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Biomedical subjects

B A Cohen

Publications and source records attributed to B A Cohen.

At least 19 recordsLinked to original sources
PubMed2002

A randomized clinical trial of CPI-1189 for HIV-associated cognitive-motor impairment.

BACKGROUND: CPI-1189 is a compound with antioxidant properties that blocks tumor necrosis factor-alpha (TNFalpha) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease. OBJECTIVE: To assess the tolerability and safety of CPI-1189 in treating HIV-associated cognitive-motor impairment. METHODS: Sixty-four subjects with mild to moderate HIV-associated cognitive-motor impairment were randomized to receive either placebo or 50 or 100 mg daily of CPI-1189 in addition to optimal HIV therapy. Subjects were followed prospectively in a double-masked study for 10 weeks. The primary assessment was tolerability and safety of the compound. Secondary objectives examined neuropsychological and functional change associated with this treatment. RESULTS: The study compound was well tolerated, with 91% of CPI-1189-treated subjects and 76% of placebo-treated subjects completing the trial. Skin rash was seen equally in placebo and active arms, but the only study withdrawals due to skin rash occurred in CPI-1189-treated subjects (n = 2). One subject developed a cataract on drug (100 mg/day). CD4 lymphocyte counts and plasma HIV viral load remained stable in all groups throughout the trial. No significant treatment effects were observed on the change in composite Z-scores for eight neuropsychologic measures (NPZ-8). The Grooved Pegboard Test (nondominant) showed improved performance with CPI-1189 at 100 mg/day (p = 0.01), but no other neuropsychometric or functional measures demonstrated significant improvement. CONCLUSIONS: CPI-1189 was well tolerated in HIV subjects with cognitive-motor disorder. This study was not powered to conclusively determine efficacy and showed no consistent treatment-associated improvement in cognitive or functional measures.

AIDS Dementia Complex↗
PubMed2002

Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy.

OBJECTIVE: To explore the relationship between intraepidermal nerve fiber (IENF) density in HIV-associated sensory neuropathy (HIV-SN) to measurements of neuropathy severity and progression of HIV disease. BACKGROUND: SN affects 30% of individuals with AIDS, and treatment is often ineffective. Recombinant human nerve growth factor (rhNGF) has been proposed as a trophic factor for unmyelinated nerve fibers injured in HIV-SN, and a clinical trial has recently concluded. Skin biopsy with IENF density determination has emerged as a diagnostic test for patients with small-fiber sensory neuropathy. METHODS: Sixty-two of the 270 patients with HIV-SN who participated in the trial of rhNGF were included in a substudy examining epidermal nerve fibers. IENF density was compared with neuropathic pain intensity (measured with the Gracely Pain Scale), patient and physician global pain assessments, quantitative sensory testing, CD4 counts, and plasma HIV RNA levels both at baseline and at conclusion of the placebo-controlled phase. RESULTS: IENF density was inversely correlated with neuropathic pain as measured by patient (p = 0.004) and physician (p = 0.05) global pain assessments, but not using the Gracely Pain Scale. Decreased IENF density at the distal leg was associated with lower CD4 counts and higher plasma HIV RNA levels. IENF density measurements were stable over time. CONCLUSIONS: IENF loss at the distal leg is associated with increased neuropathic pain, lower CD4 counts, and higher plasma viral load in HIV-SN. The robustness of the longitudinal measurement of IENF density supports its use in future longitudinal studies and clinical trials.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathy.

HIV-associated distal sensory polyneuropathy (DSP) is a common complication of AIDS. No effective treatment is available. The authors investigated the long-term effect (48 weeks) of the neurotrophin nerve growth factor (NGF) in an open-label study of 200 subjects with HIV-associated DSP. Similar to their previously reported double-blind study, the authors showed that NGF was safe and well tolerated and significantly improved pain symptoms. However, there was no improvement of neuropathy severity as assessed by neurologic examination, quantitative sensory testing, and epidermal nerve fiber density.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Clinical applications of new cerebrospinal fluid analytic techniques for the diagnosis and treatment of central nervous system infections.

Advances in molecular biology and immunology provide new, highly sensitive and specific techniques that can be applied to analysis of cerebrospinal fluid to enhance the diagnosis and treatment of central nervous system (CNS) infections. In addition to improved accuracy and speed of diagnosis, these modalities may offer improved means of monitoring treatment efficacy, establishing prognosis, detecting organism resistance, and tracking epidemic sources. This brief review discusses a number of recent papers applying these methods, in order to illustrate their value and significance for clinical neurologic practice. Some of these applications are commonly available, whereas others are likely to enter the physician's armamentarium in the near future. As they do, they can be expected to improve the treatment of CNS infections.

Bacteriological Techniques↗
PubMed2000

Support for the lunar cataclysm hypothesis from lunar meteorite impact melt ages.

