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Biomedical subjects

E J Singer

Publications and source records attributed to E J Singer.

At least 19 recordsLinked to original sources
PubMed2006

Interrater reliability of the Psychiatric Research Interview for Substance and Mental Disorders in an HIV-infected cohort: experience of the National NeuroAIDS Tissue Consortium.

The interrater reliability of the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) was assessed in a multicentre study. Four sites of the National NeuroAIDS Tissue Consortium performed blinded reratings of audiotaped PRISM interviews of 63 HIV-infected patients. Diagnostic modules for substance-use disorders and major depression were evaluated. Seventy-six per cent of the patient sample displayed one or more substance-use disorder diagnoses and 54% had major depression. Kappa coefficients for lifetime histories of substance abuse or dependence (cocaine, opiates, alcohol, cannabis, sedative, stimulant, hallucinogen) and major depression ranged from 0.66 to 1.00. Overall the PRISM was reliable in assessing both past and current disorders except for current cannabis disorders when patients had concomitant cannabinoid prescriptions for medical therapy. The reliability of substance-induced depression was poor to fair although there was a low prevalence of this diagnosis in our group. We conclude that the PRISM yields reliable diagnoses in a multicentre study of substance-experienced, HIV-infected individuals.

Adult↗
PubMed2003

Invertebrate responses to the management of genetically modified herbicide-tolerant and conventional spring crops. I. Soil-surface-active invertebrates.

The effects of herbicide management of genetically modified herbicide-tolerant (GMHT) beet, maize and spring oilseed rape on the abundance and diversity of soil-surface-active invertebrates were assessed. Most effects did not differ between years, environmental zones or initial seedbanks or between sugar and fodder beet. This suggests that the results may be treated as generally applicable to agricultural situations throughout the UK for these crops. The direction of the effects was evenly balanced between increases and decreases in counts in the GMHT compared with the conventional treatment. Most effects involving a greater capture in the GMHT treatments occurred in maize, whereas most effects involving a smaller capture were in beet and spring oilseed rape. Differences between GMHT and conventional crop herbicide management had a significant effect on the capture of most surface-active invertebrate species and higher taxa tested in at least one crop, and these differences reflected the phenology and ecology of the invertebrates. Counts of carabids that feed on weed seeds were smaller in GMHT beet and spring oilseed rape but larger in GMHT maize. In contrast, collembolan detritivore counts were significantly larger under GMHT crop management.

Agriculture↗
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

The National NeuroAIDS Tissue Consortium: a new paradigm in brain banking with an emphasis on infectious disease.

The National NeuroAIDS Tissue Consortium (NNTC) was founded in 1998, in response to the scientific need for well-characterized central nervous system (CNS) and peripheral nervous system (PNS) tissues and fluids from HIV-infected individuals. In addition to performing the routine functions of non-transplant anatomic tissue banks, the Consortium offers a unique model for the integration of independent research entities in order to provide well-characterized tissues and fluids for the international research community. Herein, we describe the structure of the Consortium, pointing out the inherent strengths of linking together multiple independent sites for the purpose of banking HIV-infected nervous system tissues. We describe the neuropathology protocol that was adopted and successfully implemented at the four participating banks of the Consortium.

AIDS Dementia Complex↗
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

Influence of JC virus coding region genotype on risk of multiple sclerosis and progressive multifocal leukoencephalopathy.

Two features of the biology of JC virus make it a particularly suitable candidate for an agent in MS-like disease: its neurotropic capability targeting glial cells as evidenced in progressive multifocal leukoencephalopathy lesions, and its capacity for latency and persistence as illustrated by its behaviour in the kidney. JC virus is chronically or intermittently excreted in the urine by some 40% of the population. The existence of JC virus in multiple coding-region genotypes provides a unique approach to the study of JC virus-induced neurological disease. We have previously shown that a genotype originating in Asia but also present in Europe and the US, called Type 2B, is more frequently found in PML brain than expected based on its prevalence in urine samples from a control population. In contrast, we find that the excretion of JCV in MS patients is similar in both genotype and frequency to that of control individuals, and appears to be regulated by factors unrelated to those that control CNS disease activity.

Adjuvants, Immunologic↗
PubMed1999

HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy.

Introduction of highly active antiretroviral therapy (HAART) has been associated with many changes in the complications of human immunodeficiency virus (HIV) infection. A cohort of 25 HIV patients with progressive multifocal leukoencephalopathy (PML) treated with HAART experienced a median survival of >46 weeks. This is an improvement in prognosis compared with recent historic experience and correlated with HIV RNA viral load reductions. We conclude that current HIV therapy is important in improving the outlook of PML in the setting of HIV.

Adult↗
PubMed1998

JC virusType 2: definition of subtypes based on DNA sequence analysis of ten complete genomes.

