Biomedical subjects

J A Kelly

Publications and source records attributed to J A Kelly.

At least 19 recordsLinked to original sources

PubMed2002

Anticytokine therapy--new approach to the treatment of autoimmune and cytokine-disturbance diseases.

We pioneered the theory (Nature, 1974) that hyperproduced interferons (cytokines) can bring autoimmune diseases (AD) and neutralizing these cytokines can be therapeutic. In 1975 we first performed successful anticytokine therapy using anti-IFN-alpha antibodies in patients with rheumatoid arthritis (RA). In 1989 we proposed also treating AD including AIDS by removing TNF-alpha and IFN-alpha. Our theory has been widely confirmed: injections of IFN-alpha and -gamma can exacerbate AD, while antibodies to IFN-alpha and -gamma and TNF-alpha can be therapeutic. Anti-IFN-gamma may be a universal treatment for Th1 AD. We had good results using anti-IFN-gamma to treat RA, multiple sclerosis (MS), transplant rejection, alopecia areata, vitiligo, psoriatic arthritis, psoriasis and others. For Th1/Th2 diseases, antagonists to cortisol could prevent the Th1-Th2 shift and allow treatment as a Th1 disease. Anticytokine therapy can also be therapeutic in many neuropsychiatric diseases. Every disturbance of homeostasis may lead to cytokine disturbance. IL-10 may restore homeostasis by inhibiting the production of certain Th1 cytokines and could be used to treat some embryonic disturbances and AD including MS.

Autoimmune Diseases↗

PubMed2002

A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity.

Systemic lupus erythematosus (SLE) appears to be the consequence of complex genetics and of only partly understood environmental contributions. Previous work by ourselves and by others has established genetic effects on 1q, 2q, 4p, 6p, and 16p using SLE as the phenotype. However, individual SLE affecteds are extraordinarily different from one another by clinical and laboratory measures. This variation may have a genetic basis; if so, it is advantageous to incorporate measures of between-family clinical variability as covariates in a genetic linkage analysis of affected relative pairs (ARPs) to allow for locus heterogeneity. This approach was applied to genome scan marker data from 160 pedigrees multiplex for SLE and containing 202 ARPs. Because the number of potential covariates was large, we used both ad hoc methods and formal principal components analysis to construct four composite covariates using the SLE classification criteria plus age of onset, ethnicity, and sex. Linkage analysis without covariates has detected evidence for linkage at 1q22-24, 2q37, 4p16, 12p12-11, and 17p13. Linkage analysis with these covariates uncovered linkage at 13p11, 17q11-25, and 20q12 and greatly improved evidence for linkage at 1q22-24, 2q37, 12p12-11, and 17p13. Follow-up analysis identified the original variables contributing to locus heterogeneity in each of these locations. In conclusion, allowing for locus heterogeneity through the incorporation of covariates in linkage analysis is a useful way to dissect the genetic contributions to SLE and uncover new genetic effects.

Analysis of Variance↗

PubMed2002

The genetics of systemic lupus erythematosus: putting the pieces together.

With lambda(s) estimates of 10 to 20 and other evidence of familial aggregation, as well as a monozygotic twin concordance rate >20, systemic lupus erythematosus (SLE) would appear to be a very promising phenotype using modern genetic approaches. Indeed, genetic associations are already known at numerous candidate loci including various HLA alleles, complement component genes, Fcgamma receptors, and others, and murine genetic studies of lupus models have provided additional candidate genes and potential syntenic linkages to evaluate in man. The completed genetic linkage studies performed on various collections of pedigrees multiplex for SLE have identified 60 susceptibility loci with varying degrees of evidence for linkage in man. Seven of these meet or exceed the threshold for significant linkage (LOD > or = 3.3 or P < or = 0.00005) at 1q22-23, 1q41, 2q37, 4p16, 6p21-11, 16q13 and 17p13. In addition, these linkages usually dominate in one ethnicity or another, suggesting that the responsible polymorphisms, once identified, will also vary by ethnicity. Evidence that these linkages can be reproduced range from outright independent confirmation (1q41, 4p16 and 6p21) to additional suggestive evidence in the genomic region of the purported linkage (1q22-23 and 2q37). The results now available suggest that human lupus genetics are robust and that gene identification should be possible using existing genetic approaches and technologies.

