FROM AUTHOR]

HEALTH promotion, NURSING, HOME care services, PREVENTIVE health services, and FRAIL elderly

Aim. This paper reports a study evaluating the comparative effects and costs of a proactive nursing health promotion intervention in addition to usual home care for older people compared with usual home care services alone. Background. An ageing population, budget constraints and technological advances in many countries have increased the pressure on home care resources. The result is a shift in nursing services from health promotion to meet the more pressing need for postacute care. For frail older people with long-term needs, these changes combine to create a fragmented system of health service delivery, characterized by providing nursing on demand rather than proactively. Methods. A two-armed, single-blind, randomized controlled trial was carried out with older people ≥75 years and eligible for personal support services through a home care programme in Ontario, Canada. Participants were randomly allocated either to usual home care (control) or to a nursing (experimental) group. In addition to usual home care, the nursing group received a health assessment combined with regular home visits or telephone contacts, health education about management of illness, coordination of community services, and use of empowerment strategies to enhance independence. The data were collected in 2001–2002. Results. Of the 288 older people who were randomly allocated at baseline, 242 (84%) completed the study (120 nursing group; 122 control group). Proactively providing older people with nursing health promotion, compared with providing nursing services on-demand, resulted in better mental health functioning ( P = 0·009), a reduction in depression ( P = 0·009), and enhanced perceptions of social support ( P = 0·009) at no additional cost from a societal perspective. Conclusions. Home based nursing health promotion, proactively provided to frail older people with chronic health needs, enhances quality of life while not increasing the overall costs of health care. The results underscore the need to re-invest in nursing services for health promotion for older clients receiving home care. [ABSTRACT FROM AUTHOR]

DIAZEPINES, EPIDERMAL growth factor, CYTOKINES, and PROTEIN-tyrosine kinases

Abstract: Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure–activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC50 values in the single-digit micromolar to submicromolar range). [Copyright &y& Elsevier]

COMMUNITY health nurses, HEALTH promotion, HOME care of older people, HOME care services, and COMMUNITY health services

Despite the large potential role that community nurses have in providing individualized health promotion to older people, there is a lack of consensus in the literature regarding this role's effectiveness and efficiency. This article presents a literature review and synthesis of 12 randomized controlled trials selected from 344 published studies on preventive home visitation programs for older people. The findings suggest that a diversity of home visiting interventions carried out by nurses can favorably affect health and functional status, mortality rates, use of hospitalization and nursing homes, and costs. Further research is needed that focuses on the outcomes of quality of life, mental health, social support, caregiver burden, the acceptability of intervention, and specific subgroups of clients who benefit most. Findings also indicate the need for a theoretical foundation, increased emphasis on health-promotion strategies, and more research using a more complete economic evaluation to establish efficiency. [ABSTRACT FROM AUTHOR]

WORLD Trade Center Bombing, New York, N.Y., 1993, RESCUE work, EMERGENCY medical services, SEPTEMBER 11 Terrorist Attacks, 2001, TERRORISM, MEDICAL screening, HEALTH risk assessment, DIAGNOSTIC services, and MEDICAL care

BACKGROUND: Approximately 40,000 rescue and recovery workers were exposed to caustic dust and toxic pollutants following the 11 September 2001 attacks on the World Trade Center (WTC). These workers included traditional first responders, such as firefighters and police, and a diverse population of construction, utility, and public sector workers. METHODS: To characterize WTC-related health effects, the WTC Worker and Volunteer Medical Screening Program was established. This multicenter clinical program provides free standardized examinations to responders. Examinations include medical, mental health, and exposure assessment questionnaires; physical examinations; spirometry; and chest X rays. RESULTS: Of 9,442 responders examined between July 2002 and April 2004, 69% reported new or worsened respiratory symptoms while performing WTC work. Symptoms persisted to the time of examination in 59% of these workers. Among those who had been asymptomatic before September 11, 61% developed respiratory symptoms while performing WTC work. Twenty-eight percent had abnormal spirometry; forced vital capacity (FVC) was low in 21%; and obstruction was present in 5%. Among nonsmokers, 27% had abnormal spirometry compared with 13% in the general U.S. population. Prevalence of low FVC among nonsmokers was 5-fold greater than in the U.S. population (20% vs. 4%). Respiratory symptoms and spirometry abnormalities were significantly associated with early arrival at the site. CONCLUSION: WTC responders had exposure-related increases in respiratory symptoms and pulmonary function test abnormalities that persisted up to 2.5 years after the attacks. Long-term medical monitoring is required to track persistence of these abnormalities and identify late effects, including possible malignancies. Lessons learned should guide future responses to civil disasters. [ABSTRACT FROM AUTHOR]

NEUROMUSCULAR diseases, HUMAN chromosome abnormality diagnosis, GENETIC mutation, and GENETIC testing

Mutations in DOK7 have recently been shown to underlie a recessive congenital myasthenic syndrome (CMS) associated with small simplified neuromuscular junctions (‘synaptopathy’) but normal acetylcholine receptor and acetylcholinesterase function. We identified DOK7 mutations in 27 patients from 24 kinships. Mutation 1124_1127dupTGCC was common, present in 20 out of 24 kinships. All patients were found to have at least one allele with a frameshift mutation in DOK7 exon 7, suggesting that loss of function(s) associated with the C-terminal region of Dok-7 underlies this disorder. In 15 patients, we were able to study the clinical features in detail. Clinical onset was usually characterized by difficulty in walking developing after normal motor milestones. Proximal muscles were usually more affected than distal, leading to a ‘limb-girdle’ pattern of weakness; although ptosis was often present from an early age, eye movements were rarely involved. Patients did not show long-term benefit from anticholinesterase medication and sometimes worsened, and where tried responded to ephedrine. The phenotype can be distinguished from ‘limb-girdle’ myasthenia associated with tubular aggregates, where DOK7 mutations were not detected and patients respond to anticholinesterase treatments. CMS due to DOK7 mutations are common within our UK cohort and is likely to be under-diagnosed; recognition of the phenotype will help clinical diagnosis, targeted genetic screening and appropriate management. [ABSTRACT FROM AUTHOR]

HEALTH of poor children, MOTOR ability in children, PHYSIOLOGICAL control systems, LOCOMOTOR control, AFRICAN American children, MOTOR ability research, SOCIOECONOMIC factors, and PHYSIOLOGY

Children from poor, urban, and disadvantaged environments often demonstrate poor motor skill competence in both object control (OC) and locomotor skills (Goodway & Rudisill, 1996; Hamilton et al., 1999). This study examined the motor skill competence of disadvantaged, African American preschoolers. Further, it investigated the effects of a 9-week OC intervention on OC competence. Two instructional approaches were compared: low autonomy (LA) consisting of direct-instruction and a mastery motivational climate (MMC). Participants were randomly assigned to a LA (n = 36), MMC (n = 38), or comparison (no motor intervention) group (n = 39). The LA and MMC groups participated in 18 30-min OC sessions and the comparison group participated in the same amount of unstructured recess. All children were pre-and posttested on the OC subscale of the TGMD-2 (Ulrich, 2001). Preintervention OC competence was low based on percentile ranks (LA = 23%, MMC = 20%, comparison = 20%). A 3 (Group) x 2 (Sex) ANOVA on pre-OC scores revealed no significant group differences (p = .90) or Group x Sex interaction (p = .60). However, a significant sex main effect was found with boys having greater OC competence than girls, F(1, 107) = 29.34, p < .001. A 3 (Group) x 2 Time x 2 (Sex) ANOVA with repeated measures revealed a significant Group x Time interaction, F(2, 107) = 210.97, p < .001, indicating the OC intervention was effective. Post hoc Tukey HSD analysis reported the LA (p ≤ = < .001) and MMC (p ≤ = < .001) groups had significantly better OC competence than the Comparison group from pre- to postintervention. There was no difference between the LA and MMC groups (p = .88). A nonsignificant Group x Time x Sex interaction (p = .94) showed that there were no sex differences within groups from pre- to postintervention. Clearly, disadvantaged preschoolers had low OC competence and needed motor intervention. When instruction was provided by either LA or MMC, preschool children improved their OC skills. [ABSTRACT FROM AUTHOR]

CYTOKINES, CELLULAR immunity, APOPTOSIS, CELL death, GENETIC mutation, and LIGANDS (Biochemistry)

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a cytokine that preferentially induces apoptosis in tumor cells compared with normal cells through two receptors (DR4 and DR5). Somatic mutations in these receptors have been found in different kinds of cancer; however, it is poorly under- stood how the mutations affect signaling. We found that point mutations (L334F, E326K, E338K, and K386N) that were identified in human tumors result in the DR5 receptor losing its ability to form a functional death-inducing signaling complex and induce apoptosis. The mutant receptors also have a ‘dominant negative’ effect whereby they inhibit the ability of TRAIL to induce apoptosis through functional DR4 receptors. This dominant negative mechanism is achieved through competition for TRAIL binding as shown by experiments where the ability of the mutant DR5 receptor to bind with the ligand was abolished, thus restoring TRAIL signaling through DR4. The inhibitory effect on signaling through the wild-type DR4 protein can be overcome if the inhibitory mechanism is bypassed by using a DR4-agonistic antibody that is not subject to this competition. This study provides a molecular basis for the use of specific therapeutic agonists of TRAIL receptors in people whose tumors harbor somatic DR5 mutations. [ABSTRACT FROM AUTHOR]

PROTEINS, NEURONS, SENSE organs, AUDITORY pathways, SENSORY receptors, and COCHLEA

A unifying principle of sensory system organization is feature extraction by modality-specific neuronal maps in which arrays of neurons show systematically varied response properties and receptive fields. Only beginning to be understood, however, are the mechanisms by which these graded systems are established. In the peripheral auditory system, we have shown previously that the intrinsic firing features of spiral ganglion neurons are influenced by brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). We now show that is but a part of a coordinated package of neurotrophin actions that also includes effects on presynaptic and postsynaptic proteins, thus encompassing the input, transmission, and output functions of the spiral ganglion neurons. Using immunocytochemical methods, we determined that proteins targeted to opposite ends of the neuron were organized and regulated in a reciprocal manner. AMPA receptor subunits GluR2 and GluR3 were enriched in base neurons compared with their apex counterparts. This distribution pattern was enhanced by exposure to BDNF but reduced by NT-3. SNAP-25 and synaptophysin were distributed and regulated in the mirror image: enriched in the apex, enhanced by NT-3 and reduced by BDNF. Moreover, we used a novel coculture to identify potential endogenous sources of neurotrophins by showing that sensory receptors from different cochlear regions were capable of altering presynaptic and postsynaptic protein levels in these neurons. From these studies, we suggest that BDNF and NT-3, which are systematically distributed in complementary gradients, are responsible for orchestrating a comprehensive set of electrophysiological specializations along the frequency contour of the cochlea. [ABSTRACT FROM AUTHOR]

ORTHOGRAPHY & spelling, LEARNING, LITERACY, SECOND grade (Education), SCHOOL children, TEACHING, and GENES

As part of a longitudinal twin study of literacy and language, we conducted a behaviour-genetic analysis of orthographic learning, spelling and decoding in Grade 2 children (225 identical and 214 fraternal twin pairs) in the United States and Australia. Each variable showed significant genetic and unique environment influences. Multivariate analyses revealed very high genetic correlations among the variables, indicating that the same genes are involved in their aetiology. These genes are partly independent of those contributing to intelligence. A further analysis indicated that the covariation between decoding and orthographic learning is mediated by shared genes rather than by a direct causal path. The authors argue that a learning parameter, most directly assessed by orthographic learning in this study, underlies all three literacy variables. The results are also discussed in relation to Share's self-teaching hypothesis, which may require modification. [ABSTRACT FROM AUTHOR]

SEPTEMBER 11 Terrorist Attacks, 2001, HAZARDOUS substance exposure, MEDICAL screening, HAZARDS, and HEALTH risk assessment

