Regulation of the growth of multinucleated muscle cells by an NFATC2-dependent pathway.

The nuclear factor of activated T cells (NFAT) family of transcription factors regulates the development and differentiation of several tissue types. Here, we examine the role of NFATC2 in skeletal muscle by analyzing adult NFATC2(-/)- mice. These mice exhibit reduced muscle size due to a decrease in myofiber cross-sectional area, suggesting that growth is blunted. Muscle growth was examined during regeneration after injury, wherein NFATC2-null myofibers form normally but display impaired growth. The growth defect is intrinsic to muscle cells, since the lack of NFATC2 in primary muscle cultures results in reduced cell size and myonuclear number in myotubes. Retroviral-mediated expression of NFATC2 in the mutant cells rescues this cellular phenotype. Myonuclear number is similarly decreased in NFATC2(-/)- mice. Taken together, these results implicate a novel role for NFATC2 in skeletal muscle growth. We demonstrate that during growth of multinucleated muscle cells, myoblasts initially fuse to form myotubes with a limited number of nuclei and that subsequent nuclear addition and increases in myotube size are controlled by a molecular pathway regulated by NFATC2.

Altered primary myogenesis in NFATC3(-/-) mice leads to decreased muscle size in the adult.

Signal transduction pathways involving calcineurin and its downstream effector NFAT have been implicated in regulating myogenesis. Several isoforms of NFAT exist that may differentially contribute to regulating skeletal muscle physiology. The purpose of this study was to determine the role of the NFATC3 isoform in skeletal muscle development. Adult mice lacking NFATC3 have reduced muscle mass compared to control mice. The smaller size of the muscles is not due to atrophy or blunted myofiber growth, but rather to a reduced number of myofibers. This reduction in myofiber number is not limited to a specific fiber type nor are the proportions of fiber types altered. The lower fiber number found in the adult NFATC3(-/-) mice is a consequence of impaired muscle development during embryogenesis. Immunohistochemical studies of E15 EDL muscles indicate that the total number of primary myofibers is decreased in NFATC3(-/-) embryos. At E17.5 no further decrease in primary myofiber number occurs; the size and organization of the myofibers are unaltered, and secondary myogenesis proceeds normally, suggesting a role for NFATC3 during early events in primary myogenesis. These results suggest a heretofore unknown role for the transcription factor NFAT in early skeletal muscle development.

Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant--463A of the myeloperoxidase gene.

Myeloperoxidase (MPO), an enzyme that is highly expressed in neutrophil leukocytes, transforms precarcinogens such as benzo(a)pyrene and aromatic amines to highly reactive intermediates. A G/A polymorphism located 463 bp upstream of exon 1 in the promoter region strongly reduces MPO mRNA expression. In a matched case-control study, 196 lung cancer, 245 laryngeal cancer, and 255 pharyngeal cancer patients from the Berlin area were investigated for frequency of the G-463A polymorphism by PCR/RFLP, using AciI. They were matched by age and gender to hospital patients without known malignancies. Moreover, 270 healthy volunteers were genotyped, obtaining 61.1% of individuals with MPO genotype -463G/G, 34.8% of individuals with genotype G/A, and 4.1% of individuals with genotype A/A. In lung and laryngeal cancer patients, but not in pharyngeal cancer patients, mutant genotypes were significantly less frequent. Crude odds ratios for carriers of one or two A alleles, compared to wild-type G/G, were 0.58 [95% confidence interval (CI), 0.38-0.88; P = 0.011] for lung cancer patients, 0.63 (95% CI, 0.43-0.92; P = 0.017) for laryngeal cancer patients, and 0.82 (95% CI, 0.57-1.17; P = 0.27) for pharyngeal cancer patients. The relative risks, adjusted for age, gender, and extent of cigarette smoking were 0.47 (95% CI, 0.28-0.79; P = 0.004), 0.66 (95% CI, 0.44-1.01; P = 0.054), and 0.75 (95% CI, 0.51-1.12; P = 0.16) for lung, larynx, and pharyngeal cancer, respectively. Strikingly, relative risk for carriers of -463A among adenocarcinoma of the lung was 0.24 (95% CI, 0.10-0.58; P = 0.002). Two cases with larynx cancer, one case with lung cancer, and one reference subject displayed novel G/A mutations at -297 nucleotide and -296 nucleotide, destroying a constitutive AciI cleavage site. Our data finally suggest that the MPO -463A variant is a protective factor in the etiology of lung and larynx cancer, but possibly not of pharyngeal cancer.

