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.

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.

Adaptation, Psychological, Adult, Chronic Disease, Factor Analysis, Statistical, Female, Humans, Male, Regression Analysis, Social Support, Socioeconomic Factors, Surveys and Questionnaires, Life Change Events, Pain psychology, and Quality of Life

Cognitive appraisal processes or the meaning a person gives a stressful event are believed to mediate an individual's reaction to an event and, as such, have been demonstrated to explain adjustment to illness. The purpose of this paper is to test this cognitive as well as other social and illness variables to explain the variance in a person's adjustment to chronic pain. Two hundred and twenty-two patients, who were randomly selected from an original sample of referrals to a chronic pain specialty clinic, completed a questionnaire by telephone interview or mail. The questionnaire consisted of psychosocial scales (PAIS-SR; Social Support) and cognitions including the Meaning of Illness Questionnaire (MIQ). Fifty-six percent of the sample had poor psychosocial adjustment to their pain problem. Seventy percent of the variance in adjustment was explained by social and cognitive variables which corroborates their importance. The MIQ 5-factor structure was supported and provides credible evidence of the role of cognitions in differentiating between the poor and well adjusted.

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]

Adolescent, Adult, Age of Onset, Alleles, Child, Disease Progression, Female, Haplotypes genetics, Heterozygote, Humans, Male, Middle Aged, Molecular Sequence Data, Multiple Sclerosis pathology, Phenotype, Polymorphism, Single Nucleotide genetics, Probability, Survival Analysis, Apolipoproteins E genetics, Genetic Predisposition to Disease, Multiple Sclerosis genetics, Multiple Sclerosis physiopathology, and Polymorphism, Genetic genetics

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).

Animals, Carcinogens, Environmental toxicity, Environmental Monitoring, Gasoline toxicity, Mollusca, Petroleum toxicity, and Polycyclic Aromatic Hydrocarbons toxicity

Fish and shellfish are exposed to a wide range of polycyclic aromatic hydrocarbons (PAH) following oil spills at sea, and can become contaminated as a result. Finfish have a more effective mixed-function oxidase enzyme system than shellfish, and are therefore able to metabolise and excrete PAH more effectively than the invertebrates. Thus, contamination by high-molecular weight PAH, including those with carcinogenic potential and so of concern with regard to human consumers, is therefore usually observed in shellfish, and particularly in bivalve molluscs. Oil spills are not the sole source of PAH, however, as parent compounds are also generated by a wide range of combustion processes. In this paper, consideration is given to monitoring data gathered following recent oil spills (both of crude oil and diesel fuel), alongside data from other studies. These include studies conducted around a former gasworks site and downstream of an aluminium smelter in the UK, and from mussel monitoring studies undertaken in the UK and the USA (including the Exxon Valdez oil spill and the National Status and Trends programme), and in other countries in Europe. For comparative purposes the PAH concentrations are summed and also expressed as benzo[a]pyrene equivalents, their relative concentrations being weighted in relation to the carcinogenic potential of individual PAH compounds using toxic equivalency factors (TEF). Our aim was to assess the utility of this approach in fishery resource monitoring and control following oil spills. Certainly this approach seems useful from the data assessed in this study. and the relative ranking of the various studies seems to reflect the relative degree of concern for human consumers due to the differing contamination sources. As a simple tool for control purposes it is equally applicable to PAH derived from oil spills, and from industrial and combustion sources.

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]

Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 6, Chromosomes, Human, Pair 7, Genetic Heterogeneity, HLA-DR2 Antigen genetics, Humans, Lod Score, Multiple Sclerosis etiology, Genetic Linkage, Genetic Predisposition to Disease, and Multiple Sclerosis genetics

Multiple sclerosis (MS) is a common and frequently disabling autoimmune disorder mediated by autoaggressive T cells and autoantibodies that target central nervous system myelin. While numerous studies have demonstrated a strong genetic component to MS, it has been difficult to identify the specific genes involved. Several genomic screens have been undertaken to locate such genes, but have not provided consistent gene localization, except for the MHC on chromosome 6p21 and a locus on chromosome 19q13. To determine which of the original genomic locations presented in the US genome screen could be replicated, a more detailed analysis of additional families was performed. The results, derived from a population of 266 affected individuals belonging to 98 multiplex families, continue to support linkage to chromosomes 6p21, 6q27, and 19q13 with LOD scores>3.0, and suggest that regions on chromosomes 12q23-24 and 16p13 may also harbor susceptibility loci for MS. Analysis taking into account the known HLA-DR2 association identified two additional potential linkage regions on chromosomes 7q21-22 and 13q33-34. These regions can now be targeted for detailed study to identify the underlying MS susceptibility genes.