Animals↗

PubMed2002

A genetic marker within the CD44 gene confirms linkage at 11p13 in African-American families with lupus stratified by thrombocytopenia, but genetic association with CD44 is not present.

Systemic lupus erythematosus (SLE) is complicated from both a clinical and genetic standpoint. We have stratified SLE families by the presence of thrombocytopenia, which is associated with increased mortality among SLE patients, and found genetic linkage at chromosome 11p13 in African-American families. In the present study we have evaluated CD44, a gene very close (0.5 cM) to the peak LOD score marker, as a candidate gene. Using a newly identified short DNA repeat within the CD44 gene, we find a LOD score of 2.7, which confirms linkage within this genetic interval. However, using a panel of four single nucleotide markers spanning the CD44 gene, we find no genetic association with SLE. Therefore, these data further suggest an SLE susceptibility gene at 11p13, but also imply that an ancestral mutation in the CD44 gene does not account for the linkage.

Black People↗

PubMed2002

The genetics of systemic lupus erythematosus stratified by renal disease: linkage at 10q22.3 (SLEN1), 2q34-35 (SLEN2), and 11p15.6 (SLEN3).

Renal disease occurs in 40-75% of systemic lupus erythematosus (SLE) patients and significantly contributes to morbidity and mortality. We used two pedigree stratification strategies to explore the impact of the ACR renal criterion for SLE classification upon genetic linkage with SLE. In both we used SLE as the phenotype. First, we evaluated genome scan data from >300 microsatellite markers in the 75 pedigrees that had at least one SLE affected with the SLE renal criterion. A maximum-likelihood parametric model approach produced a maximum screening LOD score of 3.16 at 10q22.3 in the European-American (EA) pedigrees. The African-American (AA) pedigrees obtained a maximum screening LOD score of 2.58 at 11p15.6. A multipoint sib-pair regression analysis produced P = 0.0000008 in EA at 10q22.3 (SLEN1) and P = 0.000001 in AA at 2q34-35 (SLEN2). A second stratification strategy explored the renal criterion in 35 pedigrees with two or more SLE patients with renal disease and produced a LOD score of 3.34 at 11p15.6 in AA (SLEN3). Sib-pair analysis in these 35 pedigrees revealed P = 0.00003 at 4q13.1 in EA, P = 0.00003 at 11p13 and 0.00007 at 3q23 in AA. Thus, multiple genetic linkages are related to the renal criterion in SLE. Of the significant genetic linkages with SLE described herein, those at 10q22.3 in the EA pedigrees (SLEN1) and at 2q34-35 in the AA pedigrees (SLEN2) have not been previously described.

Black People↗

PubMed2002

Genetic linkage of systemic lupus erythematosus with chromosome 11q14 (SLEH1) in African-American families stratified by a nucleolar antinuclear antibody pattern.

Systemic lupus erythematosus (SLE) is an autoimmune disease with complex genetics. We evaluated pedigrees multiplex for SLE that had an affected with antinucleolar antibodies to increase the homogeneity for genetic linkage analysis. We found a significant linkage effect on chromosome 11q14 at marker D11S2002 in African-American Pedigrees. This effect produced a maximum LOD score of 5.62 using a dominant inheritance model with 95% penetrance in males and 99% penetrance in females. The results were supported by multipoint linkage analysis. Fine mapping of the region with two additional markers within 6 cM of D11S2002 further provided evidence of linkage in this region. Linkage at D11S2002, named SLEH1, was previously found in some of these same African-American pedigrees multiplex for SLE, but who were stratified by hemolytic anemia (Kelly et al, submitted). In conclusion, an important SLE susceptibility gene, SLEH1 at 11q14, is identified in African-Americans when stratifying pedigrees by antinucleolar autoantibodies.