The attack on the World Trade Center (WTC) on September 11th, 2001 exposed thousands of individuals to an unprecedented mix of chemicals, combustion products and micronized building materials. Clinicians at the Mount Sinai Irving Selikoff Center for Occupational and Environmental Medicine, in partnership with affected stakeholder organizations, developed a medical screening program to evaluate the health status of workers and volunteers who spent time at the WTC site and thus sustained exposure in the aftermath of September 11th. Standardized questionnaires were adapted for use in this unique population and all clinicians underwent training to ensure comparability. The WTC Worker and Volunteer Medical Screening Program (MSP) received federal funding in April 2002 and examinations began in July 2002. The MSP and the follow up medical monitoring program has successfully recruited nearly 22,000 responders, and serves as a model for the rapid development of a medical screening program to assess the health of populations exposed to environmental hazards as a result of natural and man-made disasters. The MSP constitutes a successful screening program for WTC responders. We discuss the challenges that confronted the program; the absence of a prior model for the rapid development of a program to evaluate results from mixed chemical exposures; little documentation of the size of the exposed population or of who might have been exposed; and uncertainty about both the nature and potential severity of immediate and long-term health effects. [ABSTRACT FROM AUTHOR]

DISASTERS, FIRST responders, HEALTH risk assessment, and SEPTEMBER 11 Terrorist Attacks, 2001

Studies of long-term health consequences of disasters face unique methodologic challenges. The authors focused on studies of the health of cleanup and recovery workers, who are often poorly enumerated at the outset and difficult to follow over time. Comparison of the experience at the World Trade Center disaster with 4 past incidents of chemical and radiation releases at Seveso, Italy; Bhopal, India; Chernobyl, Ukraine; and Three Mile Island, USA, provided useful contrasts. Each event had methodologic advantages and disadvantages that depended on the nature of the disaster and the availability of records on area residents, and the emergency-response and cleanup protocol. The World Trade Center Worker Monitoring Program has well-defined eligibility criteria but lacks information on the universe of eligible workers to characterize response proportions or the potential for distortion of reported health effects. Nonparticipation may result from lack of interest, lack of awareness of the program, availability of another source of medical care, medical conditions precluding participation, inability to take time off from work, moving out of the area, death, or shift from initially ineligible to eligible status. Some of these considerations suggest selective participation by the sickest individuals, whereas others favor participation by the healthiest. The greatest concern with the validity of inferences regarding elevated health risks relative to external populations is the potential for selective enrollment among those who are affected. If there were a large pool of nonparticipating workers and those who suffered ill health were most motivated to enroll, the rates of disease among participants would be substantially higher than among all those eligible for the program. Future disaster follow-up studies would benefit substantially by having access to accurate estimates of the number of workers and information on the individuals who contributed to the cleanup and recovery effort. [ABSTRACT FROM AUTHOR]

MENTAL health, VOLUNTEERS, SEPTEMBER 11 Terrorist Attacks, 2001, EMOTIONAL trauma, and MENTAL health services

Background: Disaster workers responding to the events of September 11th were exposed to traumatic events. No study has systematically investigated the diverse mental health status and needs of the heterogeneous population of disaster workers responding to the events of September 11th. Methods: Using PubMed and Medline and the search terms of "September 11, 2001" or "September 11" or "9/11" or "WTC" or "World Trade Center", the authors reviewed all articles that examined the mental health outcomes of workers at one of the three September 11th crash sites or the Fresh Kills landfill in New York City. Results: In total, 25 articles met study inclusion criteria, often using different methodologies. The articles described varying degrees of mental health symptomatology, risk factors for adverse mental health outcomes, and utilization of mental health services. Conclusions: The mental health needs of workers exposed to the events of September 11th ranged from little to no care to pharmacotherapy. A range of risk factors, including exposures at the WTC site and occupational activities, impacted on these needs but the role of specific mental health interventions was less clear. These findings suggest the need for a future program for disaster workers consisting of an accessible mental health treatment service supported by comprehensive postdisaster surveillance and emphasis on pre-disaster mental wellness. A number of areas for further consideration and study were identified, including the need for a more diverse exploration of involved responder populations as well as investigation of potential mental health outcomes beyond post-traumatic stress disorder (PTSD). [ABSTRACT FROM AUTHOR]

Background: The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral suppression [VS] group). In the DC group, participants started ART when the CD4+ cell count was <250 cells/microL. Clinical outcomes in participants not receiving ART at entry inform the early use of ART.Methods: Patients who were either ART naive (n=249) or who had not been receiving ART for >or= 6 months (n=228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths; and (iv) the composite of outcomes (ii) and (iii).Results: A total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for >or= 6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for 6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56; p=.02); outcome (ii), 3.26 (95% CI, 1.04-10.25; p=.04); outcome (iii), 7.02 (95% CI, 1.57-31.38; p=.01); and outcome (iv), 4.19 (95% CI, 1.69-10.39; p=.002 ).Conclusions: Initiation of ART at CD4+ cell counts >350 cells/microL compared with <250 cells/microL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial. [ABSTRACT FROM AUTHOR]

PROTEIN kinases, OLIGODENDROGLIA, GENETIC translation, MESSENGER RNA, NUCLEOPROTEINS, and RNA

Central nervous system myelination requires the synthesis of large amounts of myelin basic protein (MBP) at the axon-glia contact site. MBP messenger RNA (mRNA) is transported in RNA granules to oligodendroglial processes in a translationally silenced state. This process is regulated by the trans-acting factor heterogeneous nuclear ribonucleoprotein (hnRNP) A2 binding to the cis-acting A2 response element (A2RE). Release of this repression of MBP mRNA translation is thus essential for myelination. Mice deficient in the Src family tyrosine kinase Fyn are hypomyelinated and contain reduced levels of MBP. Here, we identify hnRNP A2 as a target of activated Fyn in oligodendrocytes. We show that active Fyn phosphorylates hnRNP A2 and stimulates translation of an MBP A2RE-containing reporter construct. Neuronal adhesion molecule L1 binding to oligodendrocytes results in Fyn activation, which leads to an increase in hnRNP A2 phosphorylation. These results suggest that Fyn kinase activation results in the localized translation of MBP mRNA at sites of axon-glia contact and myelin deposition. [ABSTRACT FROM AUTHOR]

EARLY childhood education, LITERACY programs, ACTIVITY programs in kindergarten, and SCHOOL attendance

Abstract: Genetic and environmental influences on early reading and spelling at the end of kindergarten and Grade 1 were compared across three twin samples tested in the United States, Australia, and Scandinavia. Proportions of variance due to genetic influences on kindergarten reading were estimated at .84 in Australia, .68 in the U.S., and .33 in Scandinavia. The effects of shared environment on kindergarten reading were estimated at .09 in Australia, .25 in the U.S., and .52 in Scandinavia. A similar pattern of genetic and environmental influences was obtained for kindergarten spelling. One year later when twins in all three samples had received formal literacy instruction for at least one full school year, heritability was similarly high across country, with estimated genetic influences varying between .79 and .83 for reading and between .62 and .79 for spelling. These findings indicate that the pattern of genetic and environmental influences on early reading and spelling development varies according to educational context, with genetic influence increasing as a function of increasing intensity of early instruction. Longitudinal analyses revealed genetic continuity for both reading and spelling between kindergarten and Grade 1 across country. However, a new genetic factor comes into play accounting for independent variance in reading at Grade 1 in the U.S. and Scandinavia, suggesting a change in genetic influences on reading. Implications for response-to-instruction are discussed. [Copyright &y& Elsevier]

CERVICAL cancer treatment, RADIOTHERAPY, RADIOISOTOPE brachytherapy, and COMORBIDITY

Purpose: To assess the outcome of patients treated with radical radiotherapy for cervical cancer who received an external beam boost, in place of intracavitary brachytherapy (ICT), after irradiation to the whole pelvis. Methods and Materials: Case notes were reviewed for all patients treated in this way in a single center between 1996 and 2004. Patient and tumor details, the reasons why ICT was not possible, and treatment outcome were documented. Results: Forty-four patients were identified. The mean age was 56.4 years (range, 26–88 years). Clinical International Federation of Gynecology and Obstetrics or radiologic stage for Stages I, II, III, and IV, respectively, was 16%, 48%, 27%, and 7%. A total radiation dose of 54–70 Gy was given (75% received ≥60 Gy). Reasons for ICT not being performed were technical limitations in 73%, comorbidity or isolation limitations in 23%, and patient choice in 4%. The median follow-up was 2.3 years. Recurrent disease was seen in 48%, with a median time to recurrence of 2.3 years. Central recurrence was seen in 16 of the 21 patients with recurrent disease. The 5-year overall survival rate was 49.3%. The 3-year cancer-specific survival rate by stage was 100%, 70%, and 42% for Stages I, II, and III, respectively. Late Grades 1 and 2 bowel, bladder, and vaginal toxicity were seen in 41%. Late Grade 3 toxicity was seen in 2%. Conclusion: An external beam boost is a reasonable option after external beam radiotherapy to the pelvis when it is not possible to perform ICT. [Copyright &y& Elsevier]

ENVIRONMENTAL toxicology research, EMOTIONAL trauma, SEPTEMBER 11 Terrorist Attacks, 2001, POST-traumatic stress disorder, COMORBIDITY, and MENTAL health

BACKGROUND: The World Trade Center (WTC) attacks exposed thousands of workers to hazardous environmental conditions and psychological trauma. In 2002, to assess the health of these workers, Congress directed the National Institute for Occupational Safety and Health to establish the WTC Medical Monitoring and Treatment Program. This program has established a large cohort of WTC rescue, recovery, and cleanup workers. We previously documented extensive pulmonary dysfunction in this cohort related to toxic environmental exposures. OBJECTIVES: Our objective in this study was to describe mental health outcomes, social function impairment, and psychiatric comorbidity in the WTC worker cohort, as well as perceived symptomatology in workers' children. METHODS: Ten to 61 months after the WTC attack, 10,132 WTC workers completed a self-administered mental health questionnaire. RESULTS: Of the workers who completed the questionnaire, 11.1% met criteria for probable posttraumatic stress disorder (PTSD), 8.8% met criteria for probable depression, 5.0% met criteria for probable panic disorder, and 62% met criteria for substantial stress reaction. PTSD prevalence was comparable to that seen in returning Afghanistan war veterans and was much higher than in the U.S. general population. Point prevalence declined from 13.5% to 9.7% over the 5 years of observation. Comorbidity was extensive and included extremely high risks for impairment of social function. PTSD was significantly associated with loss of family members and friends, disruption of family, work, and social life, and higher rates of behavioral symptoms in children of workers. CONCLUSIONS: Working in 9/11 recovery operations is associated with chronic impairment of mental health and social functioning. Psychological distress and psychopathology in WTC workers greatly exceed population norms. Surveillance and treatment programs continue to be needed. [ABSTRACT FROM AUTHOR]

MEAT quality, PORK, PRODUCT quality, and ANIMAL products

Abstract: This work focused on Listeria monocytogenes growth inhibition and growth rebound in raw and cooked pork meat inoculated with Lactobacillus curvatus strains. During storage of raw meat homogenates in the presence of the bacteriocin-producing strain Lactobacillus curvatus CWBI-B28wt, the Listeria monocytogenes cfu count was initially reduced to an undetectable level, but a growth rebound occurred after two weeks, coinciding with loss of 70% of the bacteriocin activity present at the end of week 2. The Listeria growth rebound was suppressed when proteolysis of bacteriocin was countered by the absence of proteases (bacteriocin addition to cooked meat) or the presence of 1% soy flour (added to provide competing substrates). Further experiments confirmed that bacteriocin is sensitive to the action of proteolytic enzymes isolated from both Lactobacillus curvatus CWBI-B28wt and the meat matrix. Bacteriocin proteolysis thus emerges as a cause of Listeria growth rebound. [Copyright &y& Elsevier]

PYRIDAZINES, VASCULAR endothelial growth factor antagonists, DRUG bioavailability, ORGANIC synthesis, ENZYME inhibitors, MITOGENS, and LABORATORY mice

Abstract: A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice. [Copyright &y& Elsevier]

IMIDAZOLES, PROTEIN kinase C, ENZYME inhibitors, TARGETED drug delivery, IMMUNOLOGIC diseases, and INFLAMMATION

Abstract: The inhibition of PKC-ζ has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-ζ). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH2 derivative. The analog displays good selectivity over other PKC isoforms (α, βII, γ, δ, ε, μ, θ, η and ι/λ) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled). [Copyright &y& Elsevier]

OCCUPATIONAL diseases, LUNG diseases, SPIROMETRY, VITAL capacity (Respiration), and WEIGHT gain

The article presents a study that evaluates prevalence of spirometric abnormalities and changes in spirometry between baseline and first follow-up assessment in participants in the World Trade Center Worker and Volunteer Medical Monitoring Program in New York City. The research found that elevated rates of spirometric abnormalities were present in two examinations, with reduced forced vital capacity most common.

