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M P Dubé

Publications and source records attributed to M P Dubé.

At least 19 recordsLinked to original sources
PubMed2006

A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13.

The authors investigated genetic factors contributing to restless legs syndrome (RLS) by performing a 10-cM genome-wide scan in a large French-Canadian pedigree. They detected an autosomal-dominant locus mapping to chromosome 20p13, with a maximum multipoint lod score of 3.86 at marker D20S849. This is the third reported autosomal-dominant locus for RLS and the first autosomal-dominant RLS locus in the French-Canadian population.

Chromosome Mapping↗
PubMed2004

Prevalence of proteinuria and the development of chronic kidney disease in HIV-infected patients.

AIMS: HIV-related renal diseases are increasingly prevalent and are associated with proteinuria and rapid progression to end-stage renal failure. Early treatment with highly active antiretroviral therapy (HAART) and ACE inhibition may prevent the development of chronic kidney disease (CKD), but studies evaluating the epidemiology of proteinuria and early CKD in HIV-infected patients are lacking. METHODS: All consecutive patients at Wishard Memorial Hospital (Indiana University) whose initial HIV documentation occurred from 1990 to 1998, were retrospectively studied using a computerized medical record system. Clinical data were abstracted from time of first HIV documentation through 12/31/2000. The proportions of patients who developed CKD (doubling of serum creatinine from an initial level < or = 1.5 mg/dl) and who had proteinuria (> or = 1+ protein on the first urine dipstick after HIV documentation) were calculated. Case mix and laboratory variables at the time of HIV documentation were compared between those who did and did not develop CKD and between those who had and did not have initial proteinuria. RESULTS: Of 487 subjects with initially normal renal function, 10 (2% (95% CI, 1-4%)) developed CKD. In univariable analysis, black race, a diagnosis of diabetes or hypertension and proteinuria were all significantly associated with the development of CKD; 89 (29% (95% CI, 24-35%)) of 289 evaluable subjects had > or = 1+ proteinuria on urine analysis. Multivariable regression revealed only older age (OR 1.08 per year increase; 95% CI, 1.03-1.14) to be associated with proteinuria. CONCLUSIONS: A small, but potentially clinically meaningful proportion of HIV-infected patients develop CKD, and there appears to be a high prevalence of proteinuria on the first urine analysis obtained after HIV documentation.

Adult↗
PubMed2001

A randomized study of the utility of human immunodeficiency virus RNA measurement for the management of antiretroviral therapy.

To compare frequent measurement with infrequent measurement of human immunodeficiency virus (HIV) RNA levels in the management of antiretroviral therapy, we conducted a clinical strategy study of 206 HIV-infected patients who had <500 CD4 cells/mm(3). Patients were randomized (1.5:1) to undergo frequent monitoring (at baseline and every 2 months) or infrequent monitoring (at baseline and twice yearly), with CD4 cell counts determined every 2 months. Patients received unrestricted antiretroviral therapy. In the primary analysis (at month 6), the frequent group had a mean HIV RNA reduction (+/- standard deviation) of 0.93+/-0.79 log(10) copies/mL, versus 0.48+/-0.83 log(10) copies/mL for the infrequent group (P=.0002). A trend (P=.1) toward improved survival was seen in the frequent group. Given this improved virological response, more frequent HIV RNA measurement than is recommended in published guidelines (every 3-4 months) may be appropriate.

Adult↗
PubMed2001

Prospective evaluation of the effect of initiating indinavir-based therapy on insulin sensitivity and B-cell function in HIV-infected patients.

OBJECTIVE: To determine whether initiation of antiretroviral therapy that includes the protease inhibitor indinavir causes insulin resistance or abnormal B-cell function in study subjects with HIV infection. METHODS: Nonwasted, HIV-infected study subjects who did not have concurrent diabetes were prospectively evaluated by oral and intravenous glucose tolerance testing at baseline, at 2 weeks after starting indinavir monotherapy, and at another 6 weeks after initiating indinavir-based triple-therapy. RESULTS: Mean CD4 count at entry was 282 cells/microl and median HIV RNA was 33,000 copies/ml; all experienced a virologic response. Fasting glucose increased from 83.2 +/- 3.7 mg/dl at baseline to 86.8 +/- 3.2 at week 2 and 91.7 +/- 3.5 at week 8 (p =.003). Insulin sensitivity by minimal model analysis decreased by 30.5% over 8 weeks, from 3.83 +/- 0.63 min-1 per microU/ml x 10-4 to 3.09 +/- 0.53 at week 2 and 2.66 +/- 0.35 at week 8 (p =.01). Insulin secretion by the acute insulin response to intravenous glucose did not change (baseline 822 +/- 283 microU/ml x min, week 8 880 +/- 289; p = 0.4), and the insulin response to oral glucose (30 minute insulin:glucose ratio) fell from 1.69 +/- 0.54 microU/ml per mg/dl at baseline to 1.18 +/- 0.34 at week 8 (p =.05). CONCLUSION: During 8 weeks of indinavir-based therapy, fasting glucose increased and insulin sensitivity decreased, without a compensatory increase in insulin release. This combination of insulin resistance without augmented B-cell response may explain the hyperglycemia and other metabolic abnormalities seen in some protease inhibitor-treated patients.

