Medical school inquiry. Staff report to the Committee on Interstate and Foreign Commerce, House of Representatives, 85th Cong. 1st sess. containing background information relating to schools of medicine, dentistry, osteopathy and public health.

Mode of access: Internet.

The relationship between obesity, autoimmune disease, and C-reactive protein: A secondary data analysis of the National Health and Nutrition Examination Survey (NHANES) 2009--2010

Autoimmune diseases are a group of inflammatory conditions in which the body's immune system attacks its own cells. There are over 80 diseases classified as autoimmune disorders, affecting up to 23.5 million Americans. Obesity affects 32.3% of the US adult population, and could also be considered an inflammatory condition, as indicated by the presence of chronic low-grade inflammation. C-reactive protein (CRP) is a marker of inflammation, and is associated with both adiposity and autoimmune inflammation. This study sought to determine the cross-sectional association between obesity and autoimmune diseases in a large, nationally representative population derived from NHANES 2009–10 data, and the role CRP might play in this relationship. Overall, the results determined that individuals with autoimmune disease were 2.11 times more likely to report being overweight than individuals without autoimmune disease and that CRP had a mediating affect on the obesity-autoimmune relationship. ^

Disease risk factors and humoral antibody response to periodontal-associated pathogens: A model to evaluate periodontal disease in older adults

Periodontal diseases (PD) are infectious, inflammatory, and tissue destructive events which affect the periodontal ligament that surround and support the teeth. Periodontal diseases are the major cause of tooth loss after age 35, with gingivitis and periodontitis affecting 75% of the adult population. A select group of bacterial organisms are associated with periodontal pathogenesis. There is a direct association between oral hygiene and prevention of PD. The importance of genetic differences and host immune response capabilities in determining host, susceptibility or resistance to PD has not been established. This study examined the risk factors and serum (humoral) immune response to periodontal diseased-associated pathogens in a 55 to 80+ year old South Texas study sample with PD. This study sample was described by: age, sex, ethnicity, the socioeconomic factors marital status, income and occupation, IgG, IgA, IgM immunoglobulin status, and the autoimmune response markers rheumatoid factor (RF) and antinuclear antibody (ANA). These variables were used to determine the risk factors associated with development of PD. Serum IgG, IgA, IgM antibodies to bacterial antigens provided evidence for disease exposure.^ A causal model for PD was constructed from associations for risk factors (ethnicity, marital status, income, and occupation) with dental exam and periodontitis. The multiple correlation between PD and ethnicity, income and dental exam was significant. Hispanics of low income were least likely to have had a dental exam in the last year and most likely to have PD. The etiologic agents for PD, as evidenced by elevated humoral antibody responses, were the Gram negative microorganisms Bacteroides gingivalis, serotypes FDC381 and SUNYaBA7A1-28, and Wolinella recta. Recommendation for a PD prevention and control program are provided. ^

Virus-Host Interaction during Therapy against Hepatitis C Virus

Le virus de l’hépatite C (VHC) est un problème mondial. La majorité des personnes infectées (70-85%) développent une infection chronique qui cause des complications hépatiques. Le seul régime thérapeutique approuvé pour le VHC est l'interféron alpha (IFN-α). Ce traitement a un taux de réussite de 50-80% selon le génotype de virus et le moment de l'initiation de la thérapie. Les facteurs régissant la réponse au traitement ne sont pas bien définis. Des études antérieures ont suggéré un rôle potentiel de la réponse immunitaire de l'hôte au succès de la thérapie, toutefois, ces résultats sont controversés. Nous avons émis l'hypothèse que la réponse immunitaire de l’hôte sera plus efficace chez les patients qui commencent la thérapie tôt pendant la phase aiguë de l'infection. En revanche, la réponse immunitaire sera épuisée lorsque le traitement est initié pendant la phase chronique. L'objectif principal de ce mémoire est d’étudier les facteurs immunologiques qui régissent la réponse à la thérapie, et de déterminer si la contribution de la réponse immunitaire de l'hôte peut être influencée par la période de l'infection. Nos résultats démontrent l'efficacité de la restauration de la réponse immunitaire spécifique au VHC lorsque la thérapie par l'interféron est initiée tôt. Ceci est démontré par le sauvetage des cellules T efficaces spécifiques au VHC efficace similaires à celles observées chez les individus qui ont résolu spontanément, suggérant ainsi qu'elles jouent un rôle actif dans la réponse au traitement. Toutefois, cette réponse n'a pas été restaurée chez les patients traités au cours de la phase chronique. Ces résultats ont des implications importantes dans la compréhension des mécanismes sous-jacents à la réponse aux traitements actuels et au développement des nouvelles thérapies.