Lunar meteorites represent a more random sampling of lunar material than the Apollo or Luna collections and, as such, lunar meteorite impact melt ages are the most important data in nearly 30 years with which to reexamine the lunar cataclysm hypothesis. Within the lunar meteorite breccias MAC 88105, QUE 93069, DaG 262, and DaG 400, seven to nine different impact events are represented with 40Ar-39Ar ages between 2.76 and 3.92 billion years ago (Ga). The lack of impact melt older than 3.92 Ga supports the concept of a short, intense period of bombardment in the Earth-moon system at approximately 3.9 Ga. This was an anomalous spike of impact activity on the otherwise declining impact- frequency curve.

Journal Article↗
PubMed2000

A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291.

OBJECTIVE: To evaluate the safety and efficacy of recombinant human nerve growth factor (rhNGF) in HIV-associated sensory neuropathy (SN) within a multicenter, placebo-controlled, randomized trial (ACTG 291). BACKGROUND: SN affects 30% of individuals with AIDS, is worsened by neurotoxic antiretrovirals, and its treatment is often ineffective. NGF is trophic for small sensory neurons and stimulates the regeneration of damaged nerve fibers. METHODS: A total of 270 patients with HIV-associated SN were randomized to receive placebo, 0.1 microg/kg rhNGF, or 0.3 microg/kg rhNGF by double-blinded subcutaneous injection twice weekly for 18 weeks. The primary outcome was change in self-reported neuropathic pain intensity (Gracely Pain Scale). Secondary outcomes included an assessment of global improvement in neuropathy by patients and investigators, neurologic examination, use of prescription analgesics, and quantitative sensory testing. In a subset, epidermal nerve fiber densities were determined in punch skin biopsies. RESULTS: Both doses of NGF produced significant improvements in average and maximum daily pain compared with placebo. Positive treatment effects were also observed for global pain assessments (p = 0.001) and for pin sensitivity (p = 0.019). No treatment differences were found with respect to mood, analgesic use, or epidermal nerve fiber densities. Injection site pain was the most frequent adverse event, and resulted in unblinding in 39% of subjects. Severe transient myalgic pain occurred in eight patients, usually from accidental overdosing. There were no changes in HIV RNA levels or other laboratory indices. CONCLUSIONS: We found a positive effect of recombinant human nerve growth factor on neuropathic pain and pin sensitivity in HIV-associated sensory neuropathy. rhNGF was safe and well tolerated, but injection site pain was frequent.

Adult↗
PubMed2000

A computational analysis of whole-genome expression data reveals chromosomal domains of gene expression.

Chromosome correlation maps display correlations between the expression patterns of genes on the same chromosome. Using these maps, we show here that adjacent pairs of genes, as well as nearby non-adjacent pairs of genes, show correlated expression independent of their orientation. We present specific examples of adjacent pairs with highly correlated expression patterns, in which the promoter of only one of the two genes contains an upstream activating sequence (UAS) known to be associated with that expression pattern. Finally, we show that genes with similar functions tend to occur in adjacent positions along the chromosomes. Our results suggest that, in certain chromosomal expression domains, an UAS can affect the transcription of genes that are not immediately downstream from it.

Cell Cycle↗
PubMed2000

Pauci-immune renal vasculitis: natural history, prognostic factors, and impact of therapy.

The purpose of this study is to describe the clinical presentation and natural history of pauci-immune renal vasculitis and determine whether particular presenting features or administered therapies predict outcome. We reviewed our experience since 1984 with such vasculitides, and 94 cases of pauci-immune vasculitis were identified. Presenting features were as follows: men, 63%; mean age at biopsy, 59 years; and mean serum creatinine level, 5.0 mg/dL. Patients with no extrarenal involvement had a tendency to present with a greater serum creatinine level. Since the antineutrophil cytoplasmic autoantibody (ANCA) assay became available, 77% of the patients tested were ANCA positive. In terms of natural history, 27 patients required dialysis immediately, there were 22 renal relapses, 28 patients progressed to dialysis, 10 patients died before requiring dialysis, 19 patients were lost to follow-up, and 37 patients remain active, not on dialysis. Overall, half the patients recovered some renal function, one third remained stable, and one sixth deteriorated. Female sex and angiotensin-converting enzyme inhibitor use predicted favorable outcome (P < 0.05). Advanced age, male sex, respiratory tract involvement, and a greater relapse rate predicted unfavorable outcome (P < 0.05). The incidence of pauci-immune renal vasculitis appears to be increasing, likely related to the emergence of the ANCA assay. Attempts to classify patients based on existing schemes may result in delayed diagnosis and therapy, with subsequent poorer outcomes. Also, given the increased mortality of patients with respiratory tract involvement, we speculate that respiratory tract disease therapeutic and monitoring regimens are ineffective. In general, we conclude that pauci-immune renal vasculitis is a heterogeneous disorder with an unfavorable prognosis.

