High affinity presentation of an autoantigenic peptide in type I diabetes by an HLA class II protein encoded in a haplotype protecting from disease

Tissue composition and the distribution of body mass are described for four genera of East African Bovidae (Madoqua, Gazella, Damaliscus, Hippotragus) with supporting data from four others (Neotragus, Oryx, Tragelaphus, Connochaetes). These species are high in muscle mass, an adaptation convergent with other high-speed terrestrial cursors, bounders, and saltators. The segments below the elbow/cubitus and knee/stifle/genu joints in small bovids are both lighter in percent of total body mass (8.6% TBM) and less heavily muscled (10-15% of total limb musculature) than those segments in macaques (13.6% TBM, 20-25% of the limb musculature). Bovid species differ from one another in the regional distribution of muscle mass. Madoqua kirkii (4-5 kg) concentrates muscle in the lumbar extensors and hindlimbs; large species such as Damaliscus doreas (50-60 kg) and Hippotragus niger (160-220 kg) distribute it more evenly between the lumbar and cervical regions and between the hindlimbs and forelimbs. Gazella dorcas (10-20 kg) is quantitatively intermediate in those characteristics. The redistribution of muscle mass with increasing size correlates with the loss of axial bending of the vertebral column: in small, hindlimb dominant, 'dorsomobile' species such as Madoqua sagittal mobility increases stride length through 'extended' suspension; in large 'dorsostable' species such as Damaliscus and Hippotragus the vertebral column resists bending, consequently abbreviating or omitting this non-contact phase of the gait cycle. Locomotor adaptation as it is reflected in size, shape, and musculoskeletal structure is the key to habitat choice, dietary specialization, social structure, and male agonistic behavior and, therefore, central to the fabric of behavioral ecology.     

The Sleep Heart Health Study: design, rationale, and methods

The Sleep Heart Health Study (SHHS) is a prospective cohort study designed to investigate obstructive sleep apnea (OSA) and other sleep-disordered breathing (SDB) as risk factors for the development of cardiovascular disease. The study is designed to enroll 6,600 adult participants aged 40 years and older who will undergo a home polysomnogram to assess the presence of OSA and other SDB. Participants in SHHS have been recruited from cohort studies in progress. Therefore, SHHS adds the assessment of OSA to the protocols of these studies and will use already collected data on the principal risk factors for cardiovascular disease as well as follow-up and outcome information pertaining to cardiovascular disease. Parent cohort studies and recruitment targets for these cohorts are the following: Atherosclerosis Risk in Communities Study (1,750 participants), Cardiovascular Health Study (1,350 participants), Framingham Heart Study (1,000 participants), Strong Heart Study (600 participants), New York Hypertension Cohorts (1,000 participants), and Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study (900 participants). As part of the parent study follow-up procedures, participants will be surveyed at periodic intervals for the incidence and recurrence of cardiovascular disease events. The study provides sufficient statistical power for assessing OSA and other SDB as risk factors for major cardiovascular events, including myocardial infarction and stroke.     

Entry of US medical school graduates into family practice residencies: 1997-1998 and 3-year summary

This is the 17th report prepared by the American Academy of Family Physicians (AAFP) on the percentage of each US medical school's graduates entering family practice residency programs. Approximately 16.6% of the 15,894 graduates of US medical schools between July 1996 and June 1997 were first-year family practice residents in October 1997, compared with 15.9% in 1996 and 14.6% in 1995. This is the highest percentage since this series of studies began in 1980-1981 (12.8%). Medical school graduates from publicly funded medical schools were almost twice as likely to be first-year family practice residents in October 1997 than were residents from privately funded schools, 19.8% compared with 11.8%. The Mountain region reported the highest percentage of medical school graduates who were first-year residents in family practice programs in October 1997 at 25.8%; the Middle Atlantic and New England regions reported the lowest percentages at 11.7% and 10.7%, respectively. Nearly half of the medical school graduates (48.1%) entering a family practice residency program as first-year residents in October 1997 entered a program in the same state where they graduated from medical school. The percentages for each medical school have varied substantially from year to year since the AAFP began reporting this information. This article reports the average percentage for each medical school for the last 3 years. Also reported are the number and percentage of graduates of colleges of osteopathic medicine who entered Accreditation Council for Graduate Medical Education-accredited family practice residency programs, based on estimates provided by the American Association of Colleges of Osteopathic Medicine.     

Kinetic and spectroscopic properties of the YZ* radical in Ca2+- and Cl--depleted photosystem II preparations

Depletion of Ca2+ and/or Cl- ions from PSII membranes blocks the electron-transfer reactions that precede O2 evolution on the oxidizing side of the enzyme. Illumination of these inhibited preparations at 273 K generates a paramagnetic species that is detectable by low-temperature (T < 20 K) EPR as a signal in the g = 2 region, 90-230 G wide, depending on the treatment that PSII has undergone. This signal has recently been assigned to YZ* in magnetic interaction with the manganese cluster in its S2 state [Gilchrist et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 9545-9549]. This view, however, is not universal, owing, in part, to the fact that its spectroscopic properties depend on the preparation and the experimental conditions used for its study and, in part, to uncertainties as to the room temperature behavior of YZ* in inhibited preparations. Here, we report time-resolved and conventional EPR data showing that, at room temperature and at 273 K, YZ* can be accumulated in its 20 G form in high yields in both Ca2+-depleted and acetate-inhibited preparations, and that the kinetics of its decay match the decay kinetics of the low-temperature signal generated in corresponding samples. The properties of the YZ* signal, however, are shown to depend on the polypeptide content, the temperature, and the electron donors and acceptors present in the sample under examination. Our results support assignment of the EPR signal in inhibited preparations to S2 YZ* and demonstrate a protective role of the 17 and 23 kDa extrinsic polypeptides for the manganese cluster against externally added reductants.     

