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Biomedical subjects

J Feinberg

Publications and source records attributed to J Feinberg.

At least 55 records · Page 3Linked to original sources
PubMed1998

Genomic structure of the human pre-T cell receptor alpha chain and expression of two mRNA isoforms.

The pre-TCR, which is minimally composed of the TCRbeta chain, the pre-Talpha chain, and the CD3 complex, regulates early T cell development. The pre-Talpha chain is a 33-kDa type I transmembrane glycoprotein with an extracellular part similar to the constant domain of the immunoglobulin supergene family. We have sequenced (11 kb) the human pTalpha gene, which like the murine pTalpha gene consists of four exons: exon 1 encodes the 5' untranslated region, the leader peptide and the first three amino acids of the mature protein, exon 2 the extracellular immunoglobulin (Ig)-like domain, exon 3 a 15-amino acid peptide including a cysteine required for heterodimerization with TCRbeta, exon 4 the transmembrane region, the cytoplasmic tail and the 3' untranslated sequence. The human pTalpha gene is located on chromosome 6p21.3, close to the HLA-A locus. Reverse transcription-PCR studies with human thymus and leukemic cells showed that alternative splicing produces a shorter pTalpha isoform, which lacks the Ig-like domain but contains the transmembrane elements and the extracytoplasmic cystein and which could thus permit pairing with TCRbeta chain and association with CD3 molecules. The conserved splice sites suggest a yet ill-defined biological function of the short pTalpha protein.

Humans↗
PubMed1998

Coevolution of actin and associated proteins: an alpha-actinin-like protein in a cyanobacterium (Spirulina platensis).

Actin, together with associated proteins, such as myosin, cross-linking or capping proteins, has been observed in all eukaryotic cells. Presence of actin or actin-like proteins has also been reported in prokaryotic organisms belonging to the cyanobacteria. Our aim was first to extend the characterization of an actin-like protein to another prokaryotic cell, i.e. Spirulina, then to compare the antigenic reactivity of this new protein with that of Synechocystis and skeletal actins. We observed that some of the conserved antigenic epitopes corresponded to actin regions known to interact with cross-linking proteins. We also report for the first time that alpha-actinin and filamin purified from chicken gizzard both interact with a prokaryotic actin-like protein. Finally, we searched for the occurrence of a cross-linking protein in these cyanobacteria and identified a 105-kDa protein as an alpha-actinin-like protein using specific antibodies.

Actinin↗
PubMed1998

On the role of the pre-T cell receptor in alphabeta versus gammadelta T lineage commitment.

The role of the pre-T cell receptor (TCR) in lineage commitment to the gammadelta versus alphabeta lineage of T cells was addressed by analyzing TCRbeta chain rearrangements in gammadelta T cells from wild-type and pre-TCR-deficient mice by single cell polymerase chain reaction. Results show that the pre-TCR selects against gammadelta T cells containing rearranged Vbeta genes and that gammadelta T cell precursors but not gammadelta T cells express the pre-TCRalpha protein. Furthermore, pre-TCR-induced proliferation could not be detected in gammadelta T cells. We propose that the pre-TCR commits developing T cells to the alphabeta lineage by an instructive mechanism that has largely replaced an evolutionary more ancient stochastic mechanism of lineage commitment.

Animals↗
PubMed1998

Crucial function of the pre-T-cell receptor (TCR) in TCR beta selection, TCR beta allelic exclusion and alpha beta versus gamma delta lineage commitment.

The analysis of T-cell receptor (TCR) beta selection, TCR beta allelic exclusion and TCR beta rearrangement in gamma delta T cells from normal and pre-TCR-deficient mice has shown that the pre-TCR has a crucial role in T-lymphocyte development: The pre-TCR is by far the most effective receptor that generates large numbers of CD4+8+ T cells with productive TCR beta rearrangements. In the absence of the pre-TCR, TCR beta rearrangement proceeds in developing cells irrespective of whether they already contain a productive TCR beta gene. The pre-TCR directs developing T cells to the alpha beta lineage because gamma delta T cells from pT alpha-/- mice proceed much further in TCR beta rearrangement than gamma delta T cells from wild-type mice. It is argued that the pre-TCR commits developing T cells to the alpha beta lineage by an instructive mechanism, which has largely replaced an evolutionarily more ancient mechanism that involves stochastic alpha beta lineage commitment.

Alleles↗
PubMed1998

Sickness and wickedness: new conceptions and new paradoxes.