Five major genotypes of JC virus (JCV) have been defined based on nucleotide differences in the VP1 gene of the DNA sequence. These types are probably a result of virus evolution in geographically isolated population groups. One of the first genotypes identified, Type 2, was found to represent strains of Asian origin. In order to further define the spectrum within Type 2 strains, the entire 5.1 kb genome of nine urinary strains of JCV was amplified by PCR with one pair of primers. These urine samples were obtained in the USA (California and New Mexico) from three European Americans, three Native Americans, two African Americans and one Hispanic American. The complete genome of an Asian JCV strain (Tokyo-1) isolated from progressive multifocal leukoencephalopathy (PML) brain in Japan was also sequenced. Here, we report the analysis of these ten DNA sequences and their deduced protein translations. Two phylogenetically distinct subtypes of Type 2 were found, 2A and 2B, which differ from each other by 0.8-1.1% of the coding region sequence. A 215 bp product amplified with primers in the VP1 gene contains enough sequence information to distinguish the major types and subtypes of JCV and is suitable for application in viral epidemiological studies. The investigation of these genomic variations is of special interest because JCV Type 2 strains are found at a significantly higher frequency in brain tissue of patients with PML than would be predicted from their excretion in a control population.

Adult↗
PubMed1997

JC virus (JCV) genotypes in brain tissue from patients with progressive multifocal leukoencephalopathy (PML) and in urine from controls without PML: increased frequency of JCV type 2 in PML.

Progressive multifocal leukoencephalopathy (PML) is caused by the human polyomavirus JC (JCV), and there are at least 4 different genotypes of JCV in the United States. Type 1 strains are of European origin, whereas type 2 and 3 strains are of Asian and African origin, respectively. JCV type 4 strains are derived from a type 1/3 recombinant. In this study, the genotype distribution of JCV strains found in brain tissue or cerebrospinal fluid of 50 PML patients was compared with JCV genotypes excreted in the urine of 103 control subjects. Type determination was based on the polymerase chain reaction-amplified partial sequence of the VP1 coding gene and the noncoding region left of ori. Brain tissues from patients with PML were infected with a significantly higher proportion of JCV type 2 strains than were urine samples from the control group (P = .004). This evidence indicates a biologic difference between JCV genotypes and suggests a difference in their potential to cause PML.

Acquired Immunodeficiency Syndrome↗
PubMed1997

JC virus regulatory region rearrangements and genotypes in progressive multifocal leukoencephalopathy: two independent aspects of virus variation.

JC virus (JCV) causes the central demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV strains excreted in the urine are distinguishable from those in PML tissue by the configuration of their regulatory region to the right of ori: the archetypal regulatory region, 267 nucleotides long, is rearranged in PML tissue by deletion and duplication. Within the coding region JCV shows variations as a result of virus evolution. Four major genotypes are distinguishable of which Type 1 is based in Europe and Type 2 in Asia. Here, the regulatory region rearrangements and the viral genotypes of 29 JCV strains from PML brain were determined. Rearrangement patterns and genotypes were not associated. In general, deletions occurred before duplications, but exceptions to this rule exist. Each configuration of the 29 rearranged regulatory regions was unique and could be derived directly from the non-rearranged, archetypal form.

Gene Rearrangement↗
PubMed1996

Headache in ambulatory HIV-1-infected men enrolled in a longitudinal study.

OBJECTIVE: To report headache (HA) data collected from subjects in a longitudinal study of human immunodeficiency virus (HIV)-1 and the central nervous system (CNS) DESIGN/METHODS: Baseline data from 229 ambulatory HIV-seropositive (HIV+) and 53 seronegative control subjects were analyzed. Subjects were classified by the presence or absence of HIV-1-associated HAs and HIV-1-associated systemic and neurologic disease. Subjects were followed longitudinally for up to 5 years. RESULTS: In the cross-sectional analysis, significant associations were observed between HIV-1-associated HAs and (1) anxiety and depression, and (2) a history of drug use, psychiatric disease, and non-HIV-1 neurologic disease. No significant differences in laboratory values were found between subjects with HIV-1-associated HA compared with those without HA. When HIV+ subjects were followed longitudinally, onset of new HIV-1-associated systemic or neurologic disease over 1 year was not predicted by the presence of an HIV-1-associated HA at baseline. CONCLUSION: Headaches are common in HIV+ persons at all stages of disease. Presence of HIV-1-associated HAs at baseline were not associated with neurologic disease progression over 1 year of follow-up in our sample.

Adult↗
PubMed1996

Co-infection with two JC virus genotypes in brain, cerebrospinal fluid or urinary tract detected by direct cycle sequencing of PCR products.