CLEFT lip, CLEFT palate, GENES, MYOSIN, GENETIC disorders, and HUMAN genetics

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth anomaly that requires prolonged multidisciplinary rehabilitation. Although variation in several genes has been identified as contributing to NSCLP, most of the genetic susceptibility loci have yet to be defined. To identify additional contributory genes, a high-throughput genomic scan was performed using the Illumina Linkage IVb Panel platform. We genotyped 6008 SNPs in nine non-Hispanic white NSCLP multiplex families and a single large African-American NSCLP multiplex family. Fourteen chromosomal regions were identified with LOD>1.5, including six regions not previously reported. Analysis of the data from the African-American and non-Hispanic white families revealed two likely chromosomal regions: 8q21.3–24.12 and 22q12.2–12.3 with LOD scores of 2.98 and 2.66, respectively. On the basis of biological function, syndecan 2 (SDC2) and growth differentiation factor 6 (GDF6) in 8q21.3–24.12 and myosin heavy-chain 9, non-muscle (MYH9) in 22q12.2–12.3 were selected as candidate genes. Association analyses from these genes yielded marginally significant P-values for SNPs in SDC2 and GDF6 (0.01≤P<0.05). Evidence for an altered transmission was found for four MYH9 SNPs (P<0.01). SNP rs1002246 exhibited altered transmission by all analytic methods. However, analysis of two SNP MYH9 haplotypes did not identify a single high-risk haplotype. Our results confirm a previous report that 8q21.3–24.12 may harbor a clefting gene and identify 22q12.2–12.3 as a new candidate region that contains MYH9. Most importantly, we confirm the previous report of an association with MYH9.European Journal of Human Genetics (2009) 17, 195–204; doi:10.1038/ejhg.2008.149; published online 20 August 2008 [ABSTRACT FROM AUTHOR]

THYROID gland, REGULATION of blood pressure, HYPERTENSION, ENDOCRINE glands, and HYPOTHALAMUS

Introduction Thyroid function and genetic variation in the hypothalamus–pituitary–thyroid axis have been implicated in blood pressure regulation and susceptibility to hypertension. However studies conducted thus far were small with controversial results. Objective To examine whether serum thyroid parameters and polymorphisms in the type 2 deiodinase and the TSH receptor are associated with blood pressure and the presence of hypertension in two large cohorts of elderly subjects. Design and participants We studied a random sample of 1444 subjects of the Rotterdam study, and 997 subjects of the Rotterdam Scan study, two population-based cohort studies among elderly individuals aged 55–90 years. Outcome measurements Data on blood pressure and hypertension were obtained, and serum thyroid parameters, D2-Thr92Ala, D2-ORFa-Gly3Asp and TSHR-Asp727Glu polymorphisms were determined. Results In contrast to previous findings, no consistent and/or significant associations were found between serum TSH and FT4 and blood pressure in both cohorts. In addition, the D2-Thr92Ala, D2-ORFa-Gly3Asp and TSHR-Asp727Glu polymorphisms were not associated with blood pressure or the risk of hypertension. Conclusions In two large populations of elderly subjects, neither serum thyroid parameters nor polymorphisms in the type 2 deiodinase and the TSH receptor, were associated with blood pressure or the presence of hypertension. Our data suggest that thyroid function is not an important determinant of hypertension in elderly Dutch subjects. [ABSTRACT FROM AUTHOR]

MULTIPLE myeloma, B cell lymphoma, FIRST responders, and SEPTEMBER 11 Terrorist Attacks, 2001

The article presents a study which examines cases of multiple myeloma (MM) observed in World Trade Center (WTC) responders registered in the World Trade Center Medical Program in New York City. Eight cases of MM were observed among 28, 252 responders of known sex and age. The findings concluded that it is important to maintain surveillance for cancer and other emerging diseases among WTC responders.

FISHES, MICROBIOLOGICAL synthesis, ANTIBIOTICS, PATHOGENIC microorganisms, PATHOGENIC bacteria, and FERMENTATION

Lactococcus lactis subsp, lactis strain CWBI B1410, which produces various antibacterial compounds including organic acids and nisin, was used as a starter culture to improve the traditional Senegalese fish fermentation in which fish are mostly transformed to guedj by spontaneous fermentation for 24 to 48 h at ambient temperatures near 30°C followed by salting (with NaCI) and sun drying. Assays were performed on lean fish (Podamasys jubelini) and fat fish (Arius heudelotii) purchased at a local market. The total viable microbial counts in raw fillets of P. jubelini and A. heudelotii were 5.78 and 5.39 log CFU/g respectively. Populations of enteric bacteria (which can include pathogenic bacteria) in P. jubelini and A. heudelotii were 4.08 and 4.12 log CFU/g, respectively. Spontaneous fermentation of raw fillets at 30°C led to the proliferation of enteric bacteria to 9 log CFU/g after 24 h in fermented P. jubelini and A. heudelotii fillets with pH values of 6.83 and 7.50, respectively. When raw fish fillets were supplemented with glucose (1%, wt/wt) and inoculated with Lactococcus lactis (107 CFU/g), the pH decreased to about 4.60 after 10 h at 30°C, and nisin activity was detected in juice from the fillets. Traditionally fermented fillets of P. jubelini and A. heudelotii contained enteric bacteria at higher levels of 4 and 2 log CFU/g, respectively, than did fillets of the same fish supplemented with glucose and fermented with the starter culture. These data suggest that this new fish fermentation strategy combined with salting and drying can be used to enhance the safety of guedj. [ABSTRACT FROM AUTHOR]

PATHOLOGICAL psychology, MENTAL health, MEDICAL screening, TERRORISM, and MENTAL health services

A qualitative study of the experiences of rescue and recovery workers/volunteers at Ground Zero following the terrorist attacks of 9/11/01 is reported. Information was extracted from a semi-structured clinical evaluation of 416 responders who were the initial participants in a large scale medical and mental health screening and treatment program for 9/11 responders. Qualitative analysis revealed themes that spanned four categories— occupational roles, exposures, attitudes/experiences, and outcomes related to the experience of Ground Zero. Themes included details regarding Ground Zero roles, grotesque experiences such as smells, the sense of the surreal nature of responding, and a turning to rituals to cope after leaving Ground Zero. These findings personalize the symptom reports and diagnoses that have resulted from the 9/11 responders’ exposure to Ground Zero, yielding richer information than would otherwise be available for addressing the psychological dimensions of disasters. This work shows that large scale qualitative surveillance of trauma-exposed populations is both relevant and feasible. [ABSTRACT FROM AUTHOR]

ORGANOPHOSPHORUS compounds, BUTYRYLCHOLINESTERASE, ALBUMINS, OXIMES, TYROSINE, BIOMARKERS, and CHOLINESTERASES

Organophosphorus nerve agents inhibit the activity of cholinesterases by phosphylation of the active site serine. In addition, sarin, cyclosarin, soman and tabun have been shown to phosphylate a tyrosine residue in albumin. Therapies against nerve agent poisoning include the use of oximes to reactivate inhibited cholinesterases by displacement of the phosphyl moiety and hence detectable levels of adducts with cholinesterases may be reduced. Adducts with tyrosine have been shown to be persistent in the guinea pig in the presence of oxime therapy. Plasma samples obtained from an animal study aimed at improving therapy against nerve agent poisoning were used to compare the suitability of tyrosine and butyrylcholinesterase (BuChE) adducts as biomarkers of nerve agent exposure after treatment with therapeutic oximes. Under the terms of the project licence, these samples could be collected only on death of the animal, which occurred within hours of exposure or when culled at 23 or 24 days. Tyrosine adducts were detected in all samples collected following intra-muscular administration of twice the LD50 dose of the respective nerve agent. Aged BuChE adducts were detected in samples collected within a few hours after administration of soman and tabun, but not after 23 or 24 days. No BuChE adducts were detected in animals exposed to sarin and cyclosarin where samples were collected only after 23 or 24 days. [ABSTRACT FROM AUTHOR]

ACIDIFICATION, LACTIC acid bacteria, FATTY acids, LACTOBACILLUS, SORBITOL, MONOSODIUM glutamate, GLYCERIN, ADDITIVES, and FERMENTATION

The protective effects of the fatty acid composition and membrane action of the acidification activity of two strains of Lactobacillus kept at 20?C were studied. The addition of sorbitol, monosodium glutamate and glycerol during storage is causing the decline of acidification and increased concentrations of unsaturated fatty acids observed in both strains. The addition of sorbitol and monosodium glutamate does not alter the fatty acid composition, whatever the strain, but increases the resistance to freeze-drying of L. plantarum CWBI-B1419 and improves survival during storage. The addition of these preservatives and decreased activity of acidification improves the ratio unsaturated. These results indicate that the survival during storage and freeze-drying resistance are closely related to the composition of membrane fatty acids. This behaviour can be interpreted as an adaptation of L. plantarum B1419-CWBI supplemented by cryoprotectant additives such as sorbitol or monosodium glutamate sorbitol and monosodium glutamate as an additive. L. plantarum CWBI-B1419 presents a greater adaptation to culture conditions than L. paracasei ssp. paracasei LMG9192T. [ABSTRACT FROM AUTHOR]

PROTEIN-tyrosine kinases, CRYSTALLIZATION, PHOSPHORYLATION, CYTOKINES, INFLAMMATION, ONCOLOGY, and MICROFLUIDICS

Abstract: Janus-associated kinases (JAKs) play critical roles in cytokine signaling, and have emerged as viable therapeutic targets in inflammation and oncology related diseases. To date, targeting JAK proteins with highly selective inhibitor compounds have remained elusive. We have expressed the active kinase domains for both JAK2 and JAK3 and devised purification protocols to resolve the non-, mono- (Y1007) and diphosphorylated (Y1007 and Y1008) states of JAK2 and non- and monophosphorylated states of JAK3 (Y980). An optimal purified protein yield of 20, 29 and 69mg per 20L cell culture was obtained for the three JAK2 forms, respectively, and 12.2 and 2.3mg per 10L fermentation for the two JAK3 forms allowing detailed biochemical and biophysical studies. To monitor the purification process we developed a novel HPLC activity assay where a sequential order of phosphorylation was observed whereby the first tyrosine residue was completely phosphorylated prior to phosphorylation of the tandem tyrosine residue. A Caliper-based microfluidics assay was used to determine the kinetic parameters (K m and k cat) for each phosphorylated state, showing that monophosphorylated (Y1007) JAK2 enzyme activity increased 9-fold over that of the nonphosphorylated species, and increased an additional 6-fold for the diphosphorylated (Y1007/Y1008) species, while phosphorylation of JAK3 resulted in a negligible increase in activity. Moreover, crystal structures have been generated for each isolated state of JAK2 and JAK3 with resolutions better than 2.4Å. The generation of these reagents has enabled kinetic and structural characterization to inform the design of potent and selective inhibitors of the JAK family. [Copyright &y& Elsevier]

MICROFABRICATION, GAS chromatography, PHOTOIONIZATION, SEPARATION (Technology), VOLATILE organic compounds, HYDROFLUORIC acid, GLASS, SURFACES (Technology), VAN der Waals forces, and DIMETHYLPOLYSILOXANES