Consultants, Humans, Librarians, Personnel Staffing and Scheduling standards, Societies, Workforce, Information Management standards, Libraries, Hospital standards, Library Services standards, and Professional Role

The Medical Library Association's "Standards for Hospital Libraries 2002" have been developed as a guide for hospital administrators, librarians, and accrediting bodies to ensure that hospitals have the resources and services to effectively meet their needs for knowledge-based information. Specific requirements for knowledge-based information include that the library be a separate department with its own budget. Knowledge-based information in the library should be directed by a qualified librarian who functions as a department head and is a member of the Academy of Health Information Professionals. The standards define the role of the medical librarian and the links between knowledge-based information and other functions such as patient care, patient education, performance improvement, and education. In addition, the standards address the development and implementation of the knowledge-based information needs assessment and plans, the promotion and publicity of the knowledge-based information services, and the physical space and staffing requirements. The role, qualifications, and functions of a hospital library consultant are outlined. The health sciences library is positioned to play a key role in the hospital. The increasing use of the Internet and new information technologies by medical, nursing, and allied health staffs; patients; and the community require new strategies, strategic planning, allocation of adequate resources, and selection and evaluation of appropriate information resources and technologies. The Hospital Library Standards Committee has developed this document as a guideline to be used in facing these challenges.

Air Pollutants analysis, Aircraft, Humans, Musculoskeletal Diseases etiology, Musculoskeletal Diseases psychology, New York City, Occupational Diseases psychology, Occupational Health, Pilot Projects, Respiratory Tract Diseases psychology, Air Pollutants adverse effects, Occupational Diseases etiology, Occupational Exposure adverse effects, Rescue Work, Respiratory Tract Diseases etiology, and Terrorism

Aspergillus genetics, Aspergillus growth development, Blotting, Northern, Blotting, Southern, Fermentation, Heme metabolism, Mitosporic Fungi genetics, Peroxidase metabolism, Plasmids, Promoter Regions, Genetic, Aspergillus enzymology, Biotechnology methods, Mitosporic Fungi enzymology, and Peroxidase genetics

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.

Apoptosis drug effects, Butyrates pharmacology, Caco-2 Cells, Carcinoma drug therapy, Carcinoma metabolism, Carcinoma physiopathology, Caspase 3, Caspases drug effects, Caspases metabolism, Cell Adhesion drug effects, Cell Differentiation drug effects, Colonic Neoplasms drug therapy, Colonic Neoplasms metabolism, Colonic Neoplasms physiopathology, Down-Regulation drug effects, Down-Regulation physiology, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, Integrin beta1 drug effects, Integrin beta1 metabolism, Integrins drug effects, Intestinal Mucosa drug effects, NF-kappa B drug effects, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases drug effects, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation drug effects, Protein-Tyrosine Kinases drug effects, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins drug effects, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2 drug effects, Proto-Oncogene Proteins c-bcl-2 metabolism, Signal Transduction drug effects, Signal Transduction physiology, Sucrase drug effects, Sucrase metabolism, Apoptosis physiology, Cell Adhesion physiology, Cell Differentiation physiology, Integrins metabolism, Intestinal Mucosa metabolism, and Protein Serine-Threonine Kinases

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 kappaB (NF-kappaB). NaBT increased the level of sucrase. It induced apoptosis as shown by: (1) decreased Bcl-2 and Bcl-X(L) 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 beta1 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, beta1-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-kappaB 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-kappaB activation together with a defective beta1 integrin-FAK-PI 3-kinase pathways signaling.

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]

Action Potentials physiology, Animals, Cells, Cultured, Cochlear Nerve physiology, Culture Techniques, Electric Stimulation methods, Immunohistochemistry, Kv1.1 Potassium Channel, Mice, Mice, Inbred CBA, Neurons classification, Neurons metabolism, Patch-Clamp Techniques, Potassium Channels biosynthesis, Protein Subunits biosynthesis, Reaction Time physiology, Neurons physiology, Potassium Channels, Voltage-Gated, and Spiral Ganglion cytology

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.

Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 3, Cooperative Behavior, France, Genetic Predisposition to Disease, HLA-DR Antigens genetics, HLA-DR Serological Subtypes, Humans, United States, Genetic Linkage genetics, and Multiple Sclerosis genetics

Multiple sclerosis (MS) is a demyelinating autoimmune disease with a strong yet complex genetic component. To date only the HLA-DR locus, and specifically the HLA-DR15 allele, has been identified and confirmed as influencing the risk of developing MS. Genomic screens on several datasets have been performed and have identified several chromosomal regions with interesting results, but none have yet been confirmed. We tested seven of the most-promising regions (on chromosomes 1p, 2p, 3p, 3q, 5q, 19q, and Xp) identified from several genomic screens in a dataset of 98 multiplex MS families from the United States and 90 multiplex MS families from France. The results did not confirm linkage to 2p, 3q, 5q, or Xp in the overall dataset, or in subsets defined by geographic origin or HLA-DR15 status. Regions on 1p34, 3p14, and 19q13 produced lod scores >0.90 in at least one subset of the data, suggesting that these regions should be examined in more detail.

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]

Anxiety Disorders physiopathology, Brain physiopathology, Humans, Obsessive-Compulsive Disorder epidemiology, Panic Disorder epidemiology, Phobic Disorders epidemiology, Schizophrenia physiopathology, Stress Disorders, Post-Traumatic epidemiology, Anxiety Disorders epidemiology, and Schizophrenia epidemiology

Anxiety symptoms and disorders have long been described in schizophrenia. This article reviews the epidemiology, phenomenology, and neurobiologic underpinnings of comorbid anxiety symptoms and disorders in schizophrenia. Recent literature was obtained by Medline searches using key words relating to schizophrenia and anxiety symptoms or disorders. There is some evidence that anxiety may be a core symptom dimension in schizophrenia, although further work is required. There is evidence that comorbid obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social anxiety disorder are all more common than expected by chance in schizophrenia, although additional work is needed to determine the mechanisms that underlie these associations and their clinical implications. In the interim, however, the data emphasize the importance of assessing and treating comorbid anxiety symptoms and disorders in schizophrenia.

Genetic Linkage, Genetic Markers, Genetic Predisposition to Disease, Humans, Lod Score, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 9, Cleft Lip genetics, and Cleft Palate genetics

Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD]=6.6). In addition, meta-analyses with the addition of results from 186 more families (six populations; 1,033 genotyped individuals) showed genomewide significance for 10 more regions, including another novel region at 2q32-35 (P=.0004). These are the first genomewide significant linkage results ever reported for CL/P, and they represent an unprecedented demonstration of the power of linkage analysis to detect multiple genes simultaneously for a complex disorder.

Animals, Animals, Newborn, Biopsy, Needle, Cell Movement, Disease Models, Animal, Female, Immunohistochemistry, Lung Compliance, Male, Positron-Emission Tomography, Probability, Pulmonary Ventilation, Random Allocation, Respiratory Distress Syndrome diagnostic imaging, Sensitivity and Specificity, Tidal Volume, Neutrophils physiology, Positive-Pressure Respiration methods, Respiratory Distress Syndrome pathology, and Respiratory Distress Syndrome therapy

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.

Adult, Comorbidity, Ethnicity, Female, Humans, Interview, Psychological, Male, Obsessive-Compulsive Disorder complications, Prevalence, Schizophrenia epidemiology, Schizophrenia ethnology, Schizophrenic Psychology, South Africa epidemiology, Obsessive-Compulsive Disorder epidemiology, and Schizophrenia complications

Obsessive compulsive disorder (OCD) has been reported in up to 31% of schizophrenia sufferers. This study evaluated the presence of OCD in a Xhosa-speaking schizophrenia group. Xhosa patients (N = 509, including 100 sibships) with schizophrenia were recruited from hospital and community settings. The patients underwent a structured clinical interview for the presence of lifetime co-morbid schizophrenia and OCD. Only 3 patients (0.5%) fulfilled criteria for OCD. No concordance for OCD was noted in the sibship group. Our findings differ from those in other parts of the world, and if replicated, might suggest unique protective environmental or genetic factors for OCD in certain ethnic groups.