Adult↗
PubMed2001

Sequencing of protease inhibitor therapy: insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors.

OBJECTIVE: To characterize the pattern of HIV-1 susceptibility to protease inhibitors in patients failing an initial protease inhibitor-containing regimen. DESIGN: A cross-sectional analysis of antiretroviral susceptibility. SETTING: HIV clinics in six metropolitan areas. PATIENTS: Eighty-eight HIV-infected adults with HIV RNA > 400 copies/ml after > or = 6 months of antiretroviral therapy, including the use of one protease inhibitor for > or = 3 months. MEASUREMENTS: The frequency and magnitude of decreased susceptibility, measured with a phenotypic assay using recombinant constructs, to five protease inhibitors. Decreased susceptibility was defined as > 2.5-fold increase in the 50% inhibitory concentration (IC50) compared with drug sensitive control virus. RESULTS: At study entry, patients were being treated with nelfinavir (63%), indinavir (25%), or another protease inhibitor (11%). HIV isolates from these patients were susceptible (fold change < 2.5) to all five protease inhibitors in 18% of patients and to none in 8%. Isolates from patients receiving nelfinavir were less likely to have reduced susceptibility to other protease inhibitors than isolates from patients treated with indinavir (P < 0.001) or one of the other three agents (P < 0.001), even after adjustment for the duration of prior protease inhibitor use. Reduced susceptibility to saquinavir and amprenavir was observed significantly less frequently than for the other protease inhibitors. CONCLUSION: The frequency of protease inhibitor cross-resistance and the magnitude of changes in susceptibility varied according to the initial protease inhibitor used in the failing treatment regimen. Significantly less protease inhibitor cross-resistance was demonstrated for isolates from patients failing a nelfinavir-containing regimen compared with those from patients receiving other protease inhibitors.

Adult↗
PubMed2001

Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives.

Oral contraceptives have been shown to be protective against hereditary ovarian cancer. The variant progesterone receptor allele named PROGINS is characterized by an Alu insertion into intron G and two additional mutations in exons 4 and 5. The PROGINS allele codes for a progesterone receptor with increased stability and increased hormone-induced transcriptional activity. We studied the role of the PROGINS allele as a modifying gene in hereditary breast and ovarian cancer. The study included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers with neither cancer. Fifty-eight women had both forms of cancer. Five hundred and ninety-five women had a BRCA1 mutation and 183 women had a BRCA2 mutation. Overall, there was no association between disease status and the presence of the PROGINS allele. Information on oral contraception use was available for 663 of the 778 carriers of BRCA1 or BRCA2 mutations. Among the 449 subjects with a history of oral contraceptive use (74 cases and 365 controls), no modifying effect of PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5-1.3]. Among the 214 carriers with no past exposure to oral contraceptives, the presence of one or more PROGINS alleles was associated with an OR of 2.4 for ovarian cancer, compared to women without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI 1.4-4.3). The association was present after adjustment for ethnic group and for year of birth.

Adult↗
PubMed2000

Disorders of glucose metabolism in patients infected with human immunodeficiency virus.

New-onset diabetes mellitus, clinically similar to type 2 diabetes, will affect a small proportion (1%-6%) of patients infected with human immunodeficiency virus (HIV) who are treated with HIV-1 protease inhibitors (PIs). However, insulin resistance and impaired glucose tolerance will develop during PI treatment in a considerable proportion of patients. Dyslipidemia, abdominal obesity, and loss of peripheral fat frequently coexist with insulin resistance, but it is not clear whether all of these result from a common pathogenic mechanism. Recent data suggest that insulin resistance may also be associated with HIV infection in patients not receiving PI therapy. The long-term consequences of insulin resistance in this population are not known. The effect of switching to other antiretroviral therapies has not been fully determined. Treatment of established diabetes mellitus should generally follow existing guidelines. There is no clinically useful screening test that will determine the existence and degree of insulin resistance in individual patients. It is therefore reasonable to recommend general measures to increase insulin sensitivity in all patients infected with HIV, such as weight reduction for obese persons and regular aerobic exercise.