Abstract: We report the development of a microfabricated gas chromatography system suitable for the separation of volatile organic compounds (VOCs) and compatible with use as a portable measurement device. Hydrofluoric acid etching of 95×95mm Schott B270 wafers has been used to give symmetrical hemi-spherical channels within a glass substrate. Two matching glass plates were subsequently cold bonded with the channels aligned; the flatness of the glass surfaces resulted in strong bonding through van der Waals forces. The device comprised gas fluidic interconnections, injection zone and 7.5 and 1.4m long, 320μm internal diameter capillaries. Optical microscopy confirmed the capillaries to have fully circular channel profiles. Direct column heating and cooling could be achieved using a combination of resistive heaters and Peltier devices. The low thermal conductivity of glass allowed for multiple uniform temperature zones to be achieved within a single glass chip. Temperature control over the range 10–200°C was achieved with peak power demand of approximately 25W. The 7.5m capillary column was static coated with a 2μm film of non-polar dimethylpolysiloxane stationary phase. A standard FID and a modified lightweight 100mW photoionization detector (PID) were coupled to the column and performance tested with gas mixtures of monoaromatic and monoterpene species at the parts per million concentration level. The low power GC-PID device showed good performance for a small set of VOCs and sub ng detection sensitivity to monoaromatics. [Copyright &y& Elsevier]

LUNG diseases, SEPTEMBER 11 Terrorist Attacks, 2001, AIR pollution, HEALTH, MINERALOGY, RESPIRATION, CHEST endoscopic surgery, HISTOPATHOLOGY, and CHRONIC granulomatous disease

Context: After the collapse of the World Trade Center (WTC) on 11 September 2001, a dense cloud of dust containing high levels of airborne pollutants covered Manhattan and parts of Brooklyn, New York. Between 60,000 and 70,000 responders were exposed. Many reported adverse health effects. Case presentation: In this report we describe clinical, pathologic, and mineralogic findings in seven previously healthy responders who were exposed to WTC dust on either 11 September or 12 September 2001, who developed severe respiratory impairment or unexplained radiologic findings and underwent video-assisted thoracoscopic surgical lung biopsy procedures at Mount Sinai Medical Center. WTC dust samples were also examined. We found that three of the seven responders had severe or moderate restrictive disease clinically. Histopathology showed interstitial lung disease consistent with small airways disease, bronchiolocentric parenchymal disease, and nonnecrotizing granulomatous condition. Tissue mineralogic analyses showed variable amounts of sheets of aluminum and magnesium silicates, chrysotile asbestos, calcium phosphate, and calcium sulfate. Small shards of glass containing mostly silica and magnesium were also found. Carbon nanotubes (CNT) of various sizes and lengths were noted. CNT were also identified in four of seven WTC dust samples. Discussion: These findings confirm the previously reported association between WTC dust exposure and bronchiolar and interstitial lung disease. Long-term monitoring of responders will be needed to elucidate the full extent of this problem. The finding of CNT in both WTC dust and lung tissues is unexpected and requires further study. [ABSTRACT FROM AUTHOR]

GENE expression, PROTEIN-tyrosine kinases, INFLAMMATION, ENZYMOLOGY, PHOSPHORYLATION, CHEMICAL kinetics, and ENZYME inhibitors

Abstract: The Janus kinase family consists of four members: JAK-1, -2, -3 and TYK-2. While JAK-2 and JAK-3 have been well characterized biochemically, there is little data on TYK-2. Recent work suggests that TYK-2 may play a critical role in the development of a number of inflammatory processes. We have carried out a series of biochemical studies to better understand TYK-2 enzymology and its inhibition profile, in particular how the TYK-2 phosphorylated forms differ from each other and from the other JAK family members. We have expressed and purified milligram quantities of the TYK-2 kinase domain (KD) to high purity and developed a method to separate the non-, mono- (pY1054) and di-phosphorylated forms of the enzyme. Kinetic studies (k cat(app)/K m(app)) indicated that phosphorylation of the TYK-2-KD (pY1054) increased the catalytic efficiency 4.4-fold compared to its non-phosphorylated form, while further phosphorylation to generate the di-phosphorylated enzyme imparted no further increase in activity. These results are in contrast to those obtained with the JAK-2-KD and JAK-3-KD, where little or no increase in activity occurred upon mono-phosphorylation, while di-phosphorylation resulted in a 5.1-fold increase in activity for the JAK-2-KD. Moreover, ATP-competitive inhibitors demonstrated 10–30-fold shifts in potency (K i(app)) as a result of the TYK-2-KD phosphorylation state, while the shifts for JAK-3-KD were only 2–3-fold and showed little or no change for JAK-2-KD. Thus, the phosphorlyation state imparted differential effects on both activity and inhibition within the JAK family of kinases. [Copyright &y& Elsevier]

MOLECULAR structure, THERMODYNAMICS, PROTEIN kinases, CELLULAR control mechanisms, CELLULAR signal transduction, MYELOPROLIFERATIVE neoplasms, CRYSTALS, and INFLAMMATION

Abstract: Janus kinases (JAKs) are critical regulators of cytokine pathways and attractive targets of therapeutic value in both inflammatory and myeloproliferative diseases. Although the crystal structures of active JAK1 and JAK2 kinase domains have been reported recently with the clinical compound CP-690550, the structures of both TYK2 and JAK3 with CP-690550 have remained outstanding. Here, we report the crystal structures of TYK2, a first in class structure, and JAK3 in complex with PAN-JAK inhibitors CP-690550 ((3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile) and CMP-6 (tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one), both of which bind in the ATP-binding cavities of both JAK isozymes in orientations similar to that observed in crystal structures of JAK1 and JAK2. Additionally, a complete thermodynamic characterization of JAK/CP-690550 complex formation was completed by isothermal titration calorimetry, indicating the critical role of the nitrile group from the CP-690550 compound. Finally, computational analysis using WaterMap further highlights the critical positioning of the CP-690550 nitrile group in the displacement of an unfavorable water molecule beneath the glycine-rich loop. Taken together, the data emphasize the outstanding properties of the kinome-selective JAK inhibitor CP-690550, as well as the challenges in obtaining JAK isozyme-selective inhibitors due to the overall structural and sequence similarities between the TYK2, JAK1, JAK2 and JAK3 isozymes. Nevertheless, subtle amino acid variations of residues lining the ligand-binding cavity of the JAK enzymes, as well as the global positioning of the glycine-rich loop, might provide the initial clues to obtaining JAK-isozyme selective inhibitors. [Copyright &y& Elsevier]

SENSORY deprivation, SMELL, INFLAMMATION, and THRESHOLD limit values (Industrial toxicology)

BACKGROUND: Individuals involved in rescue, recovery, demolition, and cleanup at the World Trade Center (WTC) site were exposed to a complex mixture of airborne smoke, dust, combustion gases, acid mists, and metal fumes. Such exposures have the potential to impair nasal chemosensory (olfactory and trigeminal) function. OBJECTIVE: The goal of this study was to evaluate the prevalence of chemosensory dysfunction and nasal inflammation among these individuals. METHODS: We studied 102 individuals who worked or volunteered at the WTC site in the days and weeks during and after 11 September 2001 (9/11) and a comparison group with no WTC exposure matched to each participant on age, sex, and job title. Participants were comprehensively evaluated for chemosensory function and nasal inflammation in a single session. Individual exposure history was obtained from self-reported questionnaires. RESULTS: The prevalence of olfactory and trigeminal nerve sensitivity loss was significantly greater in the WTC-exposed group relative to the comparison group [prevalence ratios (95% confidence intervals) = 1.96 (1.2-3.3) and 3.28 (2.7-3.9) for odor and irritation thresholds, respectively]. Among the WTC responders, however, individuals caught in the dust cloud from the collapse on 9/11 exhibited the most profound trigeminal loss. Analysis of the nasal lavage samples supported the clinical findings of chronic nasal inflammation among the WTC-exposed cohort. CONCLUSIONS: The prevalence of significant chemosensory impairment in the WTC-exposed group more than 2 years after their exposure raises concerns for these individuals when the ability to detect airborne odors or irritants is a critical safety factor. RELEVANCE TO CLINICAL PRACTICE: This outcome highlights the need for chemosensory evaluations among individuals with exposure to acute high or chronic levels of airborne pollutants. [ABSTRACT FROM AUTHOR]

GAS chromatography, MEASUREMENT, VOLATILE organic compounds, ELECTRONIC modulators, SEPARATION (Technology), MICROFABRICATION, and EQUIPMENT & supplies

This article reports the early development of a microfabricated comprehensive gas chromatography(GC) system suitable for the separation of volatile organic compounds (VOCs) and competitive for uses as a portable measurement device. Thus low-power device showed good separation performance for a small set of VOCs and sub-ng detection sensitivity to monoaromatics. Comprehensive GC separation was achieved by coupling the primary column to the secondary via a differential flow modulator. Preliminary results from the 2D separation of gas mixes of several of gas mixes of several VOCs in the ppm range are promising. [ABSTRACT FROM AUTHOR]

FOOD chains, RESTORATION ecology, COELOSTOMIDIIDAE, HONEYDEW (Entomology), GECKOS, and HOPLODACTYLUS

OXIDATION, LACTONES, YEAST, RHODOTORULA, FATTY acids, OXIDASES, ESTERASES, and NUCLEOTIDE sequence

VOCABULARY, READING, NATURE & nurture, EFFECT of environment on human beings, and INFLUENCE

Genetic and environmental relations between vocabulary and reading skills were explored longitudinally from preschool through Grades 2 and 4. At preschool there were strong shared-environment and weak genetic influences on both vocabulary and print knowledge but substantial differences in their source. Separation of etiology for vocabulary and reading continued for word recognition and decoding through Grade 4, but genetic and environmental correlations between vocabulary and reading comprehension approached unity by Grade 4, when vocabulary and word recognition accounted for all of the genetic and shared environment influences on reading comprehension. [ABSTRACT FROM AUTHOR]

H1N1 influenza, HOSPITAL patients, POLYMERASE chain reaction, HOSPITAL admission & discharge, NEURAMINIDASE, INTENSIVE care units, and DIAGNOSIS

Given the potential worsening clinical severity of 2009 pandemic influenza A (H1N1) virus (pH1N1) infection from spring to fall 2009, we conducted a clinical case series among patients hospitalized with pH1N1 infection from September through October 2009. A case patient was defined as a hospitalized person who had test results positive for pH1N1 virus by real-time reverse-transcription polymerase chain reaction. Among 255 hospitalized patients, 34% were admitted to an intensive care unit and 8% died. Thirty-four percent of patients were children <18 years of age, 8% were adults ≥65 years of age, and 67% had an underlying medical condition. Chest radiographs obtained at hospital admission that had findings that were consistent with pneumonia were noted in 103 (46%) of 255 patients. Among 255 hospitalized patients, 208 (82%) received neuraminidase inhibitors, but only 47% had treatment started ≤2 days after illness onset. Overall, characteristics of hospitalized patients with pH1N1 infection in fall 2009 were similar to characteristics of patients hospitalized with pH1N1 infection in spring 2009, which suggests that clinical severity did not change substantially over this period. [ABSTRACT FROM AUTHOR]

RESPIRATORY diseases and INDUSTRIAL safety

Following the World Trade Center (WTC) collapse on September 11, 2001, more than 40,000 people were exposed to a complex mixture of inhalable nanoparticles and toxic chemicals. While many developed chronic respiratory symptoms, to what degree olfaction was compromised is unclear. A previous WTC Medical Monitoring and Treatment Program study found that olfactory and nasal trigeminal thresholds were altered by the toxic exposure, but not scores on a 20-odor smell identification test. Objectives: To employ a well-validated 40-item smell identification test to definitively establish whether the ability to identify odors is compromised in a cohort of WTC-exposed individuals and, if so, whether the degree of compromise is associated with self-reported severity of rhinitic symptoms. Methods: The University of Pennsylvania Smell Identification Test (UPSIT) was administered to 99 WTC-exposed persons and 99 matched normal controls. The Sino-Nasal Outcomes Test (SNOT-20) was administered to the 99 WTC-exposed persons and compared to the UPSIT scores. Results: The mean (SD) UPSIT scores were lower in the WTC-exposed group than in age-, sex-, and smoking history-matched controls [respective scores: 30.05 (5.08) vs 35.94 (3.76); p = 0.003], an effect present in a subgroup of 19 subjects additionally matched on occupation ( p < 0.001). Fifteen percent of the exposed subjects had severe microsmia, but only 3% anosmia. SNOT-20 scores were unrelated to UPSIT scores ( r = 0.20; p = 0.11). Conclusion: Exposure to WTC air pollution was associated with a decrement in the ability to identify odors, implying that such exposure had a greater influence on smell function than previously realized. [ABSTRACT FROM AUTHOR]

DISEASE incidence, COHORT analysis, SEPTEMBER 11 Terrorist Attacks, 2001, RESPIRATORY diseases, and MENTAL health

The article presents a cohort study which examines the 9-year incidence and prevalence of physical and mental health disorders of the rescue and recovery workers in the September 11, 2001 (9/11) terrorist attacks on the World Trade Center (WTC) in New York City. The study explores the incidence rates of multiple health problems and their associations with occupational risk exposures. Findings show incidences of physical disorders such as asthma and sinusitis and mental disorders like depression.

