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Biomedical subjects

D B Clifford

Publications and source records attributed to D B Clifford.

At least 19 recordsLinked to original sources
PubMed2006

HIV neuropathy natural history cohort study: assessment measures and risk factors.

BACKGROUND: Distal sensory polyneuropathy (DSP) is the most common neurologic complication of human immunodeficiency virus (HIV) infection. Risk factors for DSP have not been adequately defined in the era of highly active antiretroviral therapy. METHODS: The authors evaluated 101 subjects with advanced HIV infection over 48 weeks. Assessments included a brief peripheral neuropathy (PN) screen (BPNS), neurologic examination, nerve conduction studies, quantitative sensory testing (QST), and skin biopsies with quantitation of epidermal nerve fiber density. Data were summed into a Total Neuropathy Score (TNS). The presence, severity, and progression of DSP were related to clinical and laboratory results. RESULTS: The mean TNS (range 0 to 36) was 8.9, with 38% of subjects classified as PN-free, 10% classified as having asymptomatic DSP, and 52% classified as having symptomatic DSP. Progression in TNS from baseline to week 48 occurred only in the PN-free group at baseline (mean TNS change = 1.16 +/- 2.76, p = 0.03). Factors associated with progression in TNS were lower current TNS, distal epidermal denervation, and white race. As compared with the TNS diagnosis of PN at baseline, the BPNS had a sensitivity of 34.9% and a specificity of 89.5%. CONCLUSIONS: In this cohort of advanced human immunodeficiency virus (HIV)-infected subjects, distal sensory polyneuropathy was common and relatively stable over 48 weeks. Previously established risk factors, including CD4 cell count, plasma HIV RNA, and use of dideoxynucleoside antiretrovirals were not predictive of the progression of distal sensory polyneuropathy (DSP). Distal epidermal denervation was associated with worsening of DSP. As compared with the Total Neuropathy Score, the brief peripheral neuropathy screen had relatively low sensitivity and high specificity for the diagnosis of DSP.

Cohort Studies↗
PubMed2005

Genotyping of Toxoplasma gondii strains from immunocompromised patients reveals high prevalence of type I strains.

Toxoplasma gondii is an important food- and waterborne opportunistic pathogen that causes severe disease in immunocompromised patients. T. gondii has an unusual clonal population structure consisting of three widespread lineages known as I, II, and III. To establish the genotypes of strains of T. gondii associated with human toxoplasmosis, we have developed a set of four highly sensitive and polymorphic nested PCR markers. Multiplex nested PCR analysis was used to genotype parasites in cerebral spinal fluid samples from 8 of 10 human immunodeficiency virus-positive patients. Remarkably, a majority of these patients had infections with type I strains or strains containing type I alleles, despite the fact that this lineage is normally uncommon in humans and animals. Multiplex analysis of these four unlinked makers was able to distinguish all three common genotypes and also detected two strains with mixed genotypes. Further analysis based on sequencing of a polymorphic intron revealed that one of these recombinant strains was an exotic lineage distinct from the archetypal clonal lineages. The multiplex nested PCR analysis described here will be useful for analyzing the contribution of parasite genotype to toxoplasmosis.

AIDS-Related Opportunistic Infections↗
PubMed2003

Effects of fructose-1,6-bisphosphate on morphological and functional neuronal integrity in rat hippocampal slices during energy deprivation.

D-fructose-1,6-bisphosphate, a high energy glycolytic intermediate, attenuates ischemic damage in a variety of tissues, including brain. To determine whether D-fructose-1,6-bisphosphate serves as an alternate energy substrate in the CNS, rat hippocampal slices were treated with D-fructose-1,6-bisphosphate during glucose deprivation. Unlike pyruvate, an endproduct of glycolysis, 10 mM D-fructose-1,6-bisphosphate did not preserve synaptic transmission or morphological integrity of CA1 pyramidal neurons during glucose deprivation. Moreover, during glucose deprivation, 10-mM D-fructose-1,6-bisphosphate failed to maintain adenosine triphosphate levels in slices. D-fructose-1,6-bisphosphate, however, attenuated acute neuronal degeneration produced by 200 microM iodoacetate, an inhibitor of glycolysis downstream of D-fructose-1,6-bisphosphate. Because (5S, 10R)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine, an antagonist of N-methyl-D-aspartate receptors, exhibited similar protection against iodoacetate damage, we examined whether (5S, 10R)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine and D-fructose-1,6-bisphosphate share a common neuroprotective mechanism. Indeed, D-fructose-1,6-bisphosphate diminished N-methyl-D-aspartate receptor-mediated synaptic responses and partially attenuated neuronal degeneration induced by 100-microM N-methyl-D-aspartate. Taken together, these results indicate that D-fructose-1,6-bisphosphate is unlikely to serve as an energy substrate in the hippocampus, and that neuroprotective effects of D-fructose-1,6-bisphosphate are mediated by mechanisms other than anaerobic energy supply.

