Differential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice

The roles of individual nitric oxide synthases (NOS) in anthracycline-related cardiotoxicity are not completely understood. We investigated the effects of a chronic treatment with doxorubicin (DOX) on knockouts of the individual NOS isozymes and on transgenic mice with myocardial overexpression of eNOS. Fractional shortening (FS) was reduced in untreated homozygous nNOS and iNOS knockouts as well as in eNOS transgenics. DOX-induced FS decrease in wild-type mice was attenuated only in eNOS knockouts, which were found to overexpress nNOS. No worsening of contractility was observed in DOX-treated eNOS transgenics and iNOS knockouts. Although the surviving DOX-treated nNOS knockouts exhibited no further impairment in contractility, most (70%) animals died within 7 weeks after treatment onset. In comparison to untreated wild-type hearts, the nitric oxide (NO) level was lower in hearts from DOX-treated wild-type mice and in all three untreated knockouts. DOX treatment had no effect on NO in the knockouts. These data indicate differential roles of the individual NOS in DOX-induced cardiotoxicity. Protection against DOX effects conferred by eNOS deletion may be mediated by a compensatory overexpression of nNOS. NOS inhibition-based prevention of anthracycline-induced cardiotoxicity should be eNOS-selective, simultaneously avoiding inhibiting nNOS

Genetic susceptibility in tuberculosis

The importance of host genetic factors in determining susceptibility to tuberculosis (TB) has been studied extensively using various methods, such as casecontrol, candidate gene and genome-wide linkage studies. Several important candidate genes like human leucocyte antigen/alleles and non-human leucocyte antigen genes, such as cytokines and their receptors, chemokines and their receptors, pattern recognition receptors (including toll-like receptors, mannose binding lectin and the dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin), solute carrier family 11A member 1 (formerly knownas natural resistance-associated macrophage protein 1) and purinergic P2X7 receptor gene polymorphisms, have been associated with differential susceptibility to TB in various ethnic populations. This heterogeneity has been explained by host–pathogen and gene– environment interactions and evolutionary selection pressures. Although the achievements of genetics studies might not yet have advanced the prevention and treatment of TB, researchers have begun to widen their scope of investigation to encompass these practical considerations

Hyperoxia impairs postnatal alveolar epithelial development via NADPH oxidase in newborn mice

Hyperoxia disrupts postnatal lung development in part through inducing inflammation. To determine the contribution of leukocyte-derived reactive oxygen species, we exposed newborn wild-type and NADPH oxidase p47phox subunit null (p47phox−/−) mice to air or acute hyperoxia (95% O2) for up to 11 days. Hyperoxia-induced pulmonary neutrophil influx was similar in wild-type and p47−/− mice at postnatal days (P) 7 and 11. Macrophages were decreased in wild-type hyperoxia-exposed mice compared with p47phox−/− mice at P11. Hyperoxia impaired type II alveolar epithelial cell and bronchiolar epithelial cell proliferation, but depression of type II cell proliferation was significantly less in p47−/− mice at P3 and P7, when inflammation was minimal. We found reciprocal results for the expression of the cell cycle inhibitor p21cip/waf in type II cells, which was induced in 95% O2-exposed wild-type mice, but significantly less in p47phox−/− littermates at P7. Despite partial preservation of type II cell proliferation, deletion of p47phox did not prevent the major adverse effects of hyperoxia on alveolar development estimated by morphometry at P11, but hyperoxia impairment of elastin deposition at alveolar septal crests was significantly worse in wild-type vs. p47phox−/− mice at P11. Since we found that p47phox is expressed in a subset of alveolar epithelial cells, its deletion may protect postnatal type II alveolar epithelial proliferation from hyperoxia through effects on epithelial as well as phagocyte-generated superoxide

Spectrum of immune reactivity to mycobacterial (BCG) antigens in healthy hospital contacts in South India

In an effort to study the immunological responses to antigens of tubercle bacilli, 49 tuberculin positive and 41 tuberculin negative hospital contacts aged 20-29 years (staff nurses and students working in Government Rajaji Hospital, Madurai, South India) were studied for serum antibodies (IgG, IgM and IgA classes) to BCG by ELISA and diameter of induration to PPD by Mantoux procedures. The two immunological parameters were correlated in regression analysis. The results have revealed higher anti-BCG serum antibody levels in hospital contacts than in non-contacts, significantly higher antibodies in tuberculin negative hospital contacts than in tuberculin positive hospital contacts, an inverse correlation of tuberculin reactivity and antibodies and a bimodal decline (regression) of antibodies against the increase in skin test induration. This study has thus suggested the existence of an immunological spectrum in hospital contacts from south India; persons at one pole of the spectrum were tuberculin negative and possessed significantly elevated antibody levels and those at the other pole of the spectrum were tuberculin positive and possessed low antibody levels. Thus the spectrum of immune reactivity may be due to an inherent susceptibility/resistance of an individual to Mycobacterium tuberculosis