Anti-HIV Agents↗
PubMed2000

Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group.

Dyslipidemia is a prevalent condition that affects patients infected with human immunodeficiency virus (HIV) who are receiving antiretroviral therapy. These preliminary recommendations summarize the current understanding in this area and propose guidelines for management. Existing guidelines for the management of dyslipidemia in the general population formed the general basis for our recommendations. Data on the prevalence and treatment of dyslipidemia of HIV-infected patients, implications of treatment-related dyslipidemia in other chronically ill populations, and pharmacokinetic profiles for the available hypolipidemic agents in non-HIV populations were considered. Although the implications of dyslipidemia in this population are not fully known, the frequency, type, and magnitude of lipid alterations in HIV-infected people are expected to result in increased cardiovascular morbidity. We propose that these patients undergo evaluation and treatment on the basis of existing guidelines for dyslipidemia, with the caveat that avoidance of interactions with antiretroviral agents is paramount.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Clouston hidrotic ectodermal dysplasia (HED): genetic homogeneity, presence of a founder effect in the French Canadian population and fine genetic mapping.

HED is an autosomal dominant skin disorder that is particularly common in the French Canadian population of south-west Quebec. We previously mapped the HED gene to the pericentromeric region of chromosome 13q using linkage analysis in eight French Canadian families. In this study, we extend our genetic analysis to include a multiethnic group of 29 families with 10 polymorphic markers spanning 5.1 cM in the candidate region. Two-point linkage analysis strongly suggests absence of genetic heterogeneity in HED in four families of French, Spanish, African and Malaysian origins. Multipoint linkage analysis in all 29 families generated a peak lod score of 53.5 at D13S1835 with a 1 lod unit support interval spanning 1.8 cM. Recombination mapping placed the HED gene in a 2.4 cM region flanked by D13S1828 proximally and D13S1830 distally. We next show evidence for a strong founder effect in families of French Canadian origin thereby representing the first example of a founder disease in the south-west part of the province of Quebec. Significant association was found between HED in these families and all markers analysed (Fisher's exact test, P < 0.001). Complete allelic association was detected at D13S1828, D13S1827, D13S1835, D13S141 and D13S175 (P(excess) = 1) spanning 1.3 cM. A major haplotype including all 10 associated alleles was present on 65% of affected chromosomes. This haplotype most likely represents the founder haplotype that introduced the HED mutation into the French Canadian population. Luria-Delbrück equations and multipoint likelihood linkage disequilibrium analysis positioned the gene at the D13S1828 locus (likely range estimate: 1.75 cM) and 0.58 cM telomeric to this marker (support interval: 3.27 cM) respectively.

Alleles↗
PubMed1999

Efficacy of azithromycin in prevention of Pneumocystis carinii pneumonia: a randomised trial. California Collaborative Treatment Group.

BACKGROUND: Azithromycin in combination with sulphonamides is active against Pneumocystis carinii pneumonia (PCP) in animals. We assessed the clinical efficacy of azithromycin for PCP prophylaxis in human beings. METHODS: We identified HIV-1-infected patients with PCP during a prospective randomised trial comparing azithromycin, rifabutin, and the two drugs in combination for prevention of disseminated Mycobacterim avium infection. Patients had CD4-cell counts less than 100/microL at entry and received PCP prophylaxis according to the standard practice of their clinician. Analysis was by intention to treat. FINDINGS: Patients receiving azithromycin, either alone (n=233) or in combination with rifabutin (n=224), had a 45% lower risk of developing PCP than those receiving rifabutin alone (n=236; p=0.008). Compared with rifabutin alone, hazard ratio for azithromycin was 0.54 (95% CI 0.32-0.94), for azithromycin plus rifabutin was 0.55 (0.32-0.94), and for regimens containing azithromycin was 0.55 (0.35-0.86). The most common side-effects involved the gastrointestinal tract with dose-limiting toxicities, and were mainly seen in patients receiving combination therapy. INTERPRETATION: Azithromycin as prophylaxis for M. avium complex disease provides additional protection against P. carinii over and above that of standard PCP prophylaxis. Use of azithromycin is beneficial only as primary prophylaxis.

AIDS-Related Opportunistic Infections↗
PubMed1999

The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response. California Collaborative Treatment Group.