Black People↗

PubMed2002

Genome scan stratified by the presence of anti-double-stranded DNA (dsDNA) autoantibody in pedigrees multiplex for systemic lupus erythematosus (SLE) establishes linkages at 19p13.2 (SLED1) and 18q21.1 (SLED2).

Anti-double-stranded DNA (anti-dsDNA) is arguably one of the most specific autoantibodies in systemic lupus erythematosus (SLE). This antibody is associated with more severe SLE and with glomerulonephritis. From 196 pedigrees multiplex for SLE, we selected those that had any SLE affected positive for anti-dsDNA by the Crithidia luciliae kinetoplast imunofluorescence assay. This stratification strategy tested the hypothesis that anti-dsDNA would identify a more genetically homogeneous group of pedigrees, in which previously undetected linkage effects could be established. A genome screen data for linkage to SLE was available at 307 microsatellite markers for this selected group of 71 pedigrees: 37 European-American, 29 African-American, and five others. The most significant results were obtained at 19p13.2 (LOD(max) = 4.93), named SLED1, in the 37 European-American pedigrees using a dominant model with mixed penetrances (92% for females and 49% for males) at 100% homogeneity (theta = 0). A second linkage effect, SLED2, was established in the 29 African-American pedigrees at 18q21.1 (LOD(max) = 3.40) using a recessive model with 100% penetrance (theta = 0.1). Parametric and non-parametric multipoint analyses were performed, which provided further evidence and support of susceptibility genes residing in these regions. In conclusion, two powerful linkages have been detected with SLE based on the presence of anti-dsDNA. These findings show SLE to be a richly complicated disease phenotype that is now ripe for important new discovery through a genetic approach.

Animals↗

PubMed2002

HIV risk characteristics and prevention needs in a community sample of bisexual men in St. Petersburg, Russia.

A new and understudied HIV epidemic is quickly unfolding in the Central and Eastern European countries of the former Soviet Union. Men who have sex with men (MSM) in Russia constitute a population highly vulnerable to sexually-transmitted HIV infection. In a community sample of 434 Russian MSM accessed in gay venues in St. Petersburg, 126 had had both male and female partners in the past three months. In this paper, we report on their risk characteristics. Forty-five per cent of men reported recently engaging in unprotected anal intercourse with their male partners. Respondents had a mean of 3.3 male and 3.4 female partners in the past three months, and most had multiple male and female partners in this time period. There were serious and significant gaps in the AIDS risk knowledge levels of these men, and most believed they had no personal contact with HIV-positive people. Bisexual men were more likely than exclusively gay men to have engaged in commercial sex and tended to have lower AIDS risk knowledge. Although they did not differ in average age, bisexual compared to gay men more recently had their first sex with a man. Multivariate logistic and linear regression analyses showed that condom and safer sex attitudes, perceived norms, AIDS risk knowledge and age at first sex with a man were independent predictors of high-risk behaviour among bisexual men. HIV prevention interventions for bisexual men should address their sexual practices with both male and female partners, correct misconceptions about risk, address behaviour practices rather than gay identity, and recognize risk issues faced by the female partners of bisexual men.

Adult↗

PubMed2001

Influence of a partner's HIV serostatus, use of highly active antiretroviral therapy, and viral load on perceptions of sexual risk behavior in a community sample of men who have sex with men.

OBJECTIVE: To assess the perceptions of gay and bisexual men concerning the risk of HIV transmission through various sexual practices with a new sex partner depending on that partner's disclosed HIV status, antiretroviral treatment status, and viral load. METHODS: Study participants read four different scenarios describing sexual situations with a new partner and rated each scenario for risk of HIV transmission. HIV status and antiretroviral treatment status disclosed by the new sex partner were varied across four scenarios: unknown HIV status; HIV-negative; HIV-positive and not taking highly active antiretroviral therapy (HAART); and HIV-positive and taking HAART with an undetectable viral load. RESULTS: Study participants were 472 men attending a gay pride festival who reported that they were HIV-negative. Eighty-nine percent of the men were white, and the mean age of the study participants was 35.8 years. Of the four scenarios, sex with an HIV-positive partner not taking HAART was rated as posing the greatest risk. Sex with an HIV-positive partner taking HAART who had an undetectable viral load was not consistently viewed as riskier than sex with an HIV-negative partner or a man with an unknown HIV status. CONCLUSIONS: The current study provides preliminary evidence for the effect of disclosure of HIV serostatus, use of HAART, and the presence of an undetectable viral load on the perceptions of sexual risk for HIV-negative men. The findings suggest that some gay and bisexual men judge risk based on the perceived HIV status of their sex partners and not on the general assumption that all sex partners entail equal risk, as many prevention campaigns have emphasized.