This article is a discussion of the conceptual relationship between wickedness and (mental) illness, quite apart from their uses in the criminal law. One of the these defended in the article is that in ordinary language illness has lost much of its power to mitigate and excuse, so that "sickos" are treated as if they were some strange minority or political sect.

Forensic Psychiatry↗
PubMed1997

Localization of a calcium sensitive binding site for gelsolin on actin subdomain I: implication for severing process.

The binding of the N-terminal domain (S1) of gelsolin to monomeric actin has been extensively documented. In contrast, the location of the C-terminal calcium dependent domains (S4-6) interacting with the actin filament during the severing process remains uncertain. In this study, we have identified a new interface that supports calcium dependent gelsolin binding to actin. This site is located in a critical position towards actin-actin contact in the filament and in the vicinity of the phalloidin site. Using specific antibody and synthetic peptides derived from actin sequence within 105-132 residues, this interface was finally ascribed to the segment 112-120 on the actin subdomain-1.

Actins↗
PubMed1997

Conformational and functional studies of three gelsolin subdomain-1 synthetic peptides and their implication in actin polymerization.

Gelsolin, a calcium and inositol phospholipid-sensitive protein, regulates actin filament length. Its activity is complex (capping, severing, etc.) and is supported by several functional domains. The N-terminal domain alone (S1), in particular, is able to impede actin polymerization. Our investigations were attempted to precise this inhibitory process by using synthetic peptides as models mimicking gelsolin S1 activity. Three peptides issued from S1 and located in gelsolin-actin interfaces were synthesized. The peptides (15-28, 42-55, and 96-114 sequences) were tested for their conformational and actin binding properties. Although the three peptides interact well with actin, only peptide 42-55 affects actin polymerization. A detailed kinetic study shows that the latter peptide essentially inhibits the nucleation step during actin polymerization. In conclusion, the present work shows that the binding of a synthetic peptide to a small sequence located outside the actin-actin interface is essential in the actin polymerization process.

Actins↗
PubMed1997

The effect of mode of administration on medical outcomes study health ratings and EuroQol scores in AIDS.

Brief measures of health-related quality of life are being used with increased frequency in AIDS clinical trials. Self-administration of questionnaires can reduce costs in this setting because they require little time. However, the equivalence between self- and interview-administered responses in clinical trials is not known. We evaluated patient and proxy responses to the Medical Outcomes Study HIV Health Survey (MOS-HIV) and the EuroQol. We randomized 68 patients with advanced HIV disease on (1) mode of administration (self vs. interview); (2) type of interview (face-to-face vs. telephone); (3) questionnaire order (MOS-first vs. EuroQol-first); and (4) 2- vs. 3-item response categories for physical limitations. There were few differences in scores between self and interview administration and type of interview. Proxy respondents viewed patients as more impaired than did patients themselves on subjective aspects of health including mental health (63.8 vs. 75.7, p < 0.001), health distress (67.3 vs. 77.1, p = 0.007), pain (64.4 vs. 70.0, p = 0.04), and vitality (48.4 vs. 55.5, p = 0.04). Results concerning questionnaire order and number of response categories were not conclusive. Our results suggest that for patients with advanced HIV disease, data from the MOS-HIV and the EuroQol collected using different modes may be pooled, but that proxy responses should be calibrated.

Adult↗
PubMed1997

A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS.

The safety and efficacy of cidofovir gel for treatment of acyclovir-unresponsive herpes simplex virus infections in AIDS patients was evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3% or 1%) or placebo gel was applied once daily for 5 days. Ten of 20 cidofovir-treated and none of 10 placebo-treated patients had complete healing or >50% decreased area (P = .008); 30% of cidofovir-treated patients versus 0 placebo recipients had complete healing (P = .031). Viral shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9 placebo-treated patients (P = .00004). For cidofovir-treated patients, median time to complete or good response was 21 days, and median time to negative viral culture was 2 days (P = .025, P = .0001, respectively). Median lesion area decreases were 58% for cidofovir-treated versus 0 for placebo-treated patients (P = .005), and mean pain score changes were -1.84 versus -0.34 (P = .042). Application site reactions occurred in 25% of cidofovir-treated and 20% of placebo-treated patients; none was dose-limiting. Cidofovir therapy provided significant benefits in lesion healing, virologic effect, and pain reduction.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Hydroxyapatite coated implants. Total hip arthroplasty in the young patient and patients with avascular necrosis.