OBJECTIVE: To correlate self-reported antiretroviral adherence with virologic suppression. DESIGN: Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA. SETTING: Five university-affiliated HIV clinics. PATIENTS: A group of 173 HIV-infected patients with a mean baseline CD4 count of 142 x 10(6) cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively. INTERVENTION: Individualized, unrestricted antiretroviral therapy. MEASUREMENTS: Patients were classified into four groups by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. RESULTS: Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P = 0.009 for linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log10 copies/ml increase in HIV RNA and a loss of 19 x 10(6) CD4 cells/l compared with a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72 x 10(6) CD4 cells/l in those reporting 100% adherence (P = 0.02). CONCLUSION: Self-reported poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.

Adult↗
PubMed1999

Successful short-term suppression of clarithromycin-resistant Mycobacterium avium complex bacteremia in AIDS. California Collaborative Treatment Group.

During a randomized study of clarithromycin plus clofazimine with or without ethambutol in patients with AIDS and Mycobacterium avium complex (MAC) bacteremia, eight participants received additional antimycobacterial drugs following the detection of a clarithromycin-resistant isolate (MIC, > 8 micrograms/mL). A macrolide (seven received clarithromycin, one azithromycin) and clofazimine were continued; additional treatment included various combinations of ethambutol, ciprofloxacin, amikacin, and rifabutin. After the detection of a resistant isolate and before receipt of additional antimycobacterials, the median peak MAC colony count in blood was 105 cfu/mL (range, 8-81,500 cfu/mL). After additional antimycobacterials, the median nadir MAC colony count was 5 cfu/mL (range, 0-110 cfu/mL). Five (63%) of eight patients had a > or = 1 log10 decrease, including two who achieved negative blood cultures; all of these responses occurred in patients originally assigned to clarithromycin plus clofazimine. Treatment of clarithromycin-resistant MAC bacteremia that emerges during clarithromycin-based treatment can decrease levels of bacteremia and transiently sterilize blood cultures.

AIDS-Related Opportunistic Infections↗
PubMed1999

Pharmacokinetics of trimetrexate and dapsone in AIDS patients with Pneumocystis carinii pneumonia.

The objective of this study was to determine the pharmacokinetics of trimetrexate and dapsone in AIDS patients with moderate to severe pneumocystis pneumonia. Trimetrexate, leucovorin, and dapsone were administered for 21 +/- 3 days in the following doses: trimetrexate glucuronate, 45 mg/m2; leucovorin, 20 mg/m2; and dapsone, 100 mg daily. The pharmacokinetics of trimetrexate, dapsone, and dapsone's metabolite, monoacetyldapsone, were determined at three separate periods over the course of treatment. Serial blood samples were obtained over 24 hours after dosing and analyzed for trimetrexate, dapsone, and monoacetyldapsone, and pharmacokinetic parameters were determined. The mean parameters obtained for the early, mid-, and late collection periods were the following: trimetrexate: t1/2 = 8.29, 9.15, 10.00 hr; AUC = 16.85, 22.38, 24.49 mg.hr/l; CI = 5.58, 4.14, 3.96 l/hr, respectively. DDS: t1/2 = 14.99, 16.59, 15.13 hr; AUC = 30.60, 35.29, 36.08 mg.hr/l; CI = 3.82, 3.49, 3.01 l/hr, respectively. Monoacetyldapsone: t1/2 = 20.25, 18.66, 16.32 hr; AUC = 24.05, 24.06, 23.86 mg.hr/l, respectively. No statistically significant changes in pharmacokinetics for trimetrexate or dapsone were observed over the 21 +/- 3 day course of treatment. The results suggest that there are no major interactions between trimetrexate and dapsone when administered together in acutely ill patients.

AIDS-Related Opportunistic Infections↗
PubMed1998

Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS.

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

AIDS-Related Opportunistic Infections↗
PubMed1997

Genomic structure of the human GT334 (EHOC-1) gene mapping to 21q22.3.

Several inherited diseases have been mapped to the distal tip of human chromosome 21. In our recent efforts to clone candidate genes for some of these disorders, we have assembled a cosmid and BAC contig spanning 770 kb. We have identified expressed sequences from this contig by means of a cDNA hybrid selection scheme. We present here the isolation, cDNA sequence, genomic organization, and polymorphisms analysis of one such expressed sequence, GT334, which had been identified independently and designated EHOC-1. GT334 is split into 23 exons, and spans an estimated 95 kb of genomic DNA. A pseudogene of the histone H2AZ gene has been identified, and maps within the third intron. We have identified an ORF potentially encoding a protein 1259 amino acids in length, longer than that described in the EHOC-1 gene. The GT334 gene was screened for single base pair changes using single-strand conformation polymorphism (SSCP) analysis and we have identified seven sequence variations within this gene. These polymorphisms can be used as markers in the genetic mapping of other diseases localized to this region.

Amino Acid Sequence↗