Adult↗

PubMed2001

Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus.

Both systemic lupus erythematosus (SLE) and vitiligo are autoimmune disorders that have strong evidence of complex genetic contributions to their etiology, but, to date, efforts using genetic linkage to find the susceptibility genes for either phenotype have met with limited success. Since autoimmune diseases are thought to share at least some of their genetic origins, and since only a small minority (16 of 92) of the European-American pedigrees multiplex for SLE in our collection have one or more affected members with vitiligo, we hypothesized that these pedigrees might be more genetically homogeneous at loci important to both SLE and vitiligo and, hence, have increased power for detection of linkage. We therefore evaluated genomewide microsatellite-marker-scan data for markers at an average marker density of approximately 11 cM in these 16 European-American pedigrees and identified a significant linkage at 17p13, where the maximum multipoint parametric LOD score was 3.64 (P<4.3x10(-5)) and the nonparametric linkage score was 4.02 (P<2.8x10(-5)), respectively. The segregation behavior of this linkage suggests a recessive mode of inheritance with a virtually homogeneous genetic effect in these 16 pedigrees. These results support the hypotheses that SLE and vitiligo may share important genetic effects and that sampling on the basis of clinical covariates dramatically improves power to identify genetic effects.

Chromosome Mapping↗

PubMed2001

Mutational analysis of the thyrotropin-releasing hormone-degrading ectoenzyme. similarities and differences with other members of the M1 family of aminopeptidases and thermolysin.

Thyrotropin-releasing hormone-degrading ectoenzyme (TRH-DE) is a TRH-specific peptidase which catalyzes the inactivation of the peptidergic signal substance TRH. As indicated by sequence alignment, TRH-DE and the other members of the M1 family of aminopeptidases have a distinct set of conserved amino acid residues in common. By replacing amino acid residues that are putatively involved in catalysis, we could demonstrate that the enzymatic activities of the mutants E408D, E442D, E464Q, E464D, Y528F, H507R, and H507F are dramatically decreased, essentially due to the changes of V(max). The mutant enzymes E408Q and E442Q are inactive, whereas the specific enzymatic activity of the mutants R488Q, R488A, and Y554F are similar to that of the wild-type enzyme. These data strongly suggest that E408, E442, Y528, and H507 are involved in the catalytic process of TRH-DE while E464 presumably represents the third zinc-coordinating residue and may be equivalent to E166 in thermolysin. In contrast, amino acid residues R488 and Y554 seem not to be involved in the catalytic mechanism of TRH-DE.

Amino Acid Sequence↗

PubMed2001

Predictors of HIV risk behavior among Russian men who have sex with men: an emerging epidemic.

BACKGROUND: Russia is experiencing one of the sharpest increases in HIV incidence in the world. Almost no research has examined patterns of risk behavior among Russian men who have sex with men (MSM). DESIGN AND METHODS: A total of 434 MSM were surveyed in all of St. Petersburg's gay-identified clubs during June 2000. Men completed questionnaires about their sexual practices, AIDS risk knowledge, safer sex attitudes, behavior change intentions, perceived safer sex norms, and fatalism. RESULTS: Most MSM were bisexual; 79% had female partners in their lives and 37% had female partners in the previous 3 months. Sexually transmitted disease treatment was reported by 32% of the men, 23% had sold sex to gain money, and knowledge about critical HIV risk-reduction steps was low. Of all men surveyed, 38% had unprotected anal sex in the previous 3 months, consistent condom use was reported by only 30% of men, and most recent anal intercourse occasions 37% of particpants'. Regression analyses showed that high-risk behavior was predicted by poor safer sex attitudes, weak behavior change intentions, low knowledge about AIDS risk, perceived peer norms that did not support safer sex, and having a boyfriend. CONCLUSION: To avert a widespread epidemic, HIV prevention interventions for Russian MSM are critically needed. Factors predicting risk were consistent with those found among MSM in other countries early in the HIV epidemic. However, unique cultural factors, including frequent bisexual behavior, the 'newness' of openly gay communities in Russia and lack of community experience in dealing with AIDS, require HIV prevention program tailoring.