<i>de novo</i> Blood Biomarkers in Autism: Autoantibodies against Neuronal and Glial Proteins

Autism spectrum disorders (ASDs) are the most common neurodevelopmental disorders with unidentified etiology. The behavioral manifestations of ASD may be a consequence of genetic and/or environmental pathology in neurodevelopmental processes. In this limited study, we assayed autoantibodies to a panel of vital neuronal and glial proteins in the sera of 40 subjects (10 children with ASD and their mothers along with 10 healthy controls, age-matched children and their mothers). Serum samples were screened using Western Blot analysis to measure immunoglobulin (IgG) reactivity against a panel of 9 neuronal proteins commonly associated with neuronal degeneration: neurofilament triplet proteins (NFP), tubulin, microtubule-associated proteins (tau), microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), &#945;-synuclein (SNCA) and astrocytes proteins such as glial fibrillary acidic protein (GFAP) and S100B protein. Our data show that the levels of circulating IgG class autoantibodies against the nine proteins were significantly elevated in ASD children. Mothers of ASD children exhibited increased levels of autoantibodies against all panel of tested proteins except for S100B and tubulin compared to age-matched healthy control children and their mothers. Control children and their mothers showed low and insignificant levels of autoantibodies to neuronal and glial proteins. These results strongly support the importance of anti-neuronal and glial protein autoantibodies biomarker in screening for ASD children and further confirm the importance of the involvement of the maternal immune system as an index that should be considered in fetal in utero environmental exposures. More studies are needed using larger cohort to verify these results and understand the importance of the presence of such autoantibodies in children with autism and their mothers, both as biomarkers and their role in the mechanism of action of autism and perhaps in its treatment

Sociobiology and HLA Genetic Polymorphism in Hill Tribes, the Irula of the Nilgiri Hills and the malayali of the Shevroy Hills, South India

Two endogamous tribes of Tamil Nadu, South India, the Irula of the Nilgiri hills and the Malayali of the Shevroy hills, were studied for their sociobiology and HLA polymorphism. For sociobiological studies 166 marriages in the Irula and 368 marriages in the Malayali were recorded. The number and spatial distribution of patrilineal clans and their marriageable range (number of clans from which the brides came) were studied. Eight clans in the Irula and 16 clans in the Malayali were identified. Of these the Kuppar of the Irula and the Malayan of Malayali were the largest clans, and both of them had the greatest marriageable range. The numerical strength and the resultant spatial distribution correlated well with the marriageable range. HLA-A, B, and DR polymorphism was studied on 191 Irula and 42 Malayali following standard procedures. HLA typing revealed high frequencies (\u3e10%) of alleles HLA-A2, A9, A l l , B17, B35, B40, DR2, and DR7 in both tribes, but the Irula had elevated HLA-A10, B8, and DR8 frequencies and the Malayali had elevated HLA-A31, B7, DR4, and DR5 frequencies. Two-locus haplotypes A10-B8 and A2-B5 were identified in both tribes, but A11-B40 and A2-B53 were present only in the Irula and A33-B44 and B15-DR6 were present only in the Malayali. The sociobiology of the Irula was correlated to the HLA genetic profile. The Irula sample was stratified based on clan and HLA data; The Kuppar clan was closer to the Kalkatti, the second largest clan, than to the Pungar and the Sambar clans. Thus the numerical strength and spatial distribution of various exogamous clans, presumably a result of migration during different periods of history, is reflected in the marriageable range and thus in the genetic distance. In studying HLA or any other genetic polymorphism of an endogamous tribe or caste, one needs to consider the social structure, spatial distribution, and marriageable range

Association of pulmonary tuberculosis and HLA in South India

In 204 patients with smear-positive pulmonary tuberculosis HLA-A10, B8 and DR2 were more frequently found than in 404 control subjects (p=0.01); the greatest attributable risk (0.29) was associated with HLA-DR2. The radiographic extent of disease was also associated with HLA-DR2 (p = 0.0001). In 152 patients with smear-negative pulmonary tuberculosis, the frequencies of HLA-A10 and B8, but not DR2, were greater in the control subjects (p = 0.001 and 0.01 respectively). HLA-DR2 may be involved in the pathogenesis of advanced pulmonary tuberculosis. Study of endogamous, genetically disparate populations (caste) revealed other HLA associations (A3, B12 and DR4) unique to them, suggesting that genes linked with the HLA complex might also be significant in the pathogenesis of tuberculosis