Systemic administration of the NF-kappaB inhibitor curcumin stimulates muscle regeneration after traumatic injury.

Skeletal muscle is often the site of tissue injury due to trauma, disease, developmental defects or surgery. Yet, to date, no effective treatment is available to stimulate the repair of skeletal muscle. We show that the kinetics and extent of muscle regeneration in vivo after trauma are greatly enhanced following systemic administration of curcumin, a pharmacological inhibitor of the transcription factor NF-kappaB. Biochemical and histological analyses indicate an effect of curcumin after only 4 days of daily intraperitoneal injection compared with controls that require >2 wk to restore normal tissue architecture. Curcumin can act directly on cultured muscle precursor cells to stimulate both cell proliferation and differentiation under appropriate conditions. Other pharmacological and genetic inhibitors of NF-kappaB also stimulate muscle differentiation in vitro. Inhibition of NF-kappaB-mediated transcription was confirmed using reporter gene assays. We conclude that NF-kappaB exerts a role in regulating myogenesis and that modulation of NF-kappaB activity within muscle tissue is beneficial for muscle repair. The striking effects of curcumin on myogenesis suggest therapeutic applications for treating muscle injuries.

Interdisciplinary education in adolescent health.

To date, evidence suggests that, across disciplines, the educational preparation of health professionals has not kept pace. Those involved in the education of clinicians, researchers, and educators in adolescent health are currently faced with the need to rethink traditional educational strategies. Concurrent with a shift in the primary causes of morbidity and mortality in adolescence, from infectious to social aetiologies, is an emerging clarity about the success of integrated comprehensive service settings in addressing adolescents' health needs. One approach for better preparing health providers to work in multiservice settings is to provide training in interdisciplinary programmes. Various models for interdisciplinary education in adolescent health exist; characteristics common to all are delineated. Whereas obstacles to the creation and implementation of interdisciplinary programmes, including institutional, financial, and educational barriers, are great, the need to overcome them is critical if we are to keep pace with the changing needs of the adolescent population.

Health insurance coverage of adolescents: a current profile and assessment of trends.

Data from the National Health Interview Survey reveal that 4.7 million or 15% of US adolescents aged 10 through 18 were uninsured in 1989. Among adolescents, 73% were privately insured, 10% were publicly insured, and 2% were both privately and publicly insured. Poor, near-poor, and minority adolescents were at the greatest risk for lack of health insurance coverage. Among adolescents without insurance, cost continued to be cited as the leading barrier to obtaining coverage. A comparison of 1989 National Health Interview Survey data with a previous analysis, in which 1984 data were used, revealed a 10% increase in the proportion of adolescents without insurance coverage. The increase in the proportion of uninsured adolescents was entirely attributable to an erosion of private health insurance coverage. No significant change occurred in the proportion of adolescents with coverage under public programs. Planned expansions of the federally and state-financed Medicaid programs will help to stem further increases in the size of the uninsured adolescent population. However, unless marked improvements occur in the private health insurance sector, progress will be limited.

Nursing competence in adolescent health: anticipating the future needs of youth.

The health problems of youth have dramatically shifted in the last 30 years from biological to social causes of morbidity and mortality. To assess the adequacy of nurses' knowledge and skills in adolescent health, a national survey of 445 nurses, including members of the American Public Health Association, the American School Health Association, and the National Association of Pediatric Nurse Associates and Practitioners, was undertaken in 1985. Results indicated that even among nurses who work with young people the most, areas of greatest knowledge and skill deficiencies included common social morbidities of adolescents. In addition to self-assessed inadequacies in knowledge and skills, nurses identified excessive time demands as a primary obstacle to the provision of health services to adolescents. To assure adequate preparation of nurses, it is recommended that accreditation criteria for baccalaureate and graduate programs specify essential adolescent health content for curricula compared to current accreditation criteria that generalizes "across the life span." Focusing on the enhancement of educational opportunities in adolescent health, nurses identified strategies for further education that would bridge the gap between the health needs of youth and nurse's self-perceived competencies in providing these services.