Adult↗

PubMed2001

A 1.2-A snapshot of the final step of bacterial cell wall biosynthesis.

The cell wall imparts structural strength and shape to bacteria. It is made up of polymeric glycan chains with peptide branches that are cross-linked to form the cell wall. The cross-linking reaction, catalyzed by transpeptidases, is the last step in cell wall biosynthesis. These enzymes are members of the family of penicillin-binding proteins, the targets of beta-lactam antibiotics. We report herein the structure of a penicillin-binding protein complexed with a cephalosporin designed to probe the mechanism of the cross-linking reaction catalyzed by transpeptidases. The 1.2-A resolution x-ray structure of this cephalosporin bound to the active site of the bifunctional serine type D-alanyl-D-alanine carboxypeptidase/transpeptidase (EC ) from Streptomyces sp. strain R61 reveals how the two peptide strands from the polymeric substrates are sequestered in the active site of a transpeptidase. The structure of this complex provides a snapshot of the enzyme and the bound cell wall components poised for the final and critical cross-linking step of cell wall biosynthesis.

Acylation↗

PubMed2001

Outcomes of a randomized small-group HIV prevention intervention trial for people with serious mental illness.

HIV prevalence is alarmingly high among persons with serious mental illness and severely mentally ill adults frequently engage in high-risk behavior practices. This study evaluated the effectiveness of a small-group HIV risk reduction intervention offered to 189 men and women in outpatient programs for severely mentally ill adults. Participants screened for HIV risk were randomly assigned to attend either a 7-session small-group cognitive-behavioral HIV risk reduction intervention or a time-matched comparison intervention and were followed at 3-month intervals for one year. Participants who attended the HIV risk reduction intervention increased their condom use, had a higher percentage of intercourse occasions protected by condoms, and held more positive attitudes toward condoms. Women showed greater response to the intervention than men. While many behavior change effects were present at 3-, 6- and 9-month followup assessments, most diminished by the 12-month followup. These results under-score the need for tailored but ongoing HIV prevention efforts integrated into community programs that serve people with serious mental illness.

Acquired Immunodeficiency Syndrome↗

PubMed2001

HIV risk behavior and risk-related characteristics of young Russian men who exchange sex for money or valuables from other men.

One of the world's newest HIV epidemics is emerging now in Russia and other countries of Central and Eastern Europe. We report on the HIV risk characteristics of young Russian men who exchange sex for money or valuables, a group that constitutes almost one-fourth of men surveyed recently in gay-identified venues in St. Petersburg. Among 96 MSM who have sex for economic gain, most reported multiple male and female partners, 45% had unprotected anal intercourse with their male partners in the past three months, and many not only received but also gave money or valuables themselves to their male partners. Relative to men who did not give sex for economic gain (n = 326), those who did were younger (n = .0001), less well-educated (p = .0001), and more often unemployed (p = .02). They also were less knowledgeable concerning even basic HIV risk reduction steps (p = .02) and held many misconceptions about safer sex. Men who exchanged sex for economic gain had more male (p = .001) and female partners (p = .01) in the past three months than men who did not, and one-third had been treated for STDs. In the context of Russia's rapid cultural and social changes, economic turmoil, and gay communities not yet experienced in AIDS, HIV prevention programs must be tailored to risk patterns and dynamics different than those found in the gay communities of many western countries.

Adolescent↗

PubMed2001

AIDS knowledge, attitudes, and behaviour in Russia: results of a population-based, random-digit telephone survey in St Petersburg.