FOOD chemistry, BODY image in women, INGESTION, COGNITIVE testing, APPETITE, SENSORY perception, and RESTRAINT of patients

Abstract: Body image can be influenced by day-to-day events, including food intake. The present study investigated the effects of foods typically perceived as “healthy” or “unhealthy” on state body image and mood. College-aged women were told the experiment was designed to assess the effects of food on cognition. Using a between-subjects design, participants consumed isocaloric amounts of foods perceived to be healthy (banana) or unhealthy (donut) or ate nothing. Next, participants completed three cognitive tasks. Prior to eating and following the cognitive tests, participants completed the BISS, POMS, the Figure Rating Scale, and the Restraint Scale. Body satisfaction decreased following intake of a donut, but was not altered in the other conditions. Depression scores significantly decreased after intake of either a donut or banana, but did not decrease in the no-food condition. Tension scores decreased significantly after consumption of a banana and in the no-food condition, but did not decrease following consumption of a donut. These results indicate that intake of a food that is perceived as unhealthy negatively affects state body image. [Copyright &y& Elsevier]

HONEYDEW (Entomology), HONEY, METABOLITES, NATURAL sweeteners, and NECTAR

The quantity and chemical composition of honeydew produced by scale insects may influence wider community structure, but little is known about the detailed chemical composition of the honeydew found in forest ecosystems. We used gas chromatography-mass spectrometry to examine the amino acid and carbohydrate composition of honeydew from three New Zealand communities. Low molecular weight carbohydrates (mono-, di-, and tri-saccharides) were derivatized using a modified trimethylsilyl (TMS) method, and amino and non-amino organic acids were derivatized using methylchloroformate (MCF). These recently developed derivatization methods allowed us to detect atypical compounds such as sugar alcohols, fatty acids, and non-amino organic acids, in addition to the more routinely studied compounds such as sugars and amino acids. Some compounds could not be identified and may be novel. Multivariate analysis showed that honeydew from each scale insect species had a distinctive amino acid and carbohydrate signature. We suggest these chemical signatures may influence the types of consumers that are attracted to different honeydews and may explain the characteristic communities associated with these honeydews. [ABSTRACT FROM AUTHOR]

HYPERGLYCEMIA prevention, HYPOGLYCEMIA, DRUG delivery systems, DRUGS, EXPERIMENTAL design, GLYCOSYLATED hemoglobin, INSULIN, TYPE 1 diabetes, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, PATIENT compliance, PHARMACEUTICAL arithmetic, RESEARCH, RANDOMIZED controlled trials, and PREVENTION

Background: People with T1DM and insulin-treated T2DM often do not follow and/or adjust their insulin regimens as needed. Key contributors to treatment non-adherence are fear of hypoglycaemia, difficulty and lack of self-efficacy associated with insulin dose determination. Because manual calculation of insulin boluses is both complex and time consuming, people may rely on empirical estimates, which can result in persistent hypoglycaemia and/or hyperglycaemia. Use of automated bolus advisors (BA) has been shown to help insulin pump users to more accurately meet prandial insulin dosage requirements, improve postprandial glycaemic excursions, and achieve optimal glycaemic control with an increased time within optimal range. Use of a BA containing an early algorithm based on sliding scales for insulin dosing has also been shown to improve HbA1c levels in people treated with multiple daily insulin injections (MDI). We designed a study to determine if use of an automated BA can improve clinical and psychosocial outcomes in people treated with MDI. Methods/design: The Automated Bolus Advisor Control and Usability Study (ABACUS) is a 6-month, prospective, randomised, multi-centre, multi-national trial to determine if automated BA use improves glycaemic control as measured by a change in HbA1c in people using MDI with elevated HbA1c levels (>7.5%). A total of 226 T1DM and T2DM participants will be recruited. Anticipated attrition of 20% will yield a sample size of 90 participants, which will provide >80% power to detect a mean difference of 0.5%, with SD of 0.9%, using a one-sided 5% t-test, with 5% significance level. Other measures of glycaemic control, self-care behaviours and psychosocial issues will also be assessed. Discussion: It is critical that healthcare providers utilise available technologies that both facilitate effective glucose management and address concerns about safety and lifestyle. Automated BAs may help people using MDI to manage their diabetes more effectively and minimise the risk of long-term diabetes related complications. Findings from a recent study suggest that BA use positively addresses both safety and lifestyle concerns; however, randomised trials are needed to confirm these perceptions and determine whether bolus advisor use improves clinical outcomes. Our study is designed to make these assessments. Trial registration: NCT01460446 [ABSTRACT FROM AUTHOR]

HYDROCEPHALUS, BRAIN diseases, GENETIC disorders, DIENCEPHALON, GLYCOPROTEINS, HOMEOSTASIS, and GENE expression

Congenital hydrocephalus (CH) is a life-threatening medical condition in which excessive accumulation of CSF leads to ventricular expansion and increased intracranial pressure. Stenosis (blockage) of the Sylvian aqueduct (Aq; the narrow passageway that connects the third and fourth ventricles) is a common form of CH in humans, although the genetic basis of this condition is unknown. Mouse models of CH indicate that Aq stenosis is associated with abnormal development of the subcommmissural organ (SCO) a small secretory organ located at the dorsal midline of the caudal diencephalon. Glycoproteins secreted by the SCO generate Reissner's fibre (RF), a thread-like structure that descends into the Aq and is thought to maintain its patency. However, despite the importance of SCO function in CSF homeostasis, the genetic program that controls SCO development is poorly understood. Here, we show that the X-linked transcription factor SOX3 is expressed in the murine SCO throughout its development and in the mature organ. Importantly, overexpression of Sox3 in the dorsal diencephalic midline of transgenic mice induces CH via a dose-dependent mechanism. Histological, gene expression and cellular proliferation studies indicate that Sox3 overexpression disrupts the development of the SCO primordium through inhibition of diencephalic roof plate identity without inducing programmed cell death. This study provides further evidence that SCO function is essential for the prevention of hydrocephalus and indicates that overexpression of Sox3 in the dorsal midline alters progenitor cell differentiation in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

MYELIN basic protein, NUCLEIC acids, PHOSPHORYLATION, PROTEIN-tyrosine kinases, and TYROSINE

Myelin basic protein (MBP) is a major component of central nervous system (CNS) myelin. The absence of MBP results in the loss of almost all compact myelin in the CNS. MBP mRNA is sorted into RNA granules that are transported to the periphery of oligodendrocytes in a translationally inactive state. A central mediator of this transport process is the trans-acting factor heterogeneous nuclear ribonucleoprotein (hnRNP) A2 that binds to the cis-acting A2-response element in the 3'UTR of MBP mRNA. Recently, we found that activation of the Src family nonreceptor tyrosine kinase Fyn in oligodendrocytes leads to phosphorylation of hnRNP A2 and to increased translation of MBP mRNA. Here, we identify the RNA-binding protein hnRNP F as a novel component of MBP mRNA transport granules. It is associated with hnRNP A2 and MBP mRNA in cytoplasmic granular structures and is involved in post-transcriptional regulation of MBP expression. Fyn kinase activity results in phosphorylation of hnRNP F in the cytoplasm and its release from MBP mRNA and RNA granules. Our results define hnRNP F as a regulatory element of MBP expression in oligodendrocytes and imply an important function of hnRNP F in the control of myelin synthesis. [ABSTRACT FROM AUTHOR]

HONEYBEES, PARASITES, GENETICS, INFECTION, GLUTATHIONE, and ANTIOXIDANTS

The microsporidium Nosema ceranae is a newly prevalent parasite of the European honey bee (Apis mellifera). Although this parasite is presently spreading across the world into its novel host, the mechanisms by it which affects the bees and how bees respond are not well understood. We therefore performed an extensive characterization of the parasite effects at the molecular level by using genetic and biochemical tools. The transcriptome modifications at the midgut level were characterized seven days post-infection with tiling microarrays. Then we tested the bee midgut response to infection by measuring activity of antioxidant and detoxification enzymes (superoxide dismutases, glutathione peroxidases, glutathione reductase, and glutathione-S-transferase). At the gene-expression level, the bee midgut responded to N. ceranae infection by an increase in oxidative stress concurrent with the generation of antioxidant enzymes, defense and protective response specifically observed in the gut of mammals and insects. However, at the enzymatic level, the protective response was not confirmed, with only glutathione-S-transferase exhibiting a higher activity in infected bees. The oxidative stress was associated with a higher transcription of sugar transporter in the gut. Finally, a dramatic effect of the microsporidia infection was the inhibition of genes involved in the homeostasis and renewal of intestinal tissues (Wnt signaling pathway), a phenomenon that was confirmed at the histological level. This tissue degeneration and prevention of gut epithelium renewal may explain early bee death. In conclusion, our integrated approach not only gives new insights into the pathological effects of N. ceranae and the bee gut response, but also demonstrate that the honey bee gut is an interesting model system for studying host defense responses. [ABSTRACT FROM AUTHOR]

POST-traumatic stress disorder, MENTAL health services, COMORBIDITY, PANIC disorders, POLICE, and MEDICAL care

Abstract: Background: This study examined the prevalence, correlates, and perceived mental healthcare needs associated with subsyndromal PTSD in police involved in the World Trade Center (WTC) rescue and recovery effort. Methods: A total of 8466 police completed an interview/survey as part of the WTC Medical monitoring and Treatment Program an average of four years after 9/11/2001. Results: The past month prevalence of full and subsyndromal WTC-related PTSD was 5.4% and 15.4%, respectively. Loss of someone or knowing someone injured on 9/11 (odds ratios [ORs]=1.56–1.86), pre-9/11 stressors (ORs=1.30–1.50), family support (ORs=0.83–0.94), and union membership (ORs=0.50–0.52) were associated with both full and subsyndromal PTSD. Exposure to the dust cloud (OR=1.36), performing search and rescue work (OR=1.29), and work support (OR=0.89) were additionally associated with subsyndromal PTSD. Rates of comorbid depression, panic disorder, and alcohol use problems (ORs=3.82–41.74), and somatic symptoms and functional difficulties (ORs=1.30–1.95) were highest among police with full PTSD, with intermediate rates among police with subsyndromal PTSD (ORs=2.93–7.02; and ORs=1.18–1.60, respectively). Police with full and subsyndromal PTSD were significantly more likely than controls to report needing mental healthcare (41.1% and 19.8%, respectively, versus 6.8% in trauma controls). Conclusions: These results underscore the importance of a more inclusive and dimensional conceptualization of PTSD, particularly in professions such as police, as operational definitions and conventional screening cut-points may underestimate the psychological burden for this population. Accordingly, psychiatric clinicians should assess for disaster-related subsyndromal PTSD symptoms in disaster response personnel. [Copyright &y& Elsevier]

TROPICAL medicine, DISEASE prevalence, INFECTIOUS disease transmission, INFECTION, MEDICAL decision making, DOCUMENTATION, TRACHOMA, FILARIASIS, and DRUG administration

The article focuses on the development of a multiplex platform for the integrated mapping, surveillance and monitoring of neglected tropical disease (NTD). It says that the mapping and impact monitoring requires qualitative and quantitative data from each respondent to generate information on the prevalence and intensity of infection. It states that the stopping decisions will be based on the documentation of the absence of disease transmission. Furthermore, the control of trachoma, lymphatic filariasis and schistosmiasis involves the mass drug administration (MDA).