Two high risk groups for total hip arthroplasty, 136 patients (155 hips) younger than 50 years of age (average age, 38 years) and 44 patients (53 hips) with the diagnosis of avascular necrosis, have a minimum followup of 5 years and a mean followup of 6.8 years. The average Harris Hip Score at last followup totaled 93 and 90, respectively, and thigh pain was reported in 1.3% and 3.8%, respectively. All patients in both groups received the same hydroxyapatite coated femoral stem and the mechanical failure was 0%. No stem was revised for aseptic loosening, 100% of stems were bony stable by radiographic criteria, new bone formation was progressive about the femoral stem, and 0% endosteal lysis was found. The acetabular components had a mechanical failure rate of 10% and 7.5%, respectively, without osteolysis, and an additional 7% and 7.5% failure as a direct result of progressive osteolysis. The results with the porous press fit and hydroxyapatite threaded sockets were far superior to that of the smooth hydroxyapatite press fit sockets and socket failure was associated with thin polyethylene liners and the use of 32-mm head diameters. These findings show a high success rate with a nonporous hydroxyapatite coated titanium femoral stem. However, hydroxyapatite on a smooth acetabular component yielded less predictable results indicating that for long term fixation of the acetabulum an interlock of bone is preferred.

Adolescent↗
PubMed1996

Pilot study of topical trifluridine for the treatment of acyclovir-resistant mucocutaneous herpes simplex disease in patients with AIDS (ACTG 172). AIDS Clinical Trials Group.

SUMMARY: Twenty-six AIDS patients were enrolled in an open label pilot study to evaluate the efficacy and toxicity of topical 1 percent ophthalmic trifluridine solution for the treatment of chronic mucocutaneous herpes simplex virus disease unresponsive to at least 10 days of acyclovir therapy. Susceptibility testing to acyclovir, trifluridine, and foscarnet was determined by plaque reduction assay. Twenty-four patients were evaluable for efficacy and 25 for toxicity analyses. Seven patients (29 percent) had complete healing of lesions. The overall estimated median time to complete healing was 7.1 weeks. An additional seven patients had > or = 50 percent reduction in lesion area. The overall estimated median time to 50 percent healing was 2.4 weeks. Ten (42 percent) patients discontinued treatment for reasons other than primary treatment failure and seven (29 percent) for failure to respond to therapy. Baseline patient characteristics associated with greater reduction in lesion area included higher Karnofsky score (p = 0.05), fewer lesions (p = 0.07), smaller lesion area (p = 0.11), and trifluridine susceptibility (p = 0.07). Eight (33 percent) patients developed new lesions outside of the treatment area while on study, reflecting the local nature of this therapy. No dose-limiting toxicity attributable to trifluridine was reported. Given the limited options for the treatment of acyclovir-resistant herpes simplex disease, topical trifluridine may be a useful alternative in selected patients.

AIDS-Related Opportunistic Infections↗
PubMed1996

The N-terminal sequences (5-20) of thymosin beta 4 binds to monomeric actin in an alpha-helical conformation.

The relationship between the conformation of a peptide in solution and its interaction capacity is generally unclear. Trifluoroethanol (TFE), which stabilizes alpha-helical conformations, can be used to induce definite folding in synthetic peptides. The N-terminal part of thymosin beta 4, including the 5-20 sequences, is implicated in binding to monomeric actin. The corresponding peptide was synthesized and its conformation studied by CD. The peptide is unstructured in solution, and becomes folded at medium TFE concentrations, below 30%. In contrast, TFE does not significantly modify the conformation of monomeric actin which conserves its intrinsic properties, such as gelsolin interaction and DNase-I inactivation. We report here that the apparent affinity of the synthetic peptide to monomeric actin is increased by an order of magnitude in the presence of TFE, which implies that the peptide adopts a folded conformation needed for accurate interaction.

Actins↗
PubMed1996

Patterns of opportunistic infections in patients with HIV infection.

The pattern of the development of opportunistic infections (OIs) in HIV-infected patients was evaluated, based on a cohort of 1,530 patients enrolled in two AIDS Clinical Trials Group anti-retroviral studies. We quantified the increase in risk of OIs associated with the occurrence of a previous OI. This assessment was based on the observed event rates of the more common AIDS-defining OIs: Pneumocystis carinii pneumonia (PCP), Mycobacterium avium complex (MAC), cytomegalovirus (CMV), and a systemic mycosis. Additionally, for each OI, we assessed the relative risks associated with a history of prior OIs, changes in CD4 levels, and baseline prognostic factors. We found that the occurrence of each of these OIs increased the risk of subsequent OIs, even after adjusting for the CD4 count. Specifically, the occurrence of PCP significantly increased the risk of MAC and CMV, and somewhat increased the risk of systemic mycoses. Diagnosis with MAC was associated with an increased risk of subsequent CMV, whereas the occurrence of CMV increased the risk of MAC. Finally, once patients were diagnosed with a systemic mycosis, they were at a somewhat increased risk of subsequently developing MAC or CMV. Although current practice for determining the timing and initiation of prophylactic therapies relies chiefly on CD4 count, the occurrence of specific AIDS-defining OIs in patients with HIV infection should also be taken into account in making decisions regarding prophylaxis strategies.