Rôle des cellules dendritiques SIRPα+ dans l’asthme expérimental

L’asthme est une maladie multifactorielle hétérogène qui engendre une inflammation pulmonaire associée à une variété de manifestations cliniques, dont des difficultés respiratoires graves. Globalement, l’asthme touche environ une personne sur 6 et présente actuellement un sérieux problème de santé publique. Bien que de nombreux traitements soient disponibles pour soulager les symptômes de la maladie, aucun traitement curatif n’est actuellement disponible. La compréhension des mécanismes qui régissent l’état inflammatoire au cours de la maladie est primordiale à la découverte de nouvelles cibles thérapeutiques efficaces. Les cellules dendritiques captent les allergènes dans les poumons et migrent vers les ganglions drainants pour les présenter aux cellules T et engendrer la réponse inflammatoire pathogénique chez les asthmatiques. Nous avons contribué à l’avancement des connaissances mécanistiques de l’asthme en identifiant chez la souris la sous-population de cellules dendritiques responsable de l’initiation et du maintien de la réponse inflammatoire locale et systémique associée à l’asthme. En effet, nous avons démontré que le SIRPα, récepteur extracellulaire impliqué dans la régulation de la réponse immune, est sélectivement exprimé à la surface des cellules dendritiques immunogéniques. L’interruption de la liaison entre le SIRPα et son ligand, le CD47, interfère avec la migration des cellules dendritiques SIRPα+ et renverse la réponse inflammatoire allergique. Ce mécanisme constitue une avenue thérapeutique prometteuse. D’ailleurs, les molécules de fusion CD47-Fc et SIRPα-Fc se sont avérées efficaces pour inhiber l’asthme allergique dans le modèle murin. Nous avons également démontré l’implication des cellules dendritiques SIRPα dans un modèle d’inflammation pulmonaire sévère. L’administration répétée de ces cellules, localement par la voie intra-trachéale et systémiquement par la voie intra-veineuse, mène au développement d’une réponse inflammatoire mixte, de type Th2-Th17, similaire à celle observée chez les patients atteints d’asthme sévère. La présence de cellules T exprimant à la fois l’IL-17, l’IL-4, l’IL-13 et le GATA3 a été mise en évidence pour la première fois in vitro et in vivo dans les poumons et les ganglions médiastinaux grâce à ce modèle. Nos expériences suggèrent que ces cellules Th2-Th17 exploitent la plasticité des cellules T et sont générées à partir de la conversion de cellules Th17 qui acquièrent un phénotype Th2, et non l’inverse. Ces résultats approfondissent la compréhension des mécanismes impliqués dans l’initiation et le maintien de l’asthme allergique et non allergique, en plus d’ouvrir la voie à l’élaboration d’un traitement spécifique pour les patients asthmatiques, particulièrement ceux pour qui aucun traitement efficace n’est actuellement disponible.

Suppression of peripheral blood mononuclear cell proliferation by a periodontopathic bacteria {\it Actinobacillus actinomycetemcomitans\/}