Anti-Inflammatory Agents↗
PubMed1999

Neurologic manifestations of toxoplasmosis in AIDS.

Central nervous system (CNS) toxoplasmosis is the most common cause of cerebral mass lesions in AIDS patients. Toxoplasma gondii is commonly acquired through ingestion of contaminated meats resulting in latent infection. With the onset of immunosuppression, it may preferentially infect the CNS, resulting in a wide range of clinical presentations. Effective antibiotic therapy is available and capable of producing rapid remission of active infection but must be continued throughout life to prevent recurrence. Characteristic presentations and rapid therapeutic response permit presumptive diagnosis and initiation of specific antibiotics in many cases; however, appropriate clinical and radiographic monitoring to detect alternative or mixed pathologies is necessary. Unusual presentations may hinder rapid diagnosis and should be considered in AIDS patients with cryptic CNS symptoms. Despite increasing attention to primary prophylaxis, the worldwide distribution of this parasite, its potential to be the presenting illness in previously unidentified human immunodeficiency virus-infected individuals, and failures of prophylaxis are likely to make toxoplasmosis an important continuing source of neurologic morbidity in AIDS.

Animals↗
PubMed1999

Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy.

OBJECTIVE: To determine the predictive value of plasma HIV RNA and CD4 lymphocytes for HIV-associated dementia and sensory neuropathy. METHODS: A total of 1,604 AIDS-free HIV seropositive men from the Multicenter AIDS Cohort Study were followed over a 10-year period (1985 to 1995). HIV-associated dementia and sensory neuropathy were diagnosed according to standard definitions. Baseline samples were used to measure plasma HIV RNA levels with a branched DNA assay and levels of beta2-microglobulin, CD4 lymphocyte counts, and hemoglobin levels. RESULTS: Seventy-seven patients with HIV-associated dementia and 213 patients with sensory neuropathy were identified. Baseline HIV RNA levels above 3,000 copies/mL and CD4 counts below 500 cells/mm3 were predictive of both neurologic outcomes, but neither hemoglobin, body mass index, nor beta2-microglobulin were independently predictive. After adjusting for age and level of education, individuals with baseline plasma HIV RNA >30,000 copies/mL had a relative hazard for dementia 8.5 times (p < 0.001) that of those with <3,000 copies/mL, and those with CD4 counts <200 cells/mm3 had a 3.5-fold (p = 0.003) greater hazard relative to those with CD4 counts >500 cells/mm3. Individuals with HIV RNA >10,000 copies/mL had a 2.3-fold (p = 0.008) greater hazard of sensory neuropathy than those with <500 copies/mL, and men with <750 CD4 cells/mm3 had a 1.4-fold (p = 0.03) greater hazard than those with >750 CD4 cells/mm3. CONCLUSIONS: High levels of systemic HIV replication may "drive" the initiation of neurologic disease; effective suppression of HIV may reduce the incidence of dementia and neuropathy. Levels of plasma HIV RNA and CD4 counts, determined before the initiation of antiretroviral therapy, were predictive of HIV-associated dementia and sensory neuropathy.

AIDS Dementia Complex↗
PubMed1998

An artificial cell-cycle inhibitor isolated from a combinatorial library.

Understanding the genetic networks that operate inside cells will require the dissection of interactions among network members. Here we describe a peptide aptamer isolated from a combinatorial library that distinguishes among such interactions. This aptamer binds to cyclin-dependent kinase 2 (Cdk2) and inhibits its kinase activity. In contrast to naturally occurring inhibitors, such as p21(Cip1), which inhibit the activity of Cdk2 on all its substrates, inhibition by pep8 has distinct substrate specificity. We show that the aptamer binds to Cdk2 at or near its active site and that its mode of inhibition is competitive. Expression of pep8 in human cells retards their progression through the G1 phase of the cell cycle. Our results suggest that the aptamer inhibits cell-cycle progression by blocking the activity of Cdk2 on substrates needed for the G1-to-S transition. This work demonstrates the feasibility of selection of artificial proteins to perform functions not developed during evolution. The ability to select proteins that block interactions between a gene product and some partners but not others should make sophisticated genetic manipulations possible in human cells and other currently intractable systems.

Binding, Competitive↗
PubMed1998

Prevalence of IgE-mediated food allergy among children with atopic dermatitis.