Adenosine Triphosphate↗
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

Bk virus: a clinical review.

We present a review of the clinically oriented literature about BK virus, a relative of JC virus, which is the etiologic agent of progressive multifocal leukoencephalopathy (PML). The kidney, lung, eye, liver, and brain have been proposed as sites of BK virus-associated disease, both primary and reactivated. BK virus has also been detected in tissue specimens from a variety of neoplasms. We believe that BK virus is most often permissively present in sites of disease in immunosuppressed patients, rather than being an etiologic agent that causes symptoms or pathologic findings. There is, however, strong evidence for BK virus-associated hemorrhagic cystitis and nephritis, especially in recipients of solid organ or bone marrow transplants. Now that BK virus can be identified by use of specific and sensitive techniques, careful evaluation of the clinical and pathologic presentations of patients with BK virus will allow us to form a clearer picture of viral-associated pathophysiology in many organ systems.

Animals↗
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

Human immunodeficiency virus-associated dementia.

It is clear that optimal control of HIV infection using cocktails of antiretrovirals has an important beneficial effect on the neurologic manifestations of HIV. Research is required to define the pathophysiology of HIV-associated disease in the central nervous system, and to enhance delivery of therapy to this important compartment. Concurrently, trials of potentially neuroprotective agents are needed to optimize central nervous system therapy. No neuroprotective treatment to date has been successfully proven to be beneficial. However, progress has been very rewarding, with rapidly declining incidence of neurologic disease associated with dramatic improvement in HIV therapy. The prolonged life span of patients with HIV leaves the possibility that prevalence of HIV-associated neurologic disease might even increase in coming years. Therapy for HIV in the central nervous system compartment remains potentially the most challenging therapeutic frontier for HIV control.

AIDS Dementia Complex↗
PubMed1999

Neurological outcomes in late HIV infection: adverse impact of neurological impairment on survival and protective effect of antiviral therapy. AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team.

OBJECTIVE: In a large multi-center clinical trial of combination reverse transcriptase inhibitors (RTIs), we assessed the impact of antiretroviral therapy on neurological function, the relationship between neurological and systemic benefit, and the prognostic value of neurological performance in late HIV-1 infection. DESIGN: Neurological evaluations incorporated in a randomized, multi-center trial of combination antiretroviral therapy. SETTING: Forty-two AIDS Clinical Trials Group sites and seven National Hemophilia Foundation sites. PATIENTS: Adult HIV-infected patients (n = 1313) with CD4 counts < 50 x 10(6) cells/l. INTERVENTIONS: Four combinations of reverse transcriptase inhibitors consisting of zidovudine (ZDV), alternating monthly with didanosine (ddl), or in combination with zalcitabine (ddC), ddl or ddl and nevirapine. MAIN OUTCOME MEASURES: Mean change from baseline of a four-item quantitative neurological performance battery score, the QNPZ-4, administered to 1031 subjects. RESULTS: Triple therapy and ZDV/ddl combination preserved or improved neurological performance over time compared with the alternating ZDV/ddl and ZDV/ddC regimens (P < 0.001), paralleling their impact on survival in the same trial as previously reported. QNPZ-4 scores were predictive of survival (P < 0.001), after adjusting for CD4 counts and HIV-1 plasma RNA concentrations. CONCLUSIONS: Combination antiretroviral therapy can have a salutary effect on preserving or improving neurological function. Superior systemic treatments may likewise better preserve neurological function. The significant association of poor neurological performance with mortality, independent of CD4 counts and HIV-1 RNA levels indicates that neurological dysfunction is an important cause or a strong marker of poor prognosis in late HIV-1 infection. This study demonstrates the value of adjunctive neurological measures in large therapeutic trials of late HIV-1 infection.

AIDS Dementia Complex↗
PubMed1999

Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy.

The detection and semiquantitation of JC virus (JCV) DNA in cerebrospinal fluid (CSF) is prognostic of survival and is a marker of the course of progressive multifocal leukoencephalopathy (PML). CSF samples from 15 acquired immunodeficiency syndrome (AIDS) patients with biopsy-proven PML were analyzed by semiquantitative polymerase chain reaction (PCR). A low JCV burden was predictive of longer survival compared with a high JCV burden (median survival from entry, 24 [2-63] vs 7.6 [4-17] weeks). Further analyses indicated a possible threshold of 50 to 100 copies/microl separating high- and moderate-risk cases. Patients with a JCV load below this level survived longer than those with a JCV load above it.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Opportunistic viral infections in the setting of human immunodeficiency virus.