Actinobacillus actinomycetemcomitans (Aa) is a gram-negative coccobacillus implicated as a major pathogen in juvenile periodontitis. The immunosuppressive activity of a sonic extract (designated 100SN) derived from Aa was investigated. 100SN suppressed spontaneous proliferation as well as proliferative response to the mitogens, PHA and PWM, of human peripheral blood mononuclear cells (PBMC). 100SN-induced suppression of PHA-stimulated proliferation was heat-sensitive, inactivated by pronase and trypsin, dose-dependent and non-cytotoxic. There were no significant changes in the CD4$\sp+$ or CD8$\sp+$ subsets of PBMC after 7-day incubation with 100SN. There was a trend toward increased levels of the CD4$\sp+$CD45R$\sp{\rm hi}$CDw29$\sp{\rm lo}$ (naive cells, associated with suppressor-inducer activity) and CD4$\sp+$CDw29$\sp{\rm hi}$CD45R$\sp{\rm lo}$ (memory cells, associated with helper-inducer activity) subsets. The target of 100SN appeared to be the non-adherent cells and suppression by 100SN could not be reversed by indomethacin (IDM), the cyclo-oxygenase inhibitor of prostaglandin (PG) synthesis. The mechanism of 100SN-induced suppression was studied in terms of inhibition involving IL-2-regulated T cell proliferation and the results point to the possibility that suppression occurred subsequent to IL-2 receptor binding.^ The suppressive activity observed could occur through multiple mechanisms including cell-cell; contact or release of soluble factors. Supernatants derived from 7-day cultures of PBMC and 100SN (designated CSN-A) were able to suppress proliferative response of PBMC to PHA without affecting cell viability. Analysis of CSN-A showed that it contained PGE2 and soluble IL-2 receptors. Suppression by CSN-A could be partially overcome by either IDM or exogenous IL-2. Significant suppression was also maintained when both IDM and exogenous IL-2 were added at the same time. These findings suggest that PGE2 and soluble IL-2 receptors contribute to the suppression observed but other suppressive cytokine(s) may be involved. Collectively, the data indicate that a factor derived from oral bacteria associated with juvenile periodontitis have profound effects on cellular immune responses, and that these effects may be partially mediated by secondary factors produced by the host in response to the bacteria. ^

HIV-related malignancies: A community-based study using a linkage of cancer registry and HIV registry data

Background. Increased incidence of cancer is documented in immunosuppressed transplant patients. Likewise, as survival increases for persons infected with the Human Immunodeficiency Virus (HIV), we expect their incidence of cancer to increase. The objective of this study was to examine the current gender specific spectrum of cancer in an HIV infected cohort (especially malignancies not currently associated with Acquired Immunodeficiency Syndrome (AIDS)) in relation to the general population.^ Methods. Cancer incidence data was collected for residents of Harris County, Texas who were diagnosed with a malignancy between 1975 and 1994. This data was linked to HIV/AIDS registry data to identify malignancies in an HIV infected cohort of 14,986 persons. A standardized incidence ratio (SIR) analysis was used to compare incidence of cancer in this cohort to that in the general population. Risk factors such as mode of HIV infection, age, race and gender, were evaluated for contribution to the development of cancer within the HIV cohort, using Cox regression techniques.^ Findings. Of those in the HIV infected cohort, 2289 persons (15%) were identified as having one or more malignancies. The linkage identified 29.5% of these malignancies (males 28.7% females 60.9%). HIV infected men and women had incidences of cancer that were 16.7 (16.1, 17.3) and 2.9 (2.3, 3.7) times that expected for the general population of Harris County, Texas, adjusting for age. Significant SIR's were observed for the AIDS-defining malignancies of Kaposi's sarcoma, non-Hodgkin's lymphoma, primary lymphoma of the brain and cancer of the cervix. Additionally, significant SIR's for non-melanotic skin cancer in males, 6.9 (4.8, 9.5) and colon cancer in females, 4.0 (1.1, 10.2) were detected. Among the HIV infected cohort, race/ethnicity of White (relative risk 2.4 with 95% confidence intervals 2.0, 2.8) or Spanish Surname, 2.2 (1.9, 2.7) and an infection route of male to male sex, with, 3.0 (1.9, 4.9) or without, 3.4 (2.1, 5.5) intravenous drug use, increased the risk of having a diagnosis of an incident cancer.^ Interpretation. There appears to be an increased risk of developing cancer if infected with the HIV. In addition to the malignancies routinely associated with HIV infection, there appears to be an increased risk of being diagnosed with non-melanotic skin cancer in males and colon cancer in females. ^