Adaptation, Psychological, Adult, Age Distribution, Comorbidity, Female, HIV Infections psychology, Health Care Costs statistics numerical data, Health Care Surveys, Health Expenditures statistics numerical data, Health Services statistics numerical data, Health Status, Health Surveys, Humans, Male, Middle Aged, Ontario epidemiology, Prevalence, Quality of Life, Risk Factors, Sex Distribution, Socioeconomic Factors, Depression economics, Depression epidemiology, HIV Infections economics, and HIV Infections epidemiology

As new technologies extend the lives of people living with HIV/AIDS (PHA), the need increases for services that optimize their quality-of-life cost effectively. This study of PHAs (n = 297) in Ontario, Canada, examined the prevalence of depression, and its association with quality-of-life, coping strategies, social support, and use of health and social services. Results showed that depression was widespread (54.2%) and largely unrelated to demographic characteristics, but associated with diminished health status, health-related quality-of-life, and coping strategies. Depressed PHAs used significantly more crisis health care and related services, and community-based HIV/AIDS service organizations (ASOs). Findings suggest quality-of-life of PHAs may be improved by expanding the capacity of ASO workers to recognize and address depression, including helping depressed PHA access appropriate medication and sustain medication regimes.

Humans, Information Management standards, Library Associations standards, Professional Role, United States, Information Storage and Retrieval standards, Librarians, Libraries, Hospital standards, and Library Services standards

Adolescent, Base Sequence, Child, Child, Preschool, Choristoma genetics, Chromosomes, Human, X, Gene Duplication, Human Growth Hormone deficiency, Humans, Infant, Male, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Pituitary Gland, Anterior, Polymorphism, Genetic, SOXB1 Transcription Factors, DNA-Binding Proteins genetics, High Mobility Group Proteins genetics, Hypopituitarism genetics, Pituitary Gland, Posterior abnormalities, and Transcription Factors genetics

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.

Australia, Chromosome Mapping, Europe, Family, Genetic Markers genetics, Genomics methods, Humans, Middle Aged, United States, Chromosomes, Human genetics, Genetic Linkage, Genetic Predisposition to Disease genetics, Genetic Testing methods, and Multiple Sclerosis genetics

To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.

Adult, Aged, Cohort Studies, Disability Evaluation, Female, Humans, Inpatients, Longitudinal Studies, Male, Middle Aged, Ontario, Patient Transfer, Predictive Value of Tests, Probability, Prospective Studies, Recovery of Function, Risk Factors, Socioeconomic Factors, Treatment Outcome, Activities of Daily Living, Continuity of Patient Care organization administration, Patient Discharge, Physical Therapy Modalities, and Rehabilitation Centers organization administration

Objective: To determine which sociodemographic and clinical characteristics of patients admitted to a general activation service (GAS) are predictive of discharge to patients' discharge goal locations (DGLs).
Design: Prospective cohort study.
Setting: Rehabilitation and complex continuing care hospital in southern Ontario, Canada.
Participants: Patients admitted from January 2000 to December 2002 (N=154).
Intervention: The GAS.
Main Outcome Measure: Patients indicated on their service applications where they wanted to be discharged. This is termed the DGL.
Results: Fifty-three percent of the sample were discharged to their DGLs. Ninety-eight percent of these patients were discharged by 9 months. Eighty-seven percent who were discharged to their DGLs were discharged to their own home. Predictors of being discharged to the DGL were better activities of daily living scores, good vision, and having sufficient help at home. Expert clinician opinion of the likelihood of each patient being discharged to his/her DGL, based on initial assessment, was also predictive of each patient's eventual discharge to his/her DGL.
Conclusions: The GAS has a 53% success rate in discharging patients to their DGLs. Variables have been identified that should be useful in predicting whether patients will be discharged to their DGLs. Our findings are meaningful and informative in determining future admission criteria for the service.

Adult, Antipsychotic Agents therapeutic use, Humans, Hysteria drug therapy, Male, Religion and Psychology, South Africa, Syndrome, Culture, Hysteria psychology, and Hysteria rehabilitation

Antineoplastic Agents chemical synthesis, Humans, Microtubules drug effects, Molecular Structure, Structure-Activity Relationship, Triazoles chemical synthesis, Tubulin Modulators chemical synthesis, Tumor Cells, Cultured, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Triazoles chemistry, Triazoles pharmacology, Tubulin Modulators chemistry, and Tubulin Modulators pharmacology

A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.