In this paper, we report on the results of what we believe to be the first population-based, random-digit telephone AIDS survey conducted in Russia. Recent and rapidly increasing STD and HIV rates show the extremely urgent need for HIV prevention programmes in Russia. HIV sexual risk behaviour, knowledge, attitudes, and personal concern characteristics were assessed in a sample of men and women aged 15-55 years living in 435 St Petersburg households. Many factors related to high HIV risk were found in this study. Only 6% of respondents reported consistent condom use, and 78% reported that they never or seldom used condoms. At the same time, over 13% had 3 and more sexual partners during the last year and 12% had 10 and more lifetime partners. Occasional or frequent anal sex was reported by 13% of those surveyed. Two-thirds of respondents acknowledged personal risk for getting HIV but fewer than 25% indicated that they had taken steps to reduce the risks. One-third of respondents believed that condoms are not an effective protection against HIV. Forty-eight per cent of respondents believed that HIV could be transmitted through kissing, 56% through mosquito bites, and 29.2% through sharing cigarettes. HIV/AIDS prevention efforts for the general public and also targeted campaigns directed toward high-risk communities must be quickly undertaken in Russia.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Kinetic investigation of the specificity of porcine brain thyrotropin-releasing hormone-degrading ectoenzyme for thyrotropin-releasing hormone-like peptides.

Evidence indicates that neuronally released thyrotropin-releasing hormone (TRH) is selectively inactivated by TRH-degrading ectoenzyme (TRH-DE) (EC ). TRH-DE inhibitors may be used to enhance the therapeutic actions of TRH and to investigate the functions of TRH and TRH-DE in the central nervous system. Although TRH-DE appears to exhibit a high degree of specificity toward TRH, systematic specificity studies, which would facilitate inhibitor design, have not been previously conducted for this enzyme. In this paper we present the first description of TRH-DE specificity across a directed peptide library in which the histidyl (P(1)') residue of TRH was replaced by a series of amino acids. Peptides were synthesized using standard solid phase chemistry. Kinetic parameters were measured either by continuous or discontinuous fluorometric assays or by quantitative high pressure liquid chromatography. The P(1)' residue was found to influence significantly both the ability of the peptides to bind to TRH-DE, as measured by their K(i) values, and the ability of TRH-DE to catalyze their hydrolysis. Moderately bulky, uncharged P(1)' residues were found to bind preferentially to TRH-DE. Results from this screen provide valuable information for the development of TRH-DE inhibitors and have led to the identification of two potent, reversible TRH-DE inhibitors, l-pyroglutamyl-l-asparaginyl-l-prolineamide (K(i) = 17.5 micrometer) and Glp-Asn-Pro-7-amido-4-methyl coumarin (K(i) = 0.97 micrometer).

Aminopeptidases↗

PubMed2000

Impact of medical and nonmedical factors on physician decision making for HIV/AIDS antiretroviral treatment.

To examine influences of medical factors (e.g., viral load) and nonmedical factors (e.g., patient characteristics) on treatment decisions for highly active antiretroviral therapy (HAART), we sent a survey to a random sample of 995 infectious disease physicians who treat patients with HIV/AIDS in the United States in August, 1998. The response rate was 53%. Respondents were asked to report their current practices with respect to antiretroviral treatment and the extent to which each of three medical and 17 nonmedical factors would influence them for or against prescribing HAART to a hypothetical HIV-positive patient. Most reported initiating HAART with findings of low CD4+ cell counts and high viral loads, and weighing CD4+ cell counts, viral load, and opportunistic infection heavily in their decisions to prescribe HAART. Patients' prior history of poor adherence was weighed very much against initiating HAART. Patient homelessness, heavy alcohol use, injection drug use, and prior psychiatric hospitalization were cited by most physicians as weighing against HAART initiation. Thus, most physicians in this sample follow guidelines for the use of HAART, and nonmedical factors related to patients' life situations are weighed as heavily as disease severity in treatment decisions. As HIV increasingly becomes a disease associated with economic disadvantage and other social health problems, it will be essential to develop interventions and care support systems to enable patients experiencing these problems to benefit from HIV treatment advances.

Anti-HIV Agents↗