Catalytic antibody response to the Staphylococcus aureus virulence factor Efb

Staphylococcus aureus is a globally prevalent pathogen that can cause a wide variety of acute and chronic diseases in both adults and children, in both immune susceptible populations and healthy individuals. Its ability to cause persistent infections has been linked to multiple immune evasion strategies, including Efb-mediated complement inhibition. As new multi-drug-resistant strains emerge, therapeutic alternatives to traditional antibiotics must be developed. These experiments assessed the ability of healthy patient immunoglobulin to cleave Efb and disable the complement-inhibitory properties of Efb in vitro. Levels of immunoglobulin-mediated Efb catalysis varied both between immunoglobulin isoform/isotype and between individuals. Serum IgG showed the strongest catalytic activity of the immunoglobulin isotypes tested. Additionally, IgG hydrolyzed the virulence factor in a way that enabled only minimal binding to the complement component C3b, effectively blocking Efb-mediated inhibition of complement lysis. Salivary IgA and serum IgM did not block Efb-mediated inhibition of complement. Catalytic IgG selectively cleaved Efb and showed no cleavage of a variety of other proteins tested. Catalytic activity of IgG was inhibited by serine protease inhibitors, but not by other protease inhibitors, suggesting a serine-protease mechanism of catalysis. It is proposed that varying concentrations and activity levels of catalytic IgG between healthy individuals and those with current or recurrent S. aureus infections in both adult and pediatric populations be studied in order to assess the potential effectiveness of passive immunization therapy with catalytic monoclonal IgG. ^

Risk factors and inflammatory markers in pouchitis

Individuals who do not respond to medical therapy for ulcerative colitis (UC) often undergo proctocolectomy followed by ileal-pouch anal anastomosis (IPAA) in hopes of resolving symptoms associated with UC. Inflammation of the ileal pouch, better known as pouchitis, is the most common complication of the IPAA procedure. The causes and development of pouchitis is not well understood. To better understand pathogenesis of pouchitis, pouch aspirates of patients having undergone IPAA were quantitatively analyzed for fecal IL-8, IL-17, and IL-23 levels. According to published literature IL-8 has been linked to pouchitis whereas IL-17 and IL-23 are associated with intestinal inflammation. The study had 80 participants, 33 patients diagnosed with Crohn's Disease (CD) of the pouch, 19 patients diagnosed with pouchitis, and 28 diagnosed with having normal pouches. Patient characteristics and histopathological findings for all patients were noted and statistically compared in addition to fecal cytokine levels. This study supported previous literature that IL-8 production was associated with pouch inflammation. However, IL-17 and IL-23 levels in both CD of the pouch and pouchitis were not significantly different to the levels noted in normal pouch.^

The care to share HIV disclosure study - the attitudes toward and beliefs about HIV disclosure among perinatally-infected HIV-positive youth and their caregivers

HIV incidence has not changed since the introduction of the pandemic. Daily 14,000 persons are infected with HIV and 25 to 50% of the HIV-infected population and subgroups respectively are estimated to be unaware of their HIV diagnosis. Perinatally-infected HIV-positive youth, aged 13-24 years, have survived unexpectedly into adulthood, have had unique HIV disclosure experiences and now face HIV disclosure issues of adulthood and perhaps parenthood. Despite new effective HIV therapies, no HIV prevention plan exists that has diminished the rate of new HIV infections. HIV stigma and lack of universal HIV reporting laws dissuade timely HIV disclosure. Missed HIV disclosure perpetuates HIV transmission and infection. Understanding the attitudes and beliefs of HIV disclosure among perinatally-infected HIV-positive youth and their caregivers may uncover reasons to HIV disclosure delays, avoidance and intentions. The Care to Share HIV Disclosure study was designed to identify the attitudes and beliefs of HIV disclosure among HIV-positve youth (aged 13-24 years), who were infected from birth and who knew their HIV diagnosis, along with their caregivers. Twenty-six participants (15 youth and 11 caregivers) completed the theory-based questionnaires of a 21-item multiple choice survey on HIV disclosure framed in the Theory of Reasoned Action and Theory of Planned Behavior and included an additional open-ended survey that applied the Transactional Model of Stress and Coping to address youth's and caregivers' HIV disclosure experiences. Youth were found to have a selective unfavorable HIV disclosure outcome when among referents of close friends. However youth did believe in HIV partner notification. For caregivers, it mattered who disclosed the HIV illness to the youth. HIV stigma was of concern based on the youths' tendency to believe in keeping HIV a secret and their caregivers' ambivalence to HIV secrecy. However, favorable HIV disclosure outcomes were identified for both youth and caregivers the potential for HIV disclosure: when seeking HIV knowledge, when around caregivers and close family and in situations of perceived controllability as when helping others learn about HIV. These findings unveil HIV disclosure attitudes and beliefs within this population and may reveal the attributes that may inhibit or promote HIV disclosure behaviors. HIV disclosure studies that address attitudes and beliefs among larger populations of youth and HIV-infected persons are necessary to identify effective individual, group and society approaches that would promote timely, responsible and meaningful HIV disclosure methods that promote a healthy identity and interrupt HIV transmission.^

