PubMed Health⌕ Search

Biomedical subjects

J Feinberg

Publications and source records attributed to J Feinberg.

At least 19 recordsLinked to original sources
PubMed2006

Impaired interferon-gamma production in response to live bacteria and Toll-like receptor agonists in patients with ataxia telangiectasia.

Ataxia telangiectasia (AT) is a pleiotropic autosomal recessive neurodegenerative disorder with associated immunodeficiency and cancer predisposition, caused by mutational inactivation of the ATM gene. Early death usually results from lymphoreticular malignancy or recurrent, chronic respiratory infections. Immune deficiency of AT patients is heterogeneous and involves both humoral and cellular responses. Reports on the number and integrity of immunocompetent cells in AT are conflicting. In the early phase of infection, the interleukin (IL)-12/interferon (IFN)-gamma axis plays a crucial role in first-line defence against pathogens. In a whole blood assay we studied the IL-12/IFN-gamma axis in the immune response of AT cells to the Toll-like receptor agonists lipopolysaccharide and heat-killed Staphylococcus aureus, as well as whole live M. bovis bacille Calmette-Guérin (BCG). The function of AT antigen-presenting cells was normal in terms of IL-12 production, while IFN-gamma production by T and natural killer (NK) cells was severely impaired, even in the presence of adequate co-stimulation by exogenous IL-12.

Adolescent↗
PubMed2005

[Genetic susceptibility to mycobacterial disease: Mendelian disorders of the interleukin-12 -interferon-gamma axis].

INTRODUCTION: Environmental non tuberculous mycobacteria and Bacillus Calmette-Guerin vaccines are weakly virulent mycobacteria. Nevertheless they may cause severe diseases in otherwise healthy children with no overt immunodeficiency. Parental consanguinity and familial forms are frequently observed among these patients, therefore this syndrome was named "Mendelian Susceptibility to Mycobacterial Disease". STATE OF THE ART: In the last nine years, fife genes have been found to be mutated in patients with this syndrome: IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1. Allelic heterogeneity accounts for ten distinct genetic disorders. Clinical phenotype differs between patients. The spectrum of disease extends from early-onset overwhelming mycobacterial infection to adult-onset localized disease and tuberculosis. Impaired IFN-gamma-mediated immunity is the common mechanism of the disease, outlining its major role in mycobacterial immunity. PERSPECTIVES AND CONCLUSIONS: Better understanding of these disorders reveals an expanding clinical phenotype which justifies studying adult patients with pulmonary non tuberculous mycobacterial infection without known risk factors, severe BCGitis and recurrent tuberculosis. Molecular diagnosis makes it possible to introduce a specific regimen based on physiopathology.

Anti-Bacterial Agents↗
PubMed2005

Gamma interferon is dispensable for neopterin production in vivo.

Previous studies have indicated that neopterin is synthesized in vitro by human monocyte-derived macrophages and dendritic cells upon stimulation with gamma interferon (IFN-gamma). Neopterin production under specific conditions in vitro has also been obtained upon stimulation with IFN-alpha and/or IFN-beta. However, it is unknown if any IFN-gamma-independent neopterin synthesis is possible in vivo. In the present study we investigated the serum neopterin concentrations in patients affected by the syndrome of Mendelian susceptibility to mycobacterial disease (MSMD). Indeed, this syndrome is characterized by deeply impaired or absent IFN-gamma production or function due to severe mutations in molecules involved in IFN-gamma/interleukin-12 (IL-12)/IL-23-dependent pathway. Serum neopterin levels were measured by an enzyme-linked immunosorbent assay in 27 patients with MSMD. We found that serum neopterin levels are elevated in the complete absence of IFN-gamma activity due either to a complete deficiency of its receptor or to deleterious mutations of IL-12 or its receptor. These data clearly indicate that, as reported from in vitro studies, other stimuli are able to induce neopterin synthesis in vivo. Consequently, neopterin cannot be used as means of diagnosis of MSMD due to IFN-gamma-, IL-12-, and IL-23-dependent pathway defects.

Adolescent↗
PubMed2002

Inherited disorders of IL-12- and IFNgamma-mediated immunity: a molecular genetics update.

