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M Whalen

Publications and source records attributed to M Whalen.

At least 19 recordsLinked to original sources
PubMed2003

Saturation of the 5q31-q33 candidate region for coeliac disease.

The first genome wide screening performed on Italian affected sib-pair families (Greco et al. 1998) gave evidence for linkage with coeliac disease in the 5q region. This finding was replicated in a second independent dataset (Greco et al. 2001). Overall, pooling both samples, the highest MLS value (2.92) was found for the most centromeric marker tested, D5S640. In the present study, the 5q31-q33 region was saturated with 12 new markers around D5S640, in order to verify whether there would be a shift of the MLS position. This study allowed us to support our previous finding of linkage for the region 5q31-q33, with the most significant MLS value at D5S2014, very close to the marker D5S640. No evidence for interaction between this risk factor and the one in the HLA region was found. Furthermore, many different groups have independently obtained analogous results for this region, confirming the presence of a susceptibility locus in the region 5q31-q33. This region contains several interesting candidate genes for coeliac disease.

Celiac Disease↗
PubMed2002

Genome sequence of the plant pathogen Ralstonia solanacearum.

Ralstonia solanacearum is a devastating, soil-borne plant pathogen with a global distribution and an unusually wide host range. It is a model system for the dissection of molecular determinants governing pathogenicity. We present here the complete genome sequence and its analysis of strain GMI1000. The 5.8-megabase (Mb) genome is organized into two replicons: a 3.7-Mb chromosome and a 2.1-Mb megaplasmid. Both replicons have a mosaic structure providing evidence for the acquisition of genes through horizontal gene transfer. Regions containing genetically mobile elements associated with the percentage of G+C bias may have an important function in genome evolution. The genome encodes many proteins potentially associated with a role in pathogenicity. In particular, many putative attachment factors were identified. The complete repertoire of type III secreted effector proteins can be studied. Over 40 candidates were identified. Comparison with other genomes suggests that bacterial plant pathogens and animal pathogens harbour distinct arrays of specialized type III-dependent effectors.

Bacterial Proteins↗
PubMed2001

Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia.

Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.

Adolescent↗
PubMed2001

Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci.

Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRB1. We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOB genes, and the microsatellite locus TNFc, identified approximately 40% of Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits.

Chromosome Mapping↗
PubMed2000

Major factors influencing linkage disequilibrium by analysis of different chromosome regions in distinct populations: demography, chromosome recombination frequency and selection.

Linkage disequilibrium (LD) mapping of disease genes is complicated by population- and chromosome-region-specific factors. We have analysed demographic factors by contrasting intermarker LD results obtained in a large cosmopolitan population (UK), a large genetic isolate (Sardinia) and a subisolate (village of Gavoi) for two regions of the X chromosome. A dramatic increase of LD was found in the subisolate. Demographic history of populations therefore influences LD. Chromosome-region-specific effects, namely the pattern and frequency of homologous recombination, were next delineated by the analysis of chromosome 6p21, including the HLA region. Patterns of global LD in this region were very similar in the UK and Sardinian populations despite their entirely distinct demographies, and correlate well with the pattern of recombinations. Nevertheless, haplotypes extend across recombination hot spots indicative of selection of certain haplotypes. Subisolate aside, chromosome-region-specific differences in LD patterns appear to be more important than the differences in intermarker LD between distinct populations.

Chromosomes, Human, Pair 6↗
PubMed2000

Soft tissue surgery in the oral and maxillofacial region.

The practice of dentistry is most often perceived as the treatment of the hard tissues of the oral region, specifically the teeth and jaws. However, there are many disorders and conditions involving surgical treatment of the soft tissues that extend to the adjacent and associated structures of the oral and maxillofacial surgery region.

Adolescent↗
PubMed1995

Ethanol- and threonine-induced hypertension in rats: a common mechanism.

OBJECTIVE: To investigate the effects of oral L-threonine and ethanol, precursor of endogenous acetaldehyde, on systolic blood pressure, cystolic free calcium ([Ca2+]i) and vascular calcium uptake in Wistar-Kyoto (WKY) rats. METHODS: Twenty-four male WKY rats aged eight weeks were divided into four groups of six animals each. Animals were given either water or 5% ethanol, 8% L-threonine or 8% L-glycine in drinking water for 15 weeks, animals were sacrificed, aortic rings were incubated in physiological buffer containing 45Ca2+ and uptake was measured after 20 mins. ([Ca2+]i in platelets was measured with a fluorescence [Ca2+]i indicator, FURA-2. Tissues were processed for morphological investigation. RESULTS: After 15 weeks, systolic blood pressure, platelet [Ca2+]i and aortic calcium uptake were all significantly higher (P < 0.001) in rats given either threonine or ethanol than in control rats given water or glycine. Animals in threonine or ethanol group also showed smooth muscle cell hyperplasia, with some thickening of the wall and narrowing of the lumen in small arteries and arterioles of the kidney. Glycine treatment did not cause any of these changes in rats. CONCLUSION: These results suggest that acetaldehyde may be a common cause of both ethanol- and threonine-induced hypertension.