Why is asthma mortality higher in Puerto Ricans?

Asthma is a significant public health issue and the most common chronic disease in children. The disease burden of asthma is rising around the world and especially in certain populations. In the United States Puerto Rican Americans have the highest rates of mortality due to asthma, while Mexico Americans have the lowest asthma mortality in the U.S. The reasons for this have been the cause of much speculation in the past; however, no clear cause for these differences has been recognized. The present work reviews the literature bearing on this question to show that there are good reasons to believe that individuals with unusually responsive innate immune responses may be predisposed to the development of asthma. Also reviewed is the molecular basis for this connection. The evidence shows that the history and anthropology of the Puerto Rican people is quite different from that of any other surviving North American or Caribbean population, as it was a relatively isolated island population for 400 years with an environment that tended to eliminate individuals with weak innate immune systems. The Puerto Rican population successfully survived the Columbian exchange of microbes but may be poorly adapted to the modern pro-inflammatory diet coupled with exposure to cigarette smoke as well as cockroach and house dust mite feces.^

Determinants of CD4 cell count decline after treatment interruption

Patients who had started HAART (Highly Active Anti-Retroviral Treatment) under previous aggressive DHHS guidelines (1997) underwent a life-long continuous HAART that was associated with many short term as well as long term complications. Many interventions attempted to reduce those complications including intermittent treatment also called pulse therapy. Many studies were done to study the determinants of rate of fall in CD4 count after interruption as this data would help guide treatment interruptions. The data set used here was a part of a cohort study taking place at the Johns Hopkins AIDS service since January 1984, in which the data were collected both prospectively and retrospectively. The patients in this data set consisted of 47 patients receiving via pulse therapy with the aim of reducing the long-term complications. ^ The aim of this project was to study the impact of virologic and immunologic factors on the rate of CD4 loss after treatment interruption. The exposure variables under investigation included CD4 cell count and viral load at treatment initiation. The rates of change of CD4 cell count after treatment interruption was estimated from observed data using advanced longitudinal data analysis methods (i.e., linear mixed model). Using random effects accounted for repeated measures of CD4 per person after treatment interruption. The regression coefficient estimates from the model was then used to produce subject specific rates of CD4 change accounting for group trends in change. The exposure variables of interest were age, race, and gender, CD4 cell counts and HIV RNA levels at HAART initiation. ^ The rate of fall of CD4 count did not depend on CD4 cell count or viral load at initiation of treatment. Thus these factors may not be used to determine who can have a chance of successful treatment interruption. CD4 and viral load were again studied by t-tests and ANOVA test after grouping based on medians and quartiles to see any difference in means of rate of CD4 fall after interruption. There was no significant difference between the groups suggesting that there was no association between rate of fall of CD4 after treatment interruption and above mentioned exposure variables. ^

Effects of breastfeeding and naturally acquired immunity on infection with {\it Giardia lamblia}: A study in a cohort of Mexican infants