In the last 6 years, considerable advances have been made in the molecular analysis of a rare clinical syndrome: Mendelian susceptibility to mycobacterial disease (MSMD). Infection with poorly virulent environmental non-tuberculous mycobacteria (NTM) or vaccination with bacillus Calmette-Guerin (BCG) may cause disseminating and even fatal disease in individuals suffering from this syndrome. Mutations in five genes (IFNGR1, IFNGR2, STAT1, IL12B and IL12RB1) have been shown to be responsible for MSMD and further allelic heterogeneity accounts for the existence of nine distinct inherited disorders. All of these disorders are caused by impaired IFNgamma-mediated immunity. These results have important medical and biological implications. In this report, we update the disease-causing mutations reported in the literature.

Adult↗
PubMed2002

Validity and responsiveness of the euroqol as a measure of health-related quality of life in people enrolled in an AIDS clinical trial.

OBJECTIVE: Brief utility measures are needed in clinical trials in addition to existing descriptive measures of health-related quality of life (HRQOL). We examined the reliability and validity of the EuroQol (EQ-SD) and MOS-HIV and their responsiveness to HIV-related clinical events. METHODS: Subjects with advanced HIV disease (CD4 < 100) were enrolled in a randomized trial for CMV prophylaxis (n = 990). The EQ-5D includes a weighted sum of five domains (EQ-5D Index) and a visual analog scale (EQ-VAS). The MOS-HIV has 10 subscales and physical (PHS) and mental health summary scores (MHS). Construct validity of the EQ-5D was tested based on hypothesized relationships to subscales of the MOS-HIV. Relative precision and responsiveness to adverse experiences and opportunistic infections (Ols) were compared for the two instruments. RESULTS: Mean age of the patients was 38, 94% were male, 80% white, and 7% had injected drugs. Mean baseline scores for EQ-5D Index and EQ-VAS were 0.80 and 76.0, respectively, 28 and 4% reported maximum scores. Mean MOS-HIV subscales score ranged from 55 (role) to 84 (cognitive); mean PHS and MHS were 47.4 and 49.5, respectively. Correlations between MOS-HIV subscales and EQ-5D Index ranged from 0.45 (role) to 0.63 (pain); correlations with EQ-VAS ranged from 0.33 (cognitive) to 0.66 (health perceptions). Correlations between MOS-HIV PHS and MHS with EQ-5D Index were 0.61 and 0.58; and with EQ-VAS, 0.57 and 0.60, respectively. Responsiveness to adverse experiences was highest for MOS-HIV pain and PHS (effect sizes = 0.9 and 0.4); pain had the highest relative precision (2.4) for adverse experiences: EQ-VAS had the greatest relative precision (1.6) for developing an OI. CONCLUSION: In these patients with advanced HIV disease. EQ-5D showed good construct validity, but there may be a ceiling effect for its EQ-5D Index component. EQ-5D was less responsive to adverse events than the MOS-HIV. However, the EQ-VAS was most sensitive to developing an OI and is likely to be a useful measure of HRQOL for generating QALYs in cost-utility studies involving patients with advanced HIV disease.

AIDS-Related Opportunistic Infections↗
PubMed2001

Mechanism of indinavir-induced hyperbilirubinemia.

Indinavir is a viral protease inhibitor used for the treatment of HIV infection. Unconjugated hyperbilirubinemia develops in up to 25% of patients receiving indinavir, prompting drug discontinuation and further clinical evaluation in some instances. We postulated that this side-effect is due to indinavir-mediated impairment of bilirubin UDP-glucuronosyltransferase (UGT) activity and would be most pronounced in individuals with reduced hepatic enzyme levels, as occurs in approximately 10% of the population manifesting Gilbert's syndrome. This hypothesis was tested in vitro, in the Gunn rat model of UGT deficiency, and in HIV-infected patients with and without the Gilbert's polymorphism. Indinavir was found to competitively inhibit UGT enzymatic activity (K(I) = 183 microM) while concomitantly inducing hepatic bilirubin UGT mRNA and protein expression. Although oral indinavir increased plasma bilirubin levels in wild-type and heterozygous Gunn rats, the mean rise was significantly greater in the latter group of animals. Similarly, serum bilirubin increased by a mean of 0.34 mg/dl in indinavir-treated HIV patients lacking the Gilbert's polymorphism versus 1.45 mg/dl in those who were either heterozygous or homozygous for the mutant allele. Whereas saquinavir also competitively inhibits UGT activity, this drug has not been associated with hyperbilirubinemia, most likely because of the higher K(I) (360 microM) and substantially lower therapeutic levels as compared with indinavir. Taken together, these findings indicate that elevations in serum-unconjugated bilirubin associated with indinavir treatment result from direct inhibition of bilirubin-conjugating activity.