AIDS-Related Opportunistic Infections↗
PubMed1996

Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group.

OBJECTIVE: To compare the tolerability and efficacy of three oral regimens for the treatment of patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia. DESIGN: A randomized, double-blind study. SETTING: 24 U.S. academic medical centers. PATIENTS: 181 patients with morphologically confirmed P. carinii pneumonia and alveolar-arterial oxygen differences (PAO2-PaO2) of 45 mm Hg or less. INTERVENTION: Patients were randomly assigned to receive trimethoprim-sulfamethoxazole, dapsone-trimethoprim, or clindamycin-primaquine for 21 days. Patients with a PAO2-PaO2 of 35 to 45 mm Hg at study entry also received prednisone. MEASUREMENTS: Serial clinical and laboratory evaluations for therapeutic response and toxicity. Therapeutic failure at day 21 was defined by any of the following: increase in PAO2-PaO2 of greater than 20 mm Hg; no remission of baseline signs and symptoms; and change in antipneumocystis therapy for reasons other than toxicity, intubation, or death. Dose-limiting toxicity was defined as discontinuation of therapy by the primary physician because of one or more adverse reactions. RESULTS: No statistically significant differences were seen among treatment groups in the proportions of patients who had dose-limiting toxicity (P=0.2), therapeutic failure (P>0.2), or a complete course of therapy (P>0.2). Survival during therapy or for 2 months thereafter did not differ among the three groups (P>.02). However, elevation of serum aminotransferase levels to more than five times the baseline levels was more frequent in the trimethoprim-sulfamethoxazole group (P=0.003), and one or more serious hematologic toxicities (neutropenia, anemia, thrombocytopenia, or methemoglobinemia) occurred more frequently in the clindamycin-primaquine group (P=0.01). CONCLUSIONS: The rates of dose-limiting toxicity, therapeutic failure, and survival did not differ among patients with AIDS who were receiving oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, or clindamycin-primaquine for mild to moderate P. carinii pneumonia. However, the limited sample size prevents the unequivocal demonstration of the equality of these three regimens. Differences in expected categories of toxicities associated with each regimen should guide the clinician in choosing first-line therapy, particularly for patients with baseline hepatic insufficiency or myelosuppression.

AIDS-Related Opportunistic Infections↗
PubMed1996

Fever in patients with HIV infection.

Fever is a common sign during the course of HIV infection, usually represents a superimposed opportunistic infection, and is almost always a treatable condition. Proper management generally requires detection of the underlying cause, and the diagnostic evaluation is largely driven by the clinical symptoms, associated conditions such as injection drug use, and stage of disease based largely on the absolute CD4 cell count. This article provides guidelines for the management of fever in the patient with HIV infection.

Bacterial Infections↗
PubMed1996

Low-dose zalcitabine-related toxic neuropathy: frequency, natural history, and risk factors.

We studied the features and frequency of sensory neuropathy among 79 HIV-1-infected individuals participating in a multicenter clinical trial of zalcitabine (2'3'-dideoxycytidine, or ddC) antiretroviral therapy. The trial compared zalcitabine monotherapy (2.25 mg/day) versus combination therapy (2.25 mg/day ddC) with zidovudine (ZDV, formerly AZT) versus monotherapy with ZDV alone. Neuropathy developed in 34% of ddC recipients but in only 4% of comparable patients treated with ZDV alone--a 7.9-fold increase in the attack rate of neuropathy. Using risk factor analysis, we found that diabetes mellitus was significantly associated with the development of toxic neuropathy (p = 0.02), and weight loss may contribute to its appearance. Like HIV-associated sensory neuropathy, ddC-related toxic neuropathy is a predominantly sensory, length-dependent, symmetric, painful neuropathy. Dose reduction lessened the severity of symptoms, although objective signs of neuropathy persisted. Patients with subclinical neuropathies or significant neuropathy risks such as diabetes may be poor candidates for ddC therapy.

Adult↗