Animals↗
PubMed1992

Infection of cultured human adrenal cells by different strains of HIV.

OBJECTIVE: To determine whether human adrenal cells can be infected by HIV. METHODS: Cultured human fetal adrenal cells and the SW13 human adrenocortical carcinoma cell line were inoculated with several HIV-1 and HIV-2 strains. Virus replication was detected by viral core antigen enzyme-linked immunosorbent and reverse transcriptase assays. CD4 expression was measured by Northern blot and polymerase chain reaction procedures. RESULTS: HIV infection of these adrenal cells was detected and was most evident after cocultivation of the inoculated cells with peripheral blood mononuclear cells. Infection does not involve the CD4 molecule, which is not expressed by these adrenal cells. The relative level of HIV replication depended on the viral strain used. Virus production occurred best in cells that maintained evidence of adrenal cell function. Infection did not appear to disturb steroidogenesis measured in the cells. CONCLUSIONS: These observations indicate that human adrenal cells are susceptible to HIV infection, and provide further evidence of the polytropic nature of the virus.

Adrenal Cortex↗
PubMed1991

Controlled ventilation during NMR spectroscopic studies: hemodynamic and biochemical consequences.

The effects of different ventilation methods on cardiac output measured by the indicator-dilution method, liver blood flow measured by a deuterium washout technique using 2H nuclear magnetic resonance (NMR) and liver concentrations of ATP and intracellular pH determined with 31P NMR were compared in anesthetized rats. No differences in mean arterial blood pressure were demonstrable with the different modes of ventilation. However, significant drops in cardiac output were observed between freely breathing and animals ventilated with positive pressure but not the high frequency oscillatory method (407 +/- 46 and 520 +/- 88 vs. 633 +/- 86 ml/min/kg, p less than 0.05 and p = NS, respectively). Moreover, liver blood flow was significantly reduced during positive pressure but not high frequency oscillatory ventilation compared with free breathing rats (32 +/- 4 and 43 +/- 10 vs. 46 +/- 8 ml/100 g, p less than 0.05 and p = NS, respectively). 31P NMR spectroscopy revealed no effects of either ventilation method on tissue ATP or intracellular pH as estimated by the chemical shift of inorganic phosphate. These data suggest that controlled ventilation in normal rats accomplished with standard positive pressure methods is associated with major decreases in cardiac output and liver blood flow despite maintenance of normal blood pressure. High frequency oscillatory ventilation appears to effect less compromise of cardiac output and hepatic perfusion than positive pressure ventilation and may, therefore, be preferable for some biological studies.

Animals↗
PubMed1990

Hemodynamic and hepatic pH responses to sodium bicarbonate and Carbicarb during systemic acidosis.

Rats subjected to ammonium chloride-induced metabolic acidosis were given alkalinization therapy with either sodium bicarbonate or Carbicarb. Ammonium chloride-induced severe metabolic acidosis had minimal effect on mean arterial blood pressure and cardiac output. This acidosis resulted in a small but statistically significant fall in intracellular liver pH (pHi) as measured with 31P magnetic resonance spectroscopy (7.01 +/- 0.05 vs 7.08 +/- 0.04, p less than 0.05). Sodium bicarbonate treatment resulted in systemic alkalinization and increases in arterial pCO2 as well as transient but extreme decreases in cardiac output and mean arterial pressure. Alkalinization with sodium bicarbonate also resulted in a transient but significant decrease in intracellular liver pH (7.02 +/- 0.06 at 5 min vs 7.09 +/- 0.06 at baseline, p less than 0.05). Carbicarb therapy resulted in systemic alkalinization without major changes in arterial pCO2, cardiac output, or mean arterial blood pressure. Moreover, Carbicarb effected a sustained intracellular alkalinization of the liver (phi = 7.12 +/- 0.07 at 5 min, p less than 0.05, pHi = 7.19 +/- 0.07 at 10 min, p less than 0.01, pHi = 7.16 +/- 0.06 at 15 min, p less than 0.01, vs baseline pHi = 7.05 +/- 0.06). These data suggest that Carbicarb may be a more effective buffer than sodium bicarbonate during conditions where ventilation is limited and hemodynamic instability is present.