MEDICAL robotics, TEAM nursing, TELEMEDICINE, INTENSIVE care units, NEUROLOGICAL intensive care, TELEPRESENCE, and INTENSIVE care nursing

Introduction: Robotic Tele-Presence (RTP) is a form of mobile telemedicine, which enables a direct face-to-face rapid response by the physician, instead of the traditional telephonic paradigm. We hypothesized that a model of RTP for after-hour ICU rounds and emergencies would be associated with improved ICU nurse satisfaction. Methods: We implemented a prospective nighttime multidisciplinary ICU round time, using RTP at our Neuro-ICU. To test for critical ICU nurse team satisfaction, a questionnaire was implemented. The primary outcome was nurse satisfaction measured through a questionnaire with answers trichotomized into: agreement, disagreement, and no opinion. The occurrence of outcomes was compared between the groups by χ or Fisher exact tests for the difference in proportions (PD) with Bonferroni correction for multiple pairwise comparisons. Results: In total, 34 nurses completed the pre-survey and 40 nurses completed the post-survey. Night nurses were more likely to agree that RTP was associated with: ICU physicians being sufficiently available in the ICU (agreement 6-20 %, PD 14 %, p = 0.008), present during acute emergencies (agreement 44-65 %, PD 21 %, p = 0.007), and had enough time to get questions answered from the physician team (agreement 41-53 %, PD 11 %, p = NS). Conclusions: This data suggest improvement in critical care nursing team satisfaction with a model of RTP in the Neuroscience ICU, particularly during nighttime hours. RTP is a tool that may enhance communication among components of the ICU team. [ABSTRACT FROM AUTHOR]

HUMAN genome, GLYCOSYLTRANSFERASE genetics, GENETIC mutation, NUCLEOTIDE sequence, LABORATORY zebrafish, HOMOZYGOSITY, and LOCUS (Genetics)

Whole-exome sequencing (WES), which analyzes the coding sequence of most annotated genes in the human genome, is an ideal approach to studying fully penetrant autosomal-recessive diseases, and it has been very powerful in identifying disease-causing mutations even when enrollment of affected individuals is limited by reduced survival. In this study, we combined WES with homozygosity analysis of consanguineous pedigrees, which are informative even when a single affected individual is available, to identify genetic mutations responsible for Walker-Warburg syndrome (WWS), a genetically heterogeneous autosomal-recessive disorder that severely affects the development of the brain, eyes, and muscle. Mutations in seven genes are known to cause WWS and explain 50%–60% of cases, but multiple additional genes are expected to be mutated because unexplained cases show suggestive linkage to diverse loci. Using WES in consanguineous WWS-affected families, we found multiple deleterious mutations in GTDC2 (also known as AGO61). GTDC2’s predicted role as an uncharacterized glycosyltransferase is consistent with the function of other genes that are known to be mutated in WWS and that are involved in the glycosylation of the transmembrane receptor dystroglycan. Therefore, to explore the role of GTDC2 loss of function during development, we used morpholino-mediated knockdown of its zebrafish ortholog, gtdc2. We found that gtdc2 knockdown in zebrafish replicates all WWS features (hydrocephalus, ocular defects, and muscular dystrophy), strongly suggesting that GTDC2 mutations cause WWS. [ABSTRACT FROM AUTHOR]

Introduction: Slow channel congenital myasthenic syndrome is a dominant disorder characterized by prolonged acetylcholine receptor ion-channel activation. Methods: Molecular genetic techniques, electrophysiology, and binding studies in human embryonic kidney (HEK) 293 cells determined mutant function and expression levels. Patient response to treatment was measured by quantitative myasthenic gravis and Medical Research Council grade strength scores. Results: We report an unusual case due to heteroallelic mutations in CHRNE. The slow channel mutation, p.εS278del, is accompanied by a severe low-expression mutation, p.εR217L, on the second allele. Expression studies and cosegregation of p.εS278del with the disorder in the patient's offspring demonstrate robust expression of the p.εS278del mutation. The patient showed modest benefits from standard treatment with fluoxetine, but there was dramatic improvement when salbutamol was combined with fluoxetine. Conclusions: This case suggests that salbutamol, which is beneficial in some other congenital myasthenic syndromes, might also be considered in addition to fluoxetine in slow channel syndrome. Muscle Nerve, 2013 [ABSTRACT FROM AUTHOR]

ENDOTHELIAL cells, CALCIUM channels, TRP channels, SIGMA receptors, LIGANDS (Biochemistry), PLETHORA (Pathology), INTRACELLULAR calcium, and ION channels

Background and Purpose The Sigma-1 receptor ( Sig1R) impacts on calcium ion signalling and has a plethora of ligands. This study investigated Sig1R and its ligands in relation to endogenous calcium events of endothelial cells and transient receptor potential ( TRP) channels. Experimental Approach Intracellular calcium and patch clamp measurements were made from human saphenous vein endothelial cells and HEK 293 cells expressing exogenous human TRPC5, TRPM2 or TRPM3. Sig1R ligands were applied and short interfering RNA was used to deplete Sig1R. TRP channels tagged with fluorescent proteins were used for subcellular localization studies. Key Results In endothelial cells, 10-100 μ M of the Sig1R antagonist BD1063 inhibited sustained but not transient calcium responses evoked by histamine. The Sig1R agonist 4- IBP and related antagonist BD1047 were also inhibitory. The Sig1R agonist SKF10047 had no effect. Sustained calcium entry evoked by VEGF or hydrogen peroxide was also inhibited by BD1063, BD1047 or 4- IBP, but not SKF10047. 4- IBP, BD1047 and BD1063 inhibited TRPC5 or TRPM3, but not TRPM2. Inhibitory effects of BD1047 were rapid in onset and readily reversed on washout. SKF10047 inhibited TRPC5 but not TRPM3 or TRPM2. Depletion of Sig1R did not prevent the inhibitory actions of BD1063 or BD1047 and Sig1R did not co-localize with TRPC5 or TRPM3. Conclusions and Implications The data suggest that two types of Sig1R ligand ( BD1047/ BD1063 and 4- IBP) are inhibitors of receptor- or chemically activated calcium entry channels, acting relatively directly and independently of the Sig1R. Chemical foundations for TRP channel inhibitors are suggested. [ABSTRACT FROM AUTHOR]

Background and Purpose: The Sigma-1 receptor (Sig1R) impacts on calcium ion signalling and has a plethora of ligands. This study investigated Sig1R and its ligands in relation to endogenous calcium events of endothelial cells and transient receptor potential (TRP) channels.Experimental Approach: Intracellular calcium and patch clamp measurements were made from human saphenous vein endothelial cells and HEK 293 cells expressing exogenous human TRPC5, TRPM2 or TRPM3. Sig1R ligands were applied and short interfering RNA was used to deplete Sig1R. TRP channels tagged with fluorescent proteins were used for subcellular localization studies.Key Results: In endothelial cells, 10-100 μM of the Sig1R antagonist BD1063 inhibited sustained but not transient calcium responses evoked by histamine. The Sig1R agonist 4-IBP and related antagonist BD1047 were also inhibitory. The Sig1R agonist SKF10047 had no effect. Sustained calcium entry evoked by VEGF or hydrogen peroxide was also inhibited by BD1063, BD1047 or 4-IBP, but not SKF10047. 4-IBP, BD1047 and BD1063 inhibited TRPC5 or TRPM3, but not TRPM2. Inhibitory effects of BD1047 were rapid in onset and readily reversed on washout. SKF10047 inhibited TRPC5 but not TRPM3 or TRPM2. Depletion of Sig1R did not prevent the inhibitory actions of BD1063 or BD1047 and Sig1R did not co-localize with TRPC5 or TRPM3.Conclusions and Implications: The data suggest that two types of Sig1R ligand (BD1047/BD1063 and 4-IBP) are inhibitors of receptor- or chemically activated calcium entry channels, acting relatively directly and independently of the Sig1R. Chemical foundations for TRP channel inhibitors are suggested. [ABSTRACT FROM AUTHOR]

ENDOTHELINS, INFLAMMATION, CENTRAL nervous system regeneration, MYELINATION, REGENERATIVE medicine, MULTIPLE sclerosis, NATURAL immunity, and DEMYELINATION

The development of new regenerative therapies for multiple sclerosis is hindered by the lack of potential targets for enhancing remyelination. The study of naturally regenerative processes such as the innate immune response represents a powerful approach for target discovery to solve this problem. By ‘mining’ these processes using transcriptional profiling we can identify candidate factors that can then be tested individually in clinically-relevant models of demyelination and remyelination. Here, therefore, we have examined a previously described in vivo model of the innate immune response in which zymosan-induced macrophage activation in the retina promotes myelin sheath formation by oligodendrocytes generated from transplanted precursor cells. While this model is not itself clinically relevant, it does provide a logical starting point for this study as factors that promote myelination must be present. Microarray analysis of zymosan-treated retinae identified several cytokines (CXCL13, endothelin 2, CCL20 and CXCL2) to be significantly upregulated. When tested in a cerebellar slice culture model, CXCL13 and endothelin 2 promoted myelination and endothelin 2 also promoted remyelination. In studies to identify the receptor responsible for this regenerative effect of endothelin 2, analysis of both remyelination following experimental demyelination and of different stages of multiple sclerosis lesions in human post-mortem tissue revealed high levels of endothelin receptor type B in oligodendrocyte lineage cells. Confirming a role for this receptor in remyelination, small molecule agonists and antagonists of endothelin receptor type B administered in slice cultures promoted and inhibited remyelination, respectively. Antagonists of endothelin receptor type B also inhibited remyelination of experimentally-generated demyelination in vivo. Our work therefore identifies endothelin 2 and the endothelin receptor type B as a regenerative pathway and suggests that endothelin receptor type B agonists represent a promising therapeutic approach to promote myelin regeneration. [ABSTRACT FROM AUTHOR]

VESPULA, HONEYDEW (Entomology), COELOSTOMIDIIDAE, ANT communities, and INSECT food

The Avian Convergence Hypothesis states that avian-honeydew associations are likely to develop when biogeographic and/or climatic factors limit the formation of ant-honeydew associations (the dominant association in tropical ecosystems). In this study we examine a honeydew-influenced forest system in an island archipelago where ant diversity is low but invasive Vespula wasp species (Vespidae) are present. We found honeydew production was highly seasonal, with both standing crop and 24-h production peaking in summer. When Vespula wasps were abundant (summer and autumn) they preferentially visited infested trees and fed regularly on honeydew droplets on infested branches. Two ant species occasionally fed on honeydew. No other insects or birds were observed feeding on honeydew during the study period. With the exception of Vespula, honeydew does not appear to be a preferred food source in this community, possibly because of the range of other food resources available in surrounding forest, farmland and gardens. The abundance of Vespula wasps at the site may also have disrupted bird-honeydew associations. We suggest the Avian Convergence Hypothesis could be restated to explicitly include both nectar availability and invasive social insects as both are likely to influence bird use of honeydew. [ABSTRACT FROM AUTHOR]

CARCINOGENS, CONFIDENCE intervals, DISASTERS, DUST, MASS casualties, QUESTIONNAIRES, REGRESSION analysis, RESCUE work, RESEARCH funding, TERRORISM, TUMORS, ENVIRONMENTAL exposure, DISEASE incidence, DATA analysis software, and DESCRIPTIVE statistics