Endotoxin contamination of Foley catheters associated with fevers following transurethral resection of the prostate.

In 1980 an investigation was conducted due to an apparent cluster of fevers following transurethral resections of the prostate ( TURP ), where the presence of prostatitis or urinary tract infections ( UTIs ) could not account for most cases, and the usage of antimicrobials did not prevent them. When unused, prepackaged , sterilized samples from 13 lots of triple lumen catheters were analyzed, four were found to contain high levels of endotoxin (ET), with a range of 49,150-greater than or equal to 6.25 ng/catheter. Additionally, these lots were highly pyrogenic to rabbits. The maximum incidence of febrile patients (42%) correlated with usage of catheters from the lot where ET levels were the highest. The febrile rate for a second urologist, who used single lumen catheters, was less (12/33 v 0/12). Further consideration should be given to sterile operative equipment which may still be pyrogenic.

Antimicrobial susceptibilities of nutritionally variant streptococci.

Seventeen strains of nutritionally variant streptococci were examined for susceptibility to 15 antimicrobial agents. All strains grew in blood culture medium containing blood and blood products or, in the absence of blood or blood products, in broth containing glucose and pyridoxal hydrochloride. Growth was enhanced by incubation in an atmosphere containing 5%-10% CO2 or, in some cases, was CO2-dependent. Rifampin, penicillin, clindamycin, and erythromycin were the most active antibiotics tested with minimal bactericidal concentrations of 2, 1, 2, and 2 microgram/ml, respectively, for 90% of the strains; the corresponding values for vancomycin and streptomycin were 32 and 16 microgram/ml, respectively.

Comparison of the effects of arabinosyladenine, arabinosylhypoxanthine, and arabinosyladenine 5'-monophosphate against herpes simplex virus, varicella-zoster virus, and cytomegalovirus with their effects on cellular deoxyribonucleic acid synthesis.

In a single line of human foreskin fibroblasts, minimum inhibitory concentrations (MICs) and the minimum intracellular virus inactivation concentrations (MIICs) of arabinosyladenine, arabinosylhypoxanthine, and arabinosyladenine 5'-monophosphate were assayed for a number of recent isolates of herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV), and cytomegalovirus (CMV). (The term MIIC is used here to describe the selective qualitative intracellular inhibition of the virus inoculum in the primary tissue cultures. The inoculum is not recoverable in subcultures free of antiviral agent.) MICs and MIICs of each of the antiviral agents were readily obtained for each strain of HSV-1, HSV-2, and VZV tested, but all seven strains of CMV tested were much more resistant. At the endpoint, there was little variation in the MICs or MIICs among strans of the same virus. Final MIC results for HSV-1 and HSV-2 were complete after 3 days of incubation; CMV and VZV results required as long as 6 days. The MIC for each herpesvirus increased with incubation, but at the endpoint the MIC and MIIC were approximately equal. VZV was most susceptible to each drug, followed by HSV-1 and HSV-2. The latter two viruses were quite similar. There was no difference in antiviral susceptibilities among any of the strains of HSV-1, HSV-2, VZV, or CMV tested. The toxicities of arabinosyladenine, arabinosylhypoxanthine, and arabinosyladenine 5'-monophosphate were simultaneously compared by using both microscopic cytotoxicity and inhibition of uptakes of [14C]thymidine into cellular deoxyribonucleic acid and of 14C-labeled amino acids into protein. The selective inhibition of each antiviral agent against viral and cellular deoxyribonucleic acid polymerases was confirmed. Simultaneous assays of antiviral and anticellular activities of antiviral agents may be useful in projecting further in vivo experiments.