The human polyomavirus JC (JCV), which exists in different geographically based genotypes, causes the central demyelinating disease known as progressive multifocal leukoencephalopathy (PML). A coding region recombinant JCV Type 1/Type 3 (Type 4) is excreted in the urine of some 16% of individuals in the USA. In addition, occasional 'crossovers' in viral DNA sequence at type-specific sites in the coding region occur between JCV genotypes amplified from PML brain. For recombination to occur requires the existence of two different genotypes in the same host. Here we provide evidence from direct cycle sequencing of PCR products that different genotypes of JCV can be found in a single tissue sample. After non-type-specific PCR amplification, cycle sequencing produced 'split bands' at type determining sites which were resolved into type or subtype-specific sequences by subcloning of the PCR products. PCR products with split bands at typing sites were found in two brain samples and in one cerebrospinal fluid (CSF) from AIDS patients with PML and in the urine of four immunocompetent individuals. This indicates that co-infection with two viral types does not depend on severe immunocompromise. Combinations of genotypes found were Types 1A & 1B, 1A & 2, 1B & 2 and 2 & 3. In one doubly infected patient the major JCV type excreted in the urine changed within 1 week.

Adult↗
PubMed1995

Quantifying HIV-1 RNA using the polymerase chain reaction on cerebrospinal fluid and serum of seropositive individuals with and without neurologic abnormalities.

We quantified HIV-1 RNA levels (copies per milliliter) in cerebrospinal fluid (CSF) and serum from subjects at various stages of HIV-1 disease and determined the relationship of RNA levels to clinical and neurologic disease status (HND) and to laboratory values. Ninety-seven HIV-1-seropositive men without CNS opportunistic infections, tumors, or neurosyphilis and 13 high-risk seronegative controls were included in the study. Each individual underwent a structured interview and physical and neurologic examinations, followed by standardized collection of blood and CSF. A custom-designed, fully automated polymerase chain reaction (PCR) system was used to perform a minimum of four separate amplifications per specimen, using two HIV-1 gag primer pairs. Southern blotting followed by hybridization with product-specific probes was used for post-PCR detection. The number of copies per milliliter was determined by relating unknowns to a built-in dilution-series standard curve using an image analysis system. HIV-1 RNA was detectable in 96% of the sera, 78% of the concentrated CSF samples, and 54% of the unconcentrated CSF samples. Serum RNA levels were significantly higher than in CSF. Serum RNA levels were significantly inversely correlated with CD4+ cell counts (p = -0.34; p = 0.03): i.e., higher RNA levels in seropositive subjects were associated with lower numbers of CD4+ cells. Serum RNA levels correlated positively with number of AIDS-related symptoms, dysfunction scores for total neurological examination, mental status score, cranial nerve score, and CNS motor signs score. Serum RNA levels did not correlate significantly with length of time on zidovudine therapy, intrathecal IgG synthesis rate, or albumin leakage. RNA levels in CSF significantly correlated only with intrathecal IgG synthesis rate and with serum RNA levels. These results confirm that serum levels of HIV-1 RNA correlate with HND and inversely correlate with CD4 counts, demonstrating that HND occurs predominantly in late stages of HIV-1 disease, although HIV-1 RNA can be detected in CSF from a majority of HIV-1-seropositive individuals at all stages of disease, which suggests that there can be early penetration of HIV into the CNS. However, HND can occur in the absence of high levels of CSF HIV-1 RNA. We also found that the concentration of HIV-1 in CSF is correlated with intrathecal IgG synthesis rate.

AIDS Dementia Complex↗
PubMed1994

Cerebrospinal fluid p24 antigen levels and intrathecal immunoglobulin G synthesis are associated with cognitive disease severity in HIV-1.

OBJECTIVE: To test the hypothesis that selected cerebrospinal fluid (CSF) markers [intrathecal immunoglobulin G (IgG) synthesis rate, oligoclonal IgG bands, and p24 antigen levels] are associated with the presence and severity of clinical HIV-1 neurologic disease. DESIGN AND METHODS: CSF and blood parameters from 142 HIV-seropositive subjects from the baseline examination of a longitudinal study were measured and analyzed in relationship with clinically derived cognitive impairment groups (none, mild, moderate) and with other neurologic and clinical classification groups. Subjects with opportunistic infections, lymphomas or neurosyphilis were excluded. RESULTS: The mean intrathecal IgG synthesis rate and mean CSF p24 antigen levels both differed significantly among cognitive impairment groups; more impairment was associated with a higher rate or level. Mean CSF p24 antigen levels were significantly higher in HIV-1-seropositive subjects with any HIV-1 neurologic disease than in subjects without neurologic disease. In contrast, there were no significant differences among seropositive groups in any CSF parameter when stratified by systemic disease classification (asymptomatic HIV-seropositives, AIDS-related complex, or AIDS), independent of neurologic status. CONCLUSION: We conclude that there may be a relationship between the severity of HIV cognitive disease and increasing levels of intrathecal IgG synthesis and CSF p24 antigen levels.