Background: World Trade Center (WTC) rescue and recovery workers were exposed to a complex mix of pollutants and carcinogens. Objective: The purpose of this investigation was to evaluate cancer incidence in responders during the first 7 years after 11 September 2001. Methods: Cancers among 20,984 consented participants in the WTC Health Program were identified through linkage to state tumor registries in New York, New Jersey, Connecticut, and Pennsylvania. Standardized incidence ratios (SIRs) were calculated to compare cancers diagnosed in responders to predicted numbers for the general population. Multivariate regression models were used to estimate associations with degree of exposure. Results: A total of 575 cancers were diagnosed in 552 individuals. Increases above registry-based expectations were noted for all cancer sites combined (SIR = 1.15; 95% CI: 1.06, 1.25), thyroid cancer (SIR = 2.39; 95% CI: 1.70, 3.27), prostate cancer (SIR = 1.21; 95% CI: 1.01, 1.44), combined hematopoietic and lymphoid cancers (SIR = 1.36; 95% CI: 1.07, 1.71), and soft tissue cancers (SIR = 2.26; 95% CI: 1.13, 4.05). When restricted to 302 cancers diagnosed ≥ 6 months after enrollment, the SIR for all cancers decreased to 1.06 (95% CI: 0.94, 1.18), but thyroid and prostate cancer diagnoses remained greater than expected. All cancers combined were increased in very highly exposed responders and among those exposed to significant amounts of dust, compared with responders who reported lower levels of exposure. Conclusion: Estimates should be interpreted with caution given the short follow-up and long latency period for most cancers, the intensive medical surveillance of this cohort, and the small numbers of cancers at specific sites. However, our findings highlight the need for continued follow-up and surveillance of WTC responders. [ABSTRACT FROM AUTHOR]

PEPTIDE synthesis, GLYCOPEPTIDE synthesis, POLYPROLINE, ANTIFREEZE proteins, GALACTOSAMINE, and ICE crystals

Abstract: A library of peptides and glycopeptides containing (4R)-hydroxy-l-proline (Hyp) residues were designed with a view to providing stable polyproline II (PPII) helical molecules with antifreeze activity. A library of dodecapeptides containing contiguous Hyp residues or an Ala-Hyp-Ala tripeptide repeat sequence were synthesized with and without α-O-linked N-acetylgalactosamine and α-O-linked galactose-β-(1→3)-N-acetylgalactosamine appended to the peptide backbone. All (glyco)peptides possessed PPII helical secondary structure with some showing significant thermal stability. The majority of the (glyco)peptides did not exhibit thermal hysteresis (TH) activity and were not capable of modifying the morphology of ice crystals. However, an unglycosylated Ala-Hyp-Ala repeat peptide did show significant TH and ice crystal re-shaping activity suggesting that it was capable of binding to the surface of ice. All (glyco)peptides synthesized displayed some ice recrystallization inhibition (IRI) activity with unglycosylated peptides containing the Ala-Hyp-Ala motif exhibiting the most potent inhibitory activity. Interestingly, although glycosylation is critical to the activity of native antifreeze glycoproteins (AFGPs) that possess an Ala-Thr-Ala tripeptide repeat, this same structural modification is detrimental to the antifreeze activity of the Ala-Hyp-Ala repeat peptides studied here. [Copyright &y& Elsevier]

INSULIN regulation, INSULIN therapy, GLYCEMIC index, BLOOD sugar monitoring, and PATIENT satisfaction

OBJECTIVE-Use of automated bolus advisors is associated with improved glycemic control in patients treatedwith insulin pump therapy. We conducted a study to assess the impact of using an insulin bolus advisor embedded in a blood glucose (BG) meter on glycemic control and treatment satisfaction in patients treated with multiple daily insulin injection (MDI) therapy. The study goal was to achieve ≤0.5% A1C reduction in most patients. RESEARCH DESIGN AND METHODS-This was a 26-week, prospective, randomized, controlled, multinational study that enrolled 218 MDI-treated patients with poorly controlled diabetes (202 with type 1 diabetes, 16 with type 2 diabetes) who were 18 years of age or older. Participants had mean baseline A1C of 8.9% (SD, 1.2 [74 mmol/mol]), mean age of 42.4 years (SD, 14.0), mean BMI of 26.5 kg/m2 (SD, 4.2), and mean diabetes duration of 17.7 years (SD, 11.1). Control group (CNL) patients used a standard BG meter and manual bolus calculation; intervention group (EXP) patients used the Accu-Chek Aviva Expert meter with an integrated bolus advisor to calculate insulin dosages. Glucose data were downloaded and used for therapy parameter adjustments in both groups. RESULTS-A total of 193 patients (CNL, n = 93; EXP, n=100) completedthe study. Significantly more EXP than CNL patients achieved >0.5% A1C reduction (56.0% vs. 34.4%; P <0.01). Improvement in treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire scale) was significantly greater in EXP patients (11.4 [SD, 6.0] vs. 9.0 [SD, 6.3]; P < 0.01). Percentage of BG values <50 mg/dL was <2% in both groups during the study. CONCLUSIONS-Use of an automated bolus advisor resulted in improved glycemic control and treatment satisfaction without increasing severe hypoglycemia. [ABSTRACT FROM AUTHOR]

Objective: Use of automated bolus advisors is associated with improved glycemic control in patients treated with insulin pump therapy. We conducted a study to assess the impact of using an insulin bolus advisor embedded in a blood glucose (BG) meter on glycemic control and treatment satisfaction in patients treated with multiple daily insulin injection (MDI) therapy. The study goal was to achieve >0.5% A1C reduction in most patients.Research Design and Methods: This was a 26-week, prospective, randomized, controlled, multinational study that enrolled 218 MDI-treated patients with poorly controlled diabetes (202 with type 1 diabetes, 16 with type 2 diabetes) who were 18 years of age or older. Participants had mean baseline A1C of 8.9% (SD, 1.2 [74 mmol/mol]), mean age of 42.4 years (SD, 14.0), mean BMI of 26.5 kg/m(2) (SD, 4.2), and mean diabetes duration of 17.7 years (SD, 11.1). Control group (CNL) patients used a standard BG meter and manual bolus calculation; intervention group (EXP) patients used the Accu-Chek Aviva Expert meter with an integrated bolus advisor to calculate insulin dosages. Glucose data were downloaded and used for therapy parameter adjustments in both groups.Results: A total of 193 patients (CNL, n = 93; EXP, n = 100) completed the study. Significantly more EXP than CNL patients achieved >0.5% A1C reduction (56.0% vs. 34.4%; P < 0.01). Improvement in treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire scale) was significantly greater in EXP patients (11.4 [SD, 6.0] vs. 9.0 [SD, 6.3]; P < 0.01). Percentage of BG values <50 mg/dL was <2% in both groups during the study.Conclusions: Use of an automated bolus advisor resulted in improved glycemic control and treatment satisfaction without increasing severe hypoglycemia. [ABSTRACT FROM AUTHOR]

T cells, LYMPHOCYTES, LYMPHOBLASTIC leukemia, LYMPHOCYTIC leukemia, and GENE expression

RNA-seq is a promising technology to re-sequence protein coding genes for the identification of single nucleotide variants (SNV), while simultaneously obtaining information on structural variations and gene expression perturbations. We asked whether RNA-seq is suitable for the detection of driver mutations in T-cell acute lymphoblastic leukemia (T-ALL). These leukemias are caused by a combination of gene fusions, over-expression of transcription factors and cooperative point mutations in oncogenes and tumor suppressor genes. We analyzed 31 T-ALL patient samples and 18 T-ALL cell lines by high-coverage paired-end RNA-seq. First, we optimized the detection of SNVs in RNA-seq data by comparing the results with exome re-sequencing data. We identified known driver genes with recurrent protein altering variations, as well as several new candidates including H3F3A, PTK2B, and STAT5B. Next, we determined accurate gene expression levels from the RNA-seq data through normalizations and batch effect removal, and used these to classify patients into T-ALL subtypes. Finally, we detected gene fusions, of which several can explain the over-expression of key driver genes such as TLX1, PLAG1, LMO1, or NKX2-1; and others result in novel fusion transcripts encoding activated kinases (SSBP2-FER and TPM3-JAK2) or involving MLLT10. In conclusion, we present novel analysis pipelines for variant calling, variant filtering, and expression normalization on RNA-seq data, and successfully applied these for the detection of translocations, point mutations, INDELs, exon-skipping events, and expression perturbations in T-ALL. [ABSTRACT FROM AUTHOR]

OLIGODENDROGLIA, PROTEIN kinases, CELL migration, NEUROGLIA, CELL differentiation, AXONS, APOPTOSIS, and CELL culture

Oligodendrocytes are the myelinating glial cells of the central nervous system. In the course of brain development, oligodendrocyte precursor cells migrate, scan the environment and differentiate into mature oligodendrocytes with multiple cellular processes which recognize and ensheath neuronal axons. During differentiation, oligodendrocytes undergo dramatic morphological changes requiring cytoskeletal rearrangements which need to be tightly regulated. The non-receptor tyrosine kinase Fyn plays a central role in oligodendrocyte differentiation and myelination. In order to improve our understanding of the role of oligodendroglial Fyn kinase, we have identified Fyn targets in these cells. Purification and mass-spectrometric analysis of tyrosine-phosphorylated proteins in response to overexpressed active Fyn in the oligodendrocyte precursor cell line Oli-neu, yielded the adaptor molecule p130Cas. We analyzed the function of this Fyn target in oligodendroglial cells and observed that reduction of p130Cas levels by siRNA affects process outgrowth, the thickness of cellular processes and migration behavior of Oli-neu cells. Furthermore, long term p130Cas reduction results in decreased cell numbers as a result of increased apoptosis in cultured primary oligodendrocytes. Our data contribute to understanding the molecular events taking place during oligodendrocyte migration and morphological differentiation and have implications for myelin formation. [ABSTRACT FROM AUTHOR]

PHOTOSENSITIVITY disorders, SKIN diseases, PSORALENS, HUMAN skin color, ERYTHEMA, and BLISTERS

Abstract: Phytophotodermatitis is a phototoxic cutaneous eruption due to skin exposure to furocourmarins combined with ultraviolet light. Bizzare linear patterns, ranging from erythema to bullae with residual hyperpigmentaion, is the clinical clue to this diagnosis. Avoidance of furocoumarins in direct sunlight can prevent recurrences. [Copyright &y& Elsevier]

IMMUNOGENETICS, INFLUENZA vaccines, INFLUENZA A virus, H1N1 subtype, VACCINE safety, RECOMBINANT proteins, MONOMERS, HEMAGGLUTININ, and PREVENTION

Abstract: Background: Novel influenza viruses continue to pose a potential pandemic threat worldwide. In recent years, plants have been used to produce recombinant proteins, including subunit vaccines. A subunit influenza vaccine, HAC1, based on recombinant hemagglutinin from the 2009 pandemic A/California/04/2009 (H1N1) strain of influenza virus, has been manufactured using a plant virus-based transient expression technology in Nicotiana benthamiana plants and demonstrated to be immunogenic and safe in pre-clinical studies (Shoji et al., 2011). Methods: A first-in-human, Phase 1, single-center, randomized, placebo-controlled, single-blind, dose escalation study was conducted to investigate safety, reactogenicity and immunogenicity of an HAC1 formulation at three escalating dose levels (15μg, 45μg and 90μg) with and without Alhydrogel®, in healthy adults 18–50 years of age (inclusive). Eighty participants were randomized into six study vaccine groups, a saline placebo group and an approved monovalent H1N1 vaccine group. Recipients received two doses of vaccine or placebo (except for the monovalent H1N1 vaccine cohort, which received a single dose of vaccine, later followed by a dose of placebo). Results: The experimental vaccine was safe and well tolerated, and comparable to placebo and the approved monovalent H1N1 vaccine. Pain and tenderness at the injection site were the only local solicited reactions reported following vaccinations. Nearly all adverse events were mild to moderate in severity. The HAC1 vaccine was also immunogenic, with the highest seroconversion rates, based on serum hemagglutination-inhibition and virus microneutralization antibody titers, in the 90μg non-adjuvanted HAC1 vaccine group after the second vaccine dose (78% and 100%, respectively). Conclusions: This is the first study demonstrating the safety and immunogenicity of a plant-produced subunit H1N1 influenza vaccine in healthy adults. The results support further clinical investigation of the HAC1 vaccine as well as demonstrate the feasibility of the plant-based technology for vaccine antigen production. [Copyright &y& Elsevier]

INSULIN therapy, OPTIMAL control theory, BLOOD sugar, PEOPLE with diabetes, MEDICAL databases, and CLINICAL trials