Human immunodeficiency virus (HIV) infection has provided a setting in which additional neurologic problems develop. The mechanism of these complications varies from agent to agent, but the added spectrum of diseases encountered has challenged diagnosticians and provided unparalleled opportunities to develop a deeper understanding of these conditions and their treatments. This review addresses the most prominent viral-associated complications, except for progressive multifocal leukoencephalopathy, which is addressed in a separate review. The complications of greatest importance both due to their frequency and severity are caused by cytomegalovirus, so these are discussed in greater depth. However, the association of Epstein-Barr virus with induction of central nervous system lymphoma represents an important viral linked complication of great importance. In addition, the increased activity of varicella zoster virus has been notable in the setting of HIV. Finally, human herpesvirus type 6 is an emerging virus of interest that has been identified in the setting of HIV infection, whose role in pathophysiology is only now being investigated.

AIDS-Related Opportunistic Infections↗
PubMed1999

Progressive multifocal leukoencephalopathy in patients with AIDS receiving highly active antiretroviral therapy.

Recent reports suggest that human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) may improve with highly active antiretroviral therapy (HAART). We observed three patients who developed PML while receiving HAART. All patients received HAART for 4-11 months and had low plasma levels of HIV-1 RNA before the onset of symptoms of PML. Antiretroviral therapy was changed in two patients, and their plasma HIV-1 RNA levels declined significantly. Despite this virologic response, PML did not improve in these patients. The third patient's HIV-1 RNA level became undetectable while he was receiving HAART, and his symptoms of PML improved after the addition of interferon alpha. Our observations suggest that PML can develop in patients who have shown clinical response to HAART. Furthermore, PML may not improve despite an adequate virologic response to HAART. Definitive therapy is still needed for PML.

AIDS-Related Opportunistic Infections↗
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

A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team.

BACKGROUND: Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesized that amitriptyline or mexiletine would improve the pain symptoms. METHOD: A randomized, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit. RESULTS: The improvement in amitriptyline group (0.31+/-0.31 units [mean+/-SD]) and mexiletine group (0.23+/-0.41) was not significantly different from placebo (0.20+/-0.30). Both interventions were generally well tolerated. CONCLUSIONS: Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.

Adrenergic Uptake Inhibitors↗
PubMed1997

Stable neurological function in subjects treated with 2'3'-dideoxyinosine.

AIDS Dementia Complex (ADC) is a frequent and devastating complication of HIV infection. There is evidence that zidovudine (ZDV) has an effect in alleviating the symptoms of ADC, and may have a role in its prevention. It is therefore important that new antiretroviral therapies be evaluated not only for the risk of neurologic side effects, but also for their relative efficacy to ZDV in the prevention of ADC. The present study reports the effects of 2'3'-dideoxyinosine (DDI, didanosine, Videx) therapy on neuropsychological performance in the context of several large clinical trials targeting advanced systemic HIV-1 infection. Subjects treated with DDI had stable neurologic performance in quantitative tests over a 1 year period and were similar to zidovudine treated subjects.

AIDS Dementia Complex↗
PubMed1996

Cytomegalovirus encephalitis.

PURPOSE: To review the pathologic and clinical features of and establish the frequency of cytomegalovirus encephalitis in adults and to review the methods available for diagnosis and treatment. DATA SOURCE: MEDLINE search of all English-language articles from January 1965 to August 1995. STUDY SELECTION: Articles dealing with cytomegalovirus infection of the brain in adults. We also reviewed all unselected autopsies of these populations to establish the frequency of cytomegalovirus encephalitis in recipients of organ transplants and in patients infected with the human immunodeficiency virus (HIV). DATA EXTRACTION: Epidemiologic and pathologic characteristics, clinical manifestations, diagnostic methods, pathogenetic mechanisms, and use of anticytomegalovirus treatments. DATA SYNTHESIS: Of 676 patients receiving a diagnosis of cytomegalovirus encephalitis, 574 (85%) were infected with HIV, 81 (12%) had other causes of immunosuppression, and 21 (3%) were otherwise healthy. Cytomegalovirus encephalitis was confirmed during autopsy in 12% of HIV-infected patients and 2% of transplant recipients. The most common lesion was microglial nodule encephalitis, but the clinical findings corresponding to this pathologic entity are not well defined. In contrast, the pathologic entity of cytomegalovirus ventriculoencephalitis, found almost exclusively in patients with advanced HIV infection, has distinct clinical features that allow recognition even in patients with HIV encephalopathy. Polymerase chain reaction has been shown to be useful for diagnosis of cytomegalovirus encephalitis. CONCLUSIONS: Cytomegalovirus encephalitis is an important opportunistic infection in HIV-infected patients but is rarely recognized in other groups. Cytomegalovirus ventriculoencephalitis has emerged as a unique entity in patients with advanced HIV infection. Recent developments in diagnostic techniques allow early recognition and may make more aggressive approaches to therapy possible.

Antiviral Agents↗