AIDS Dementia Complex↗
PubMed1994

AIDS presenting as progressive multifocal leukoencephalopathy with clinical response to zidovudine.

Progressive multifocal leukoencephalopathy (PML) due to JC virus can be the initial manifestation of AIDS. A 40-year-old man seropositive for HIV-1 presented with aphasia, hemiparesis, and hemianopsia, and with magnetic resonance imaging of the brain typical of PML. He quickly became bed bound, incontinent, and mute. The diagnosis of PML was established by histopathology in a brain biopsy with positive immunocytochemistry for polyomavirus capsid proteins, and detection of JCV DNA by polymerase chain reaction using JCV-specific primers. High dose zidovudine therapy was initiated (1200 mg/day). Within two weeks the patient began to respond, and after three months he was able to walk and care for himself and was discharged. He lived for two years from the onset of PML. While cytarabine has been the drug most widely used for PML treatment, this is the second confirmed case with apparent response to zidovudine. High dose zidovudine may benefit some previously untreated AIDS patients with onset as PML.

AIDS Dementia Complex↗
PubMed1994

Intrathecal IgG synthesis and albumin leakage are increased in subjects with HIV-1 neurologic disease.

We analyzed matched cerebrospinal fluid and blood samples from 139 subjects enrolled in a study of the effects of human immunodeficiency virus type 1 (HIV-1) on the nervous system. Mean total intrathecal IgG synthesis rate was significantly higher in subjects with HIV-1-related neurologic disease (NeuroPos) than in HIV-1-seropositive (HIV+) subjects without neurologic disease (NeuroNeg) or at-risk seronegative controls (SNC). Mean trans-blood-brain barrier (BBB) albumin leakage (AL) rate increased significantly across groups (SNC < NeuroNeg < NeuroPos). AL was significantly higher in subjects with absolute CD4 counts < 100/mm3 versus those with > or = 100 cells/mm3 and significantly higher in AIDS compared with asymptomatic HIV+. Elevated total intrathecal IgG synthesis rate could not be accounted for solely by the presence of a damaged BBB, because 79% of subjects with elevated IgG synthesis rates had a normal BBB as assessed by the AL formula. Furthermore, the Tourtellotte formula inherently corrects for BBB leakage. We confirmed, using state-of-the-art albumin and IgG determinations, that intrathecal IgG synthesis is prevalent in all stages of HIV-1 disease. In the absence of a CNS opportunistic infection or tumor, mean total intrathecal IgG synthesis rate and trans-BBB AL are significantly higher in subjects with clinical HIV-1 CNS disease than in neurologically normally HIV+ subjects.

Adult↗
PubMed1994

Quantifying HIV-1 proviral DNA using the polymerase chain reaction on cerebrospinal fluid and blood of seropositive individuals with and without neurologic abnormalities.

To quantify the number of human immunodeficiency virus type 1 (HIV-1) proviral copies per 1,000 CD4+ cells in cerebrospinal fluid (CSF) and blood in relationship to stage of infection and HIV-1 neurologic disease (HND), 87 HIV-1 seropositive men without CNS opportunistic infections, tumors, or neurosyphilis, 9 high-risk, and 14 not-at-risk seronegative controls underwent a structured interview, and physical and neurologic examination followed by blood and CSF collection. A custom-designed, fully automated polymerase chain reaction (PCR) system performed amplification with use of two HIV-1 gag primer pairs, Southern blotting, and hybridization with product-specific probes. Image analysis was used to quantify band intensities relative to a dilution series. Eighty-one of 87 (93%) seropositive patients, 1 of 9 high-risk patients, (11%) and none of 14 seronegative controls had PCR-detectable HIV-1 in their blood. Fifty-seven of 63 (90%) seropositive patients, 2 of 5 (40%) high-risk seronegative patients, and none of 14 controls had HIV-1 in their CSF. The proviral load in seropositive patients, all stages, was significantly greater in CSF than blood [median 25 vs. 0.6 copies/1,000 CD4+ cells (p = 0.0001)]. The median proviral load in blood was 0.09 copies/1,000 CD4+ cells in seropositive, asymptomatic subjects, 10.7 in patients with AIDS, and 1.4 in patients with AIDS-related complex (p = 0.0281). CSF proviral load was greater in seropositive patients with HND than those without HND, median 43.5 vs. 17.6 copies/1,000 CD4+ cells (p = 0.0614). Proviral load was greater in the blood and CSF of subjects with more advanced systemic disease and HND. There was a substantial penetration of HIV-1 into the CNS/CSF in both systemically and neurologically asymptomatic HIV-1 disease.

AIDS Dementia Complex↗