Community-Acquired Infections epidemiology, Drug Resistance, Bacterial, Electrophoresis, Gel, Pulsed-Field, Florida epidemiology, Humans, Staphylococcus aureus isolation purification, Washington epidemiology, Wound Infection epidemiology, Wound Infection microbiology, Community-Acquired Infections microbiology, Methicillin pharmacology, Methicillin Resistance, Staphylococcal Infections epidemiology, and Staphylococcus aureus drug effects

We examined 299 methicillin-resistant, community-associated Staphylococcus aureus isolates from Florida and Washington State for the presence of the USA300 epidemic clone. Pulsed-field gel electrophoresis demonstrated the epidemic clone in 43% of our S. aureus strains and in isolates from both states. The majority of the USA300 isolates (88%) were from wound infections.

Animals, Antimitotic Agents chemistry, Antimitotic Agents classification, Biopolymers chemistry, Biopolymers metabolism, Cell Line, Tumor, Humans, Inhibitory Concentration 50, Mice, Molecular Structure, Oxadiazoles chemical synthesis, Oxadiazoles classification, Protein Conformation drug effects, Structure-Activity Relationship, Antimitotic Agents chemical synthesis, Antimitotic Agents pharmacology, Oxadiazoles chemistry, Oxadiazoles pharmacology, Tubulin chemistry, and Tubulin metabolism

Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.

Administration, Oral, Animals, Antioxidants administration dosage, Ascorbic Acid administration dosage, Dose-Response Relationship, Drug, Female, Fetal Weight drug effects, Gestational Age, Methacholine Chloride pharmacology, Phenylephrine pharmacology, Pregnancy, Rats, Rats, Mutant Strains, Vasoconstrictor Agents pharmacology, Vasodilator Agents pharmacology, Vasomotor System drug effects, Antioxidants pharmacology, Ascorbic Acid pharmacology, Ascorbic Acid Deficiency physiopathology, Mesenteric Arteries physiopathology, Pregnancy Complications physiopathology, and Vasomotor System physiopathology

Plasma ascorbic acid is decreased in women with the pregnancy disorder preeclampsia. We used a mutant strain of rats (Osteogenic Disorder Shionogi), dependent on dietary sources of vitamin C, to investigate whether reduced intake of the vitamin would differentially affect vascular function in late-pregnant (day 19) and age-matched virgin rats. The animals were given either 1 mg/mL of ascorbic acid ad libitum in drinking water [fully supplemented (FS)] or 0.25 mg/mL [marginally supplemented (MS)]. Fetal weights were 21% lower in MS than FS rats, whereas mean maternal weights and pup numbers did not differ. Small mesenteric arteries (diameter, 268+/-7 microm) were mounted in a pressurized arteriograph. Myogenic reactivity (contractile response to step increases in intraluminal pressure) was increased in arteries from MS pregnant compared with FS pregnant rats to levels observed in virgin rats. Ascorbic acid intake did not affect myogenic responses of arteries from virgin rats. Hence, the normal pregnancy-induced reduction in myogenic reactivity was abrogated in MS pregnant animals. Inhibition of nitric oxide synthase had no effect on the myogenicity of arteries from virgin or MS pregnant rats but increased myogenicity of FS pregnant rats to the level of MS pregnant rats. Free radical scavengers reversed the accentuated myogenicity of MS pregnant rats without affecting FS pregnant or virgin rat arteries. These data indicate that moderate ascorbate deprivation increases mesenteric artery myogenic responsiveness during pregnancy. This increase may result from a decrease in nitric oxide-mediated modulation of the myogenic contractile response.

Adenosine Triphosphate metabolism, Azepines chemistry, Binding Sites, Cell Proliferation drug effects, Cells, Cultured, Humans, Molecular Structure, Phosphorylation drug effects, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases antagonists inhibitors, Protein-Tyrosine Kinases antagonists inhibitors, Receptor, ErbB-2 antagonists inhibitors, Structure-Activity Relationship, Substrate Specificity, Azepines chemical synthesis, Azepines pharmacology, ErbB Receptors antagonists inhibitors, Protein Kinase Inhibitors chemical synthesis, and Protein Kinase Inhibitors pharmacology

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 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) 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.