Animals↗
PubMed2001

Impact of prophylaxis for Mycobacterium avium complex on bacterial infections in patients with advanced human immunodeficiency virus disease.

The epidemiology and natural history of bacterial infections among ambulatory patients with advanced human immunodeficiency virus (HIV) disease has not been well described. In this prospective study, 394 subjects were enrolled and followed at 8-week intervals for a median of 21 months. During follow-up, 164 (42%) of 394 patients developed at least 1 bacterial infection. The most common infections were sinusitis, bacterial pneumonia, skin and soft tissue infection, and bronchitis. Serious bacterial infections (defined as bacterial pneumonia, bacteremia, or deep visceral abscess) were reported by 56 subjects (14%). Female sex, age of <40 years, and Karnofsky score of < or =80 were independent risk factors for bacterial infections. Prophylaxis with clarithromycin, trimethoprim and sulfamethoxazole, or both had significant protective effect. The occurrence of any confirmed bacterial infection was associated with a significantly increased risk of mortality. This study documents that bacterial infections are common among patients with advanced HIV disease, especially among women.

AIDS-Related Opportunistic Infections↗
PubMed2001

Loss of cytomegalovirus-specific CD4+ T cell responses in human immunodeficiency virus type 1-infected patients with high CD4+ T cell counts and recurrent retinitis.

Clinical histories are reported for 2 patients treated with highly active antiretroviral therapy (HAART) who experienced multiple relapses of cytomegalovirus (CMV) retinitis, despite suppression of human immunodeficiency virus type 1 (HIV-1) viremia and improvement in CD4+ T cell counts (to >400 cells/microL). CMV-specific CD4+ T cell immune reconstitution was measured directly, using cytokine flow cytometry, which revealed persistent deficits in CMV-specific CD4+ T cell responses in both patients. CMV-specific T cells constituted 0.14% and 0.05% of the total CD4+ T cell count in these patients, which is significantly lower than the percentages for 34 control subjects (0.6%-46%; CD4+ T cell count range, 7-1039 cells/microL; P=.019). Deficits in pathogen-specific immune responses may persist in some individuals, despite suppression of HIV-1 replication and substantial increases in circulating CD4+ T cells after HAART, and such deficits may be associated with significant morbidity from opportunistic infections.

AIDS-Related Opportunistic Infections↗
PubMed2001

Prevalence and genotypic variability of TTV in HIV-infected patients.

TT virus is a small, circular DNA virus, that has been associated with transfusion hepatitis. We sought to determine the prevalence of TT virus (TTV) in patients with human immunodeficiency virus (HIV) infection and to characterize the virus in terms of genotypic variability and in the relationship to CD4+, HIV viral loads, HCV/HIV coinfection, and ALT abnormalities. A cross-sectional analysis of HIV-infected patients in the United States, including 86 HIV-positive subjects and 118 HIV-negative controls was performed. TTV was detected using a seminested PCR technique. Samples underwent cloning and sequence analysis and/or RFLP to determine genotype. Thirty-eight percent of HIV-positive patients had TTV infection versus 14.4% of patients within the matching cohort (P = 0.0009). The highest rate of TTV infection was in patients with concurrent HCV/HIV infection (54% vs 30%, P = 0.038). HIV-infected subjects with TTV had lower ALT levels than those without TTV (P = 0.036). Intravenous drug use was the leading factor associated with TTV positivity among HIV-positive subjects. Mixed genotypes were more common in those with HIV. Therefore, TTV prevalence, ALT levels, and genomic heterogeneity of TTV all seem to be altered in patients with HIV.

Adult↗
PubMed2001

X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.

The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.

Adolescent↗