OBJECTIVE: There is a growing body of clinical and laboratory evidence to support the notion that food allergy plays a role in the pathogenesis of atopic dermatitis (AD). However, the incidence of IgE-mediated food allergy in children with AD is not well established. DESIGN: A prospective study to determine the prevalence of IgE-mediated food hypersensitivity among patients referred to a university-based dermatologist for evaluation of AD. SETTING: University hospital pediatric dermatology clinic. PATIENTS: A total of 63 patients with AD were recruited (35 male; 32 white, 24 African-American, 7 Asian). METHODS: Patients were assigned an AD symptom score (SCORAD) and were screened for food-specific serum IgE antibodies to six foods (milk, egg, wheat, soy, peanut, fish) known to be the most allergenic in children. The levels of food-specific serum IgE were determined by the CAP System fluoroscein-enzyme immunoassay (CAP); patients with a value >/=0.7 kIUa/L were invited for an additional allergy evaluation. Those with CAP values below the cutoff were considered not food allergic. Patients were considered to be allergic if they met one of the following criteria for at least one food: 1) reaction on food challenge; 2) CAP value more than the 95% confidence interval predictive for a reaction; 3) convincing history of an acute significant (hives, respiratory symptoms) reaction after the isolated ingestion of a food to which there was a positive CAP or prick skin test. RESULTS: A total of 63 patients (median age, 2.8 years; median SCORAD, 41.1) were recruited; 22 had negative CAP values (without a significant difference in age or SCORAD score, compared with the 41 with positive specific IgE values). Further allergy evaluation was offered to the 41 remaining patients; 10 were lost to follow-up and 31 were evaluated further. Of these, 19 underwent a total of 50 food challenges (36 double-blind, placebo-controlled, and 14 open), with 11 patients experiencing 18 positive challenges (94% with skin reactions). Additionally, 6 patients had a convincing history with a predictive level of IgE; 5 had a convincing history with positive, indeterminate levels of IgE; and 1 had predictive levels of IgE (to egg and peanut) without a history of an acute reaction. Overall, 23/63 (37%; 95% confidence interval, 25% to 50%) had clinically significant IgE-mediated food hypersensitivity without a significant difference in age or symptom score between those with or without food allergy. CONCLUSIONS: Approximately one third of children with refractory, moderate-severe AD have IgE-mediated clinical reactivity to food proteins. The prevalence of food allergy in this population is significantly higher than that in the general population, and an evaluation for food allergy should be considered in these patients.

Adolescent↗
PubMed1997

The determination of ice composition with instruments on cometary landers.

The determination of the composition of materials that make up comets is essential in trying to understand the origin of these primitive objects. The ices especially could be made in several different astrophysical settings including the solar nebula, protosatellite nebulae of the giant planets, and giant molecular clouds that predate the formation of the solar system. Each of these environments makes different ices with different composition. In order to understand the origin of comets, one needs to determine the composition of each of the ice phases. For example, it is of interest to know that comets contain carbon monoxide, CO, but it is much more important to know how much of it is a pure solid phase, is trapped in clathrate hydrates, or is adsorbed on amorphous water ice. In addition, knowledge of the isotopic composition of the constituents will help determine the process that formed the compounds. Finally, it is important to understand the bulk elemental composition of the nucleus. When these data are compared with solar abundances, they put strong constraints on the macro-scale processes that formed the comet. A differential scanning calorimeter (DSC) and an evolved gas analyzer (EGA) will make the necessary association between molecular constituents and their host phases. This combination of instruments takes a small (tens of mg) sample of the comet and slowly heats it in a sealed oven. As the temperature is raised, the DSC precisely measures the heat required, and delivers the gases to the EGA. Changes in the heat required to raise the temperature at a controlled rate are used to identify phase transitions, e.g., crystallization of amorphous ice or melting of hexagonal ice, and the EGA correlates the gases released with the phase transition. The EGA consists of two mass spectrometers run in tandem. The first mass spectrometer is a magnetic-sector ion-momentum analyzer (MAG), and the second is an electrostatic time-of-flight analyzer (TOF). The TOF acts as a detector for the MAG and serves to resolve ambiguities between fragments of similar mass such as CO and N2. Because most of the compounds of interest for the volatile ices are simple, a gas chromatograph is not needed and thus more integration time is available to determine isotopic ratios. A gamma-ray spectrometer (GRS) will determine the elemental abundances of the bulk cometary material by determining the flux of gamma rays produced from the interaction of the cometary material with cosmic ray produced neutrons. Because the gamma rays can penetrate a distance of several tens of centimeters a large volume of material is analyzed. The measured composition is, therefore, much more likely to be representative of the bulk comet than a very small sample that might have lost some of its volatiles. Making these measurements on a lander offers substantial advantages over trying to address similar objectives from an orbiter. For example, an orbiter instrument can determine the presence and isotopic composition of CO in the cometary coma, but only a lander can determine the phase(s) in which the CO is located and separately determine the isotopic composition of each reservoir of CO. The bulk composition of the nucleus might be constrained from separate orbiter analyses of dust and gas in the coma, but the result will be very model dependent, as the ratio of gas to dust in the comet will vary and will not necessarily be equal to the bulk value.

Ammonia↗