Influence of absorbable dusting powders on wound infection

OBJECTIVE: To investigate the lymphocyte subpopulations (T4, T8 and macrophages) and major histocompatibility (MHC) II antigens in patients with superficial bladder cancer before and after intravesical instillations of recombinant interferon-gamma (IFN-gamma). PATIENTS AND METHODS: Four intravesical weekly instillations of either 1.3 mg (20 patients, group A) or 0.7 mg (11 patients, group B) IFN-gamma were administered in 31 evaluable patients (28 men and three women, mean age 68.5 years). The CD4+, CD8+, CD68+ and HLA-DR antigens were detected immunohistochemically in tumours and a marker tumour before and after intravesical instillations. RESULTS: The median number of T4 lymphocytes increased from 15 per high-power field (HPF) to 27.5 in group A (P = 0.0029) and to 45 in group B (P = 0.0117). Macrophages increased from 6 cells/HPF to 15 cells/HPF in group A (P = 0.0029) and from 2 to 8.75 cells/HPF in group B (P = 0.0117). The T8 lymphocyte subpopulation decreased from 4 to 3 cells/HPF (P = 0.0231) in group A and from 5 to 2 cells/HPF (P = 0.0759) in group B. The median percentage of HLA-DR antigens increased from 1.5% to 18% in general, (P < 0.001), from 2.5% to 15% in group A (P = 0.0064) and from 0% to 20% in group B (P = 0.0077). The induction of HLA-DR antigens was statistically significant in those receiving the lower dose (from 0% before instillation to 20% afterward, P = 0.0277), while it was not with the higher dose (from 0% to 5%, P = 0.068). Irrespective of the dose of IFN used. T4 lymphocytes and macrophages increased significantly after treatment in patients in whom the tumour HLA-DR antigens were either up-regulated or remained stable. The median net increase in T4 cells was 17.5 and 30 cells/HPF for groups A and B, respectively (P = 0.0429). CONCLUSION: T4 lymphocytes, macrophages and HLA-DR antigens increased after intravesical IFN-gamma in patients with superficial bladder cancer, but T8 lymphocytes decreased. Irrespective of the drug dose used, patients with either upregulated or stable HLA-DR antigens after treatment showed the same pattern of changes in the lymphocyte subpopulations. The two doses generally had the same effect on the immunological variables assessed but the lower dose was more effective in inducing HLA-DR antigens and in increasing the number of T4 lymphocytes in the tumours.     

Increased stem cell somatic mutation in the non-neoplastic colorectal mucosa of patients with familial adenomatous polyposis

Colorectal tumorigenesis in familial adenomatous polyposis (FAP) results from somatic mutation of either the normal APC allele or another growth control gene in epithelial cells bearing a germline APC defect. The rate at which tumors develop is therefore dependent on the somatic mutation frequency; it is not known whether this is normal or elevated in FAP. We aimed to quantify stem cell somatic mutation in FAP, comparing it with hereditary nonpolyposis colorectal cancer (HNPCC) and Crohn's disease (CD). Stem cell somatic mutation frequency was studied in 47 FAP patients, 5 HNPCC patients, and 13 CD patients, all younger than 49 years, by quantifying crypt-restricted loss of O-acetyltransferase activity in sections of morphologically normal colonic mucosa from individuals heterozygous for this monogenically inherited polymorphism. Median stem cell somatic mutation frequency was significantly higher in FAP than HNPCC (4.2 x 10(-4) v 1.4 x 10(-4), Mann-Whitney U, P < .02). The level in CD (4.0 x 10(-4)) was similar to FAP. Mutated crypts occurred in groups more frequently in FAP (22%) than HNPCC (12%) or CD (10%), suggesting an increase in stem cell division associated with crypt fission in FAP. We conclude that stem cell somatic mutation frequency is raised in non-neoplastic colorectal mucosa in FAP. This is probably related to increased stem cell proliferation and contributes to the high rate of tumor formation in this condition.     

The role of JNK and p38 MAPK activities in UVA-induced signaling pathways leading to AP-1 activation and c-Fos expression

To further delineate ultraviolet A (UVA) signaling pathways in the human keratinocyte cell line HaCaT, we examined the potential role of mitogen-activated protein kinases (MAPKs) in UVA-induced activator protein-1 (AP-1) transactivation and c-Fos expression. UVA-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK) proteins was detected immediately after irradiation and disappeared after approximately 2 hours. Conversely, phosphorylation of extracellular signal-regulated kinase was significantly inhibited for up to 1 hour post-UVA irradiation. To examine the role of p38 and JNK MAPKs in UVA-induced AP-1 and c-fos transactivations, the selective pharmacologic MAPK inhibitors, SB202190 (p38 inhibitor) and SP600125 (JNK inhibitor), were used to independently treat stably transfected HaCaT cells in luciferase reporter assays. Both SB202190 and SP600125 dose-dependently inhibited UVA-induced AP-1 and c-fos transactivations. SB202190 (0.25-0.5 microM) and SP600125 (62-125 nM) treatments also primarily inhibited UVA-induced c-Fos expression. These results demonstrated that activation of both JNK and p38 play critical role in UVA-mediated AP-1 transactivation and c-Fos expression in these human keratinocyte cells. Targeted inhibition of these MAPKs with their selective pharmacologic inhibitors may be effective chemopreventive strategies for UVA-induced nonmelanoma skin cancer.