Anxiety epidemiology, Asbestos adverse effects, Construction Materials adverse effects, Depression epidemiology, Dust, Humans, Inhalation Exposure adverse effects, Mineral Fibers adverse effects, Neoplasms epidemiology, Particle Size, Polycyclic Aromatic Hydrocarbons adverse effects, Respiratory Tract Diseases epidemiology, Respiratory Tract Diseases etiology, Risk Factors, Stress Disorders, Post-Traumatic epidemiology, Stress Disorders, Post-Traumatic etiology, Air Pollutants adverse effects, Environmental Exposure adverse effects, Occupational Exposure adverse effects, and September 11 Terrorist Attacks psychology

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.

Adaptation, Psychological, Aged, Aged, 80 and over, Depression psychology, Emotions, Female, Health Care Costs, Health Promotion economics, Health Status, Home Nursing economics, Humans, Male, Mental Health, Patient Acceptance of Health Care, Patient Dropouts, Quality of Life, Single-Blind Method, Social Support, Frail Elderly psychology, Health Promotion methods, and Home Nursing methods

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 > or =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.

PHYSICAL fitness, OLDER people, EXERCISE, and ATTITUDE (Psychology)

In Spain today, few studies have been carried out to provide sufficient information regarding the attitudes of older persons toward physical activity and exercise. The present study was designed to remedy this deficiency by adapting and validating the Older Person's Attitudes Toward Physical Activity and Exercise Questionnaire. Firstly, a panel of experts offered first hand evidence in support of the content validity of the Spanish adaptation of the questionnaire. Evidence regarding the viability of the instrument was obtained through a test-retest pilot study and with the use of internal consistency method. In line with theoretical expectations, respondents who reported more positive attitudes toward physical activity showed better adherence rates. Finally, recommendations for future replications are discussed, considering the fact that the data on predictive validity of the instrument was obtained only at correlational level. [ABSTRACT FROM AUTHOR]

Antineoplastic Agents pharmacology, Azepines chemistry, Cell Line, Tumor, Heterocyclic Compounds, 3-Ring chemistry, Humans, Inhibitory Concentration 50, Neoplasm Proteins antagonists inhibitors, Phosphorylation drug effects, Structure-Activity Relationship, Vascular Endothelial Growth Factor Receptor-2 antagonists inhibitors, Antineoplastic Agents chemical synthesis, Azepines chemical synthesis, Azepines pharmacology, ErbB Receptors antagonists inhibitors, Heterocyclic Compounds, 3-Ring chemical synthesis, and Heterocyclic Compounds, 3-Ring pharmacology

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, IC(50) values in the single-digit micromolar to submicromolar range).

Aged, House Calls, Humans, Randomized Controlled Trials as Topic, Geriatric Nursing, Health Promotion, Home Care Services, and Program Evaluation

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.

Adolescent, Adult, Aged, Aged, 80 and over, Air Pollution adverse effects, Air Pollution analysis, Dust analysis, Female, Humans, Male, Mass Screening methods, Middle Aged, Occupational Diseases etiology, Occupational Diseases physiopathology, Respiratory Tract Diseases etiology, Respiratory Tract Diseases physiopathology, Spirometry, Time Factors, Occupational Diseases diagnosis, Occupational Exposure adverse effects, Respiratory Tract Diseases diagnosis, and September 11 Terrorist Attacks

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 WTCrelated 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. Longterm 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.

LETTERS to the editor and SEPTEMBER 11 Terrorist Attacks, 2001

A response by Herbert et al to a letter to the editor about their article “The World Trade Center disaster and the health of workers: five-year assessment of a unique medical screening program,” which appeared in the Vol. 114, 2006 issue.

Adult, Alleles, Amino Acid Sequence, Biopsy, Cholinesterase Inhibitors therapeutic use, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Muscle, Skeletal pathology, Muscular Dystrophies, Limb-Girdle drug therapy, Muscular Dystrophies, Limb-Girdle genetics, Muscular Dystrophies, Limb-Girdle pathology, Myasthenic Syndromes, Congenital drug therapy, Myasthenic Syndromes, Congenital pathology, Pedigree, Polymerase Chain Reaction methods, Sequence Alignment, Treatment Outcome, Muscle Proteins genetics, Mutation, Myasthenic Syndromes, Congenital genetics, and Neuromuscular Junction pathology

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.

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]

Binding, Competitive, Cell Line, Tumor, Dose-Response Relationship, Drug, Electroporation, Humans, Ligands, Models, Biological, Protein Binding, Signal Transduction, Subcellular Fractions metabolism, Gene Expression Regulation, Neoplastic, Mutation, Neoplasms metabolism, and Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism

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 understood 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.