Giardia lamblia is one of the most common causes of gastrointestinal tract infection among young children worldwide. Yet host protection against this parasite and the effect of infection with Giardia on infant growth are poorly understood. It was hypothesized that among young children, protection against infection with Giardia is afforded by breastfeeding and previous infection with the parasite and further, that infection with Giardia decreases growth velocity. From 4/88 to 4/90, 197 infants in a poor area of Mexico City were followed from 0 to 18 months of age, with stool specimens, symptoms and feeding status data collected weekly. A total of 6,031 stool specimens were tested for Giardia antigen by enzyme-linked immunosorbent assay. There were 1.0 Giardia infections per child-year; 25% were symptomatic and 54% lasted more than 1 month; 94 infants had 1, and 33 had 2 or more infections. Breastfeeding status was coded and analyzed for each child-week of follow up. 91% of study infants were breastfed from birth, 57% at 6 months and 38% at 12 months of age. Rate ratios for non-breastfeeding adjusted for confounding factors were calculated from stratified analyses and the Cox proportional hazards model. Not breastfeeding was a significant risk factor for first infection with Giardia vs. any breastfeeding (adjusted RR = 1.8; 1.1, 2.8) at all ages; a dose response was demonstrated by degree of breastfeeding. The adjusted rate ratio for non-breastfeeding vs. partial breastfeeding was 1.6 (1.03, 2.6) and for non-breastfeeding vs. complete breastfeeding was 4.7 (1.4, 15.9). Among Giardia infected infants, breastfeeding did not protect against diarrheal symptoms or shorten the duration of carriage. First and repeat infections with Giardia did not differ in duration or the percent symptomatic. The analysis of growth and Giardia infection was inconclusive but suggested that a history of Giardia infection might be associated with decreased weight velocity, while an immediate chronic infection might be associated with increased weight velocity. In summary, these data indicate that breastfeeding protects infants against infection with Giardia; provide no evidence of protection against repeat infections resulting from a prior infection and suggest but do not establish that a history of Giardia infection might be associated with decreased growth in young children. ^

Immune response to hepatitis B vaccination in drug using populations: A systematic review and meta-regression analysis

Hepatitis B virus (HBV) is a significant cause of liver diseases and related complications worldwide. Both injecting and non-injecting drug users are at increased risk of contracting HBV infection. Scientific evidence suggests that drug users have subnormal response to HBV vaccination and the seroprotection rates are lower than that in the general population; potentially due to vaccine factors, host factors, or both. The purpose of this systematic review is to examine the rates of seroprotection following HBV vaccination in drug using populations and to conduct a meta-analysis to identify the factors associated with varying seroprotection rates. Seroprotection is defined as developing an anti-HBs antibody level of ≥ 10 mIU/ml after receiving the HBV vaccine. Original research articles were searched using online databases and reference lists of shortlisted articles. HBV vaccine intervention studies reporting seroprotection rates in drug users and published in English language during or after 1989 were eligible. Out of 235 citations reviewed, 11 studies were included in this review. The reported seroprotection rates ranged from 54.5 – 97.1%. Combination vaccine (HAV and HBV) (Risk ratio 12.91, 95% CI 2.98-55.86, p = 0.003), measurement of anti-HBs with microparticle immunoassay (Risk ratio 3.46, 95% CI 1.11-10.81, p = 0.035) and anti-HBs antibody measurement at 2 months after the last HBV vaccine dose (RR 4.11, 95% CI 1.55-10.89, p = 0.009) were significantly associated with higher seroprotection rates. Although statistically nonsignificant, the variables mean age>30 years, higher prevalence of anti-HBc antibody and anti-HIV antibody in the sample population, and current drug use (not in drug rehabilitation treatment) were strongly associated with decreased seroprotection rates. Proportion of injecting drug users, vaccine dose and accelerated vaccine schedule were not predictors of heterogeneity across studies. Studies examined in this review were significantly heterogeneous (Q = 180.850, p = 0.000) and factors identified should be considered when comparing immune response across studies. The combination vaccine showed promising results; however, its effectiveness compared to standard HBV vaccine needs to be examined systematically. Immune response in DUs can possibly be improved by the use of bivalent vaccines, booster doses, and improving vaccine completion rates through integrated public programs and incentives.^