Background: We assessed the impact of using an automated bolus advisor integrated into a blood glucose meter on the timing and frequency of adjusting insulin therapy parameter settings and whether the availability of this technology would increase blood glucose test strip utilization in diabetes patients treated with multiple daily insulin injection (MDI) therapy. Subjects and Methods: The Automated Bolus Advisor Control and Usability Study (ABACUS) trial, a 26-week, prospective, randomized, controlled, multinational study that enrolled 218 type 1 and type 2 diabetes patients, demonstrated that use of an automated insulin bolus advisor helps improve glycemic control in suboptimally controlled, MDI-treated patients. Patient data were assessed to determine when and how often changes in insulin parameter settings occurred during the study. Patient meters were downloaded to determine blood glucose monitoring frequency. Results: One hundred ninety-three patients completed the study: 93 control arm (CNL) and 100 intervention (experimental) arm (EXP). Significantly more EXP (47.5%) than CNL (30.7%) patients received one or more changes in their insulin sensitivity factor (ISF) settings during the study ( P=0.0191). Changes in ISF settings occurred earlier and more frequently in EXP than CNL patients throughout the study. A similar trend was seen in changes in insulin-to-carbohydrate ratios. There were no differences in daily self-monitoring of blood glucose frequency [mean (SD)] between CNL and EXP patients: 4.7 (1.5) versus 4.6 (1.3) ( P=0.4085). Conclusions: Use of an automated bolus advisor was associated with earlier, more frequent changes in key insulin parameters, which may have contributed to subsequent improvements in glycemic control but without increased glucose test strip utilization. [ABSTRACT FROM AUTHOR]

ANALYSIS of variance, ANIMAL behavior, ANIMAL experimentation, BIOLOGICAL assay, ETHANOL, GENES, INSECTS, RESEARCH funding, RNA, STATISTICS, DATA analysis, DATA analysis software, and DESCRIPTIVE statistics

Background The fruit fly Drosophila melanogaster has been used extensively to investigate genetic mechanisms of ethanol ( Et OH)-related behaviors. Many past studies in flies, including studies from our laboratory, have manipulated gene expression using transposons carrying the genetic-phenotypic marker mini-white(mini-w), a derivative of the endogenous gene white(w). Whether the mini-w transgenic marker or the endogenous w gene influences behavioral responses to acute Et OH exposure in flies has not been systematically investigated. Methods We manipulated mini-w and w expression via (i) transposons marked with mini-w, (ii) RNAi against mini-w and w, and (iii) a null allele of w. We assessed Et OH sensitivity and tolerance using a previously described e RING assay (based on climbing in the presence of Et OH) and an assay based on Et OH-induced sedation. Results In e RING assays, Et OH-induced impairment of climbing correlated inversely with expression of the mini-w marker from a series of transposon insertions. Additionally, flies harboring a null allele of w or flies with RNAi-mediated knockdown of mini-w were significantly more sensitive to Et OH in e RING assays than controls expressing endogenous w or the mini-w marker. In contrast, Et OH sensitivity and rapid tolerance measured in the Et OH sedation assay were not affected by decreased expression of mini-w or endogenous w in flies. Conclusions Et OH sensitivity measured in the e RING assay is noticeably influenced by w and mini-w, making e RING problematic for studies on Et OH-related behavior in Drosophila using transgenes marked with mini-w. In contrast, the Et OH sensitivity assay described here is a suitable behavioral paradigm for studies on Et OH sensitivity and rapid tolerance in Drosophila including those that use widely available transgenes marked with mini-w. [ABSTRACT FROM AUTHOR]

DRUG efficacy, VIMPAT, ANTICONVULSANTS, PEOPLE with epilepsy, and TREATMENT of epilepsy

Objective To evaluate the efficacy and safety of conversion to lacosamide 400 mg/day monotherapy in adults with focal epilepsy. Methods This historical-controlled, double-blind study ( NCT00520741) enrolled patients aged 16-70 years on stable doses of 1-2 antiepileptic drugs ( AEDs) and experiencing 2-40 partial-onset seizures per 28 days during the 8-week prospective Baseline. Patients were randomized to lacosamide 400 or 300 mg/day (3:1 ratio), starting at 200 mg/day and titrated over 3 weeks to randomized dose. Patients then withdrew background AEDs over 6 weeks and entered a 10-week Monotherapy Phase. The primary assessment was the Kaplan-Meier-predicted percentage of patients on 400 mg/day in the full analysis set ( FAS) meeting ≥1 predefined seizure-related exit criterion by day 112, compared with the historical-control threshold (65.3%). Results Four hundred twenty-five patients were enrolled and were eligible for safety analyses (400 mg/day, n = 319; 300 mg/day, n = 106). A total of 271 (63.8%) of 425 patients completed the Lacosamide Maintenance Phase (combined AED Withdrawal and Monotherapy Phases). Among 284 patients in the 400 mg/day group in the FAS, 82 (28.9%) met ≥1 exit criterion; the Kaplan-Meier-predicted exit percentage at day 112 for 400 mg/day (30.0%; 95% confidence interval [ CI] 24.6-35.5%) was lower than the historical control. When exit events, withdrawal due to treatment-emergent adverse events ( TEAEs), and withdrawal due to lack of efficacy were summed (n = 90), the predicted exit percentage (32.3%; 95% CI 26.8-37.8%) was also lower than the historical control. Most patients receiving 400 mg/day reported some improvement on the Clinical Global Impression of Change (75.4%) and Patient Global Impression of Change (74.3%). Overall, the most common (>10%) TEAEs were dizziness (24.0%), headache (14.4%), nausea (13.4%), convulsion (11.5%), somnolence (10.4%), and fatigue (10.1%); most (74.1%) were mild-to-moderate in intensity. Seventy-two patients (16.9%) discontinued due to TEAEs. Seventeen patients (4%, all receiving 400 mg/day) experienced serious AEs. Significance Lacosamide 400 mg/day monotherapy was effective, with a favorable safety profile in patients with focal epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

HYPOTHYROIDISM treatment, GUIDELINES, LEVOTHYROXINE, THYROID cancer, THYROID hormones, and THYROTROPIN

Background: A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force. Results: We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non-levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones. Conclusions: We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine-liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile. [ABSTRACT FROM AUTHOR]

REFORESTATION, ENDEMIC plants, PLANT succession, RESTORATION ecology, and FOREST regeneration

Native re-forestation is a widely used restoration tool, typically undertaken with the expectation that planting native trees will initiate succession processes (including the re-establishment of native fauna) that will eventually return the ecosystem to a native-dominated state. Invertebrate groups can be used to assess restoration progress, as their life history traits enable them to respond more rapidly to environmental change than many other organisms. In this study, we assessed beetle responses to re-forestation. Using two trapping methods (flight intercept traps and pitfall traps), we compared beetle assemblages in exotic pasture (pre-restoration state), <10-year-old planted native forest (restoration intervention) and approximately 40-year-old unmanaged regenerating native forest (reference state). Analysis of the flight intercept-trapped beetles suggests that re-forestation has initiated a transition from an exotic-dominated pasture fauna toward a native-dominated fauna: in planted forests, 75% of all flight-intercept-trapped beetles were native (compared with 22% in pasture and 87% in unmanaged forest). Flight intercept-trapped beetles also had higher native diversity and abundance in both forest types than in pasture. Pitfall-trapped beetle species were predominantly native in both forest types, but there were few statistically significant differences between the forests and pasture in the pit-fall trap data set. Both trapping methods detected significant compositional differences between the beetle assemblages in planted forest and unmanaged forest. Replanting native forest has increased native beetle diversity, abundance, and dominance (compared with the pre-restoration state), but convergence with the unmanaged reference forest has not yet been achieved. [ABSTRACT FROM AUTHOR]

BIOENERGETICS, GEOSPATIAL data, CONTEXTUAL analysis, PHYSICAL activity, and OBESITY

In the past 15 years, a major research enterprise has emerged that is aimed at understanding associations between geographic and contextual features of the environment (especially the built environment) and elements of human energy balance, including diet, weight and physical activity. Here we highlight aspects of this research area with a particular focus on research and opportunities in the United States as an example. We address four main areas: (1) the importance of valid and comparable data concerning behaviour across geographies; (2) the ongoing need to identify and explore new environmental variables; (3) the challenge of identifying the causally relevant context; and (4) the pressing need for stronger study designs and analytical methods. Additionally, we discuss existing sources of geo-referenced health data which might be exploited by interdisciplinary research teams, personnel challenges and some aspects of funding for geospatial research by the US National Institutes of Health in the past decade, including funding for international collaboration and training opportunities. [ABSTRACT FROM AUTHOR]

STOMATA, LEAF anatomy, PLANT epidermis, PLANT growth, and WATER

Stomata, valves on the plant epidermis, are critical for plant growth and survival, and the presence of stomata impacts the global water and carbon cycle. Although transcription factors and cell-cell signaling components regulating stomatal development have been identified, it remains unclear as to how their regulatory interactions are translated into two-dimensional patterns of stomatal initial cells. Using molecular genetics, imaging, and mathematical simulation, we report a regulatory circuit that initiates the stomatal cell-lineage. The circuit includes a positive feedback loop constituting self-activation of SCREAMs that requires SPEECHLESS. This transcription factor module directly binds to the promoters and activates a secreted signal, EPIDERMAL PATTERNING FACTOR2, and the receptor modifier TOO MANY MOUTHS, while the receptor ERECTA lies outside of this module. This in turn inhibits SPCH, and hence SCRMs, thus constituting a negative feedback loop. Our mathematical model accurately predicts all known stomatal phenotypes with the inclusion of two additional components to the circuit: an EPF2-independent negative-feedback loop and a signal that lies outside of the SPCH•SCRM module. Our work reveals the intricate molecular framework governing self-organizing two-dimensional patterning in the plant epidermis. [ABSTRACT FROM AUTHOR]

GERIATRIC assessment, ANTIBIOTICS, CLOSTRIDIUM diseases, CONFIDENCE intervals, DIARRHEA, DRUG prescribing, FACTOR analysis, FRAIL elderly, LONGITUDINAL method, MEDICAL cooperation, NURSING home patients, NURSING care facilities, NUTRITIONAL assessment, PROBABILITY theory, RESEARCH, RESEARCH funding, STATISTICS, PHYSICIAN practice patterns, MULTIPLE regression analysis, PROPORTIONAL hazards models, DATA analysis software, DESCRIPTIVE statistics, and ODDS ratio

Background: the risk factors for and frequency of antibiotic prescription and antibiotic-associated diarrhoea (AAD) among care home residents are unknown. Aim: to prospectively study frequency and risks for antibiotic prescribing and AAD for care home residents. Design and setting: a 12-month prospective cohort study in care homes across South Wales. Method: antibiotic prescriptions and the development of AAD were recorded on case report forms. We defined AAD as three or more loose stools in a 24-h period occurring within 8 weeks of exposure to an antibiotic. Results: we recruited 279 residents from 10 care homes. The incidence of antibiotic prescriptions was 2.16 prescriptions per resident year (95% CI: 1.90-2.46). Antibiotics were less likely to be prescribed to residents from dual-registered homes (OR compared with nursing homes: 0.38, 95% CI: 0.18-0.79). For those who were prescribed antibiotics, the incidence of AAD was 0.57 episodes per resident year (95% CI: 0.41-0.81 episodes). AAD was more likely in residents who were prescribed coamoxiclav (hazards ratio, HR = 2.08, 95% confidence interval, CI: 1.18-3.66) or routinely used incontinence pads (HR = 2.54, 95% CI: 1.26-5.13) and less likely in residents from residential homes (HR compared with nursing homes: 0.14, 95% CI: 0.06-0.32). Conclusion: residents of care homes, particularly of nursing homes, are frequently prescribed antibiotics and often experience diarrhoea following such prescriptions. Co-amoxiclav is associated with greater risk of AAD. [ABSTRACT FROM AUTHOR]

Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as con- genital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electro- myography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB- associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments. [ABSTRACT FROM AUTHOR]