Acidosis↗
PubMed1990

Relationship between changes in buoyant density and formation of new sites of cell wall growth in cultures of streptococci (Enterococcus hirae ATCC 9790) undergoing a nutritional shift-up.

When the glutamate concentration of cultures of Enterococcus hirae was raised from 20 to 300 micrograms/ml, the mass doubling time decreased from ca. 85 to 45 min in 9 min, but balanced growth was not reestablished for 30 to 40 min. During the unbalanced period of growth, RNA and protein synthesis proceeded more rapidly than did peptidoglycan synthesis, buoyant density increased from ca. 1.1024 to 1.1075 g/ml, and the rate of formation of new cell wall growth sites transitorily accelerated above the new growth rate. When studied as a function of cell size, all cultures showed buoyant density to decrease around cell separation, increase as cells increased in size, and then plateau when cells reached large volumes. Greater increases in buoyant density as a function of cell size were seen after shift-up, with the greatest increases observed at 15 to 20 min after shift-up, when the rate of formation of new sites was also maximal. In a population of cells examined by electron microscopy 15 min after shift-up, buoyant density and the frequency of cells with new sites increased as old sites approached the size of two poles. These data were consistent with a model whereby buoyant density increases in the terminal stages of the cell cycle when the surface grows slower than the cytoplasm. The greater the difference in the rates of inside to outside growth, the greater the increase in buoyant density and the more frequently new sites will be initiated.

Cell Wall↗
PubMed1989

Brain pH responses to sodium bicarbonate and Carbicarb during systemic acidosis.

Rats subjected to ammonium chloride-induced metabolic acidosis or respiratory acidosis caused by hypercapnia were given alkalinization therapy with either sodium bicarbonate or Carbicarb. Ammonium chloride induced dose-dependent systemic acidosis but did not affect intracellular brain pH. Hypercapnia caused dose-dependent systemic acidosis as well as decreases in intracellular brain pH. Sodium bicarbonate treatment resulted in systemic alkalinization and increases in arterial PCO2 in both acidosis models, but it caused intracellular brain acidification in rats with ammonium chloride acidosis. Carbicarb therapy resulted in systemic alkalinization without major changes in arterial PCO2 and intracellular brain alkalinization in both acidosis models. These data demonstrate that bicarbonate therapy of systemic acidosis may be associated with "paradoxical" intracellular brain acidosis, whereas Carbicarb causes both systemic and intracellular alkalinization under conditions of fixed ventilation.

Acidosis↗
PubMed1986

Variation and genomic localization of genes encoding Drosophila melanogaster male accessory gland proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Accessory gland proteins from Drosophila melanogaster males have been separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis into nine major bands. When individual males from 175 strains were examined, considerable polymorphism for nearly one-half of the major protein bands was seen, including null alleles for three bands. Variation was observed not only among long-established laboratory strains but also among stocks recently derived from natural populations. There was little difference in the amount of variation between P and M strains, indicating that P element mutagenesis is not a factor producing the variation. Codominant expression of variants for each of five bands was found in heterozygotes, suggesting structural gene variation and not posttranslational modification variation. Stocks carrying electrophoretic variants of four of the major proteins were used to map the presumed structural genes for these proteins; the loci were found to be dispersed on the second chromosome. Since males homozygous for variant proteins were fertile, the polymorphism seems to have little immediate effect on successful sperm transfer. We propose that a high degree of polymorphism can be tolerated because these proteins play a nutritive rather than enzymatic role in Drosophila reproduction.

Animals↗
PubMed1975

Lymphocyte transformation in leukemic serum.

Cultures of normal lymphocytes were induced to transform by pokeweed mitogen (PWM). Inhibition of transformation was observed when these cultures contained sera isolated from children with acute lymphoblastic leukemia (ALL). The inhibition of transformation of normal lymphocytes was best demonstrated when the concentration of the leukemic serum in the culture medium was relatively high (60 percent); however, the inhibition was also observed with a more standard serum concentration (20 percent). Not all leukemic sera were inhibitory. Pretreatment sera from newly diagnosed patients with leukocyte counts greater than 50,000/mm3 were significantly inhibitory. Pretreatment sera from newly diagnosed patients with leukocyte counts less than 50,000/mm3, and sera from patients in remission or relapse had no significant effect. The inhibition observed with the sera of the high leukocyte count group was not believed to be related to cytotoxicity. The significance of this inhibitor in relation to clinical prognosis needs to be investigated.

Child↗