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Biomedical subjects

Justin C McArthur

Publications and source records attributed to Justin C McArthur.

At least 19 recordsLinked to original sources
PubMed2007

An evaluation of neurocognitive status and markers of immune activation as predictors of time to death in advanced HIV infection.

BACKGROUND: Several markers of immune activation have been identified as potential prognostic markers for human immunodeficiency virus (HIV)-associated morbidity and mortality, but the results from studies are conflicting. OBJECTIVE: To evaluate whether neurocognitive status and baseline levels of plasma and cerebrospinal fluid tumor necrosis factor alpha (TNF-alpha), macrophage chemoattractant protein 1 (MCP-1), matrix metalloproteinase 2 (MMP-2), or macrophage colony-stimulating factor (M-CSF) are associated with time to death in a cohort with advanced HIV infection. DESIGN: Cohort study. SETTING: Enrollees in the Northeast AIDS Dementia Study. PARTICIPANTS: Three hundred twenty-nine subjects who were positive for HIV-1 and had a CD4 cell count of less than 200/microL (or <300/microL but with cognitive impairment at baseline) were assessed for CD4 cell count, neurocognitive status, pertinent demographic and clinical variables, and plasma and cerebrospinal fluid HIV RNA, TNF-alpha, MCP-1, MMP-2, and M-CSF levels. MAIN OUTCOME MEASURES: Cox proportional hazards regression models were used to examine the associations between the variables of interest (using time-dependent covariates, where applicable) and time to death, adjusting for possible confounders. RESULTS: There were 50 deaths in the cohort after a median of 25.2 months of follow-up. The cumulative incidences of death were 7% at 1 year and 16% at 2 years. In Cox proportional hazards regression analyses adjusting for demographic, clinical, and immunological variables, HIV-associated dementia (hazard rate, 6.10; P = .001) was significantly associated with time to death; (log) plasma MCP-1 level (hazard rate, 3.38; P = .08) trended toward significance. CONCLUSION: In patients with advanced HIV infection, HIV-associated dementia is an independent predictor of time to death.

Adult↗
PubMed2006

AIDS dementia complex in China.

The AIDS dementia complex (ADC) is one of the most common neurological complications in patients with AIDS. However, little is known about the clinical features of ADC in China. We prospectively studied six patients with confirmed ADC out of a total of 36 AIDS patients treated from 1999 to 2003. All patients had short-term memory loss and poor concentration, with preserved alertness. Motor disability was identified in three patients. Of the six ADC patients, two had accompanying vacuolar myelopathy. All of the patients died, with a mean age at death of 41.8 years. The median survival of these ADC patients from the time of diagnosis was 4.7 months. In this context, we suggest that early diagnosis and highly active antiretroviral therapy treatment is an urgent priority in developing countries.

AIDS Dementia Complex↗
PubMed2006

Tissue-specific associations between mitochondrial DNA levels and current treatment status in HIV-infected individuals.

BACKGROUND: Tissue mitochondrial DNA (mtDNA) levels have been proposed as a marker of nucleoside analouge reverse transcriptase inhibitor (NRTI) toxicity. However, clinical studies have yielded conflicting data regarding possible associations with mtDNA levels. This study examined mtDNA levels in matched samples of peripheral blood mononuclear cells (PBMCs) and subcutaneous fat from a large Australian cohort to examine treatment, clinical, and demographic associations with mtDNA depletion. METHODS: mtDNA was quantified by real-time polymerase chain reaction. Results were compared across patient treatment and demographic details using linear mixed models. RESULTS: One hundred sixty-three PBMCs and 161 fat samples were available from 61 individuals. Current NRTI exposure was the major determinant of mtDNA levels. Both ddI (didanosine) and d4T (stavudine) exposures were associated with mtDNA depletion in fat (P < or = 0.0001 vs. those not on NRTIs). DdI exposure (P = 0.003), but not d4T exposure (P = 0.5), was associated with mtDNA depletion in PBMCs. No association between patient demographics or time on current therapy and mtDNA was observed. CONCLUSIONS: Current NRTI exposure is the major determinant of tissue mtDNA, but the precise determinants are tissue specific. Both ddI and d4T exposure are associated with fat mtDNA depletion, whereas ddI exposure was the only observed association with mtDNA depletion in PBMCs.

Adult↗
PubMed2006

Increased vulnerability of ApoE4 neurons to HIV proteins and opiates: protection by diosgenin and L-deprenyl.

Human immunodeficiency virus (HIV) infection continues to rise in drug-abusing populations and causes a dementing illness in a subset of individuals. Factors contributing to the development of dementia in this population remain unknown. We found that HIV-infected individuals with the E4 allele of Apolipoprotein E (ApoE) or history of intravenous drug abuse had increased oxidative stress in the CNS. In vitro studies showed that HIV proteins, gp120 and Tat, Tat + morphine but not tumor necrosis factor-alpha (TNF-alpha), caused increased neurotoxicity in human neuronal cultures with ApoE4 allele. Microarray analysis showed a differential alteration of transcripts involved in energy metabolism in cultures of ApoE3 and 4 neurons upon treatment with Tat + morphine. This was confirmed using assays of mitochondrial function and exposure of the neurons to Tat + morphine. Using this in vitro model, we screened a number of novel antioxidants and found that only L-deprenyl and diosgenin protected against the neurotoxicity of Tat + morphine. Furthermore, Tat-induced oxidative stress impaired morphine metabolism which could also be prevented by diosgenin. In conclusion, opiate abusers with HIV infection and the ApoE4 allele may be at increased risk of developing dementia. L-deprenyl and a plant estrogen, diosgenin, may have therapeutic potential in this population.

AIDS Dementia Complex↗
PubMed2006

Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome.

BACKGROUND: Classic Fabry disease, an X-linked recessive lysosomal storage disease due to the deficient activity of alpha-galactosidase A, typically presents in early childhood with acroparesthesias, angiokeratomas, hypohidrosis, and corneal dystrophy. The neuropathic pain presumably results from glycosphingolipid accumulation in the vascular endothelium and in small-caliber nerve fibers, and is treatable by enzyme replacement therapy. Later-onset variants with residual alpha-galactosidase A activity lack vascular endothelial involvement and classic symptoms, which lead to the development of cardiac and/or renal disease after the fourth decade of life. OBJECTIVE: To expand the later-onset Fabry phenotype to include cramp-fasciculation syndrome without small-fiber neuropathy. METHODS: A 34-year-old man who presented with chronic exercise-induced pain, fasciculations, and cramps of the feet and legs, and his similarly affected mother, were evaluated. Clinical, biochemical, and molecular studies were performed. RESULTS: Clinical evaluation suggested the diagnosis of Fabry disease, which was confirmed by reduced plasma and leukocyte alpha-galactosidase A activities (8.8% and 13.4% of normal, respectively) due to a missense A143T mutation. His mother was heterozygous for the A143T mutation. CONCLUSION: The presentation of cramps and fasciculations without apparent small-fiber neuropathy expands the phenotype of later-onset Fabry disease.

Adult↗
PubMed2006

Cleavage of cystatin C in the cerebrospinal fluid of patients with multiple sclerosis.

OBJECTIVE: The diagnosis of multiple sclerosis (MS) can be challenging because of the lack of a specific diagnostic test. Recent advances in proteomics, however, offer new opportunities for biomarker discovery and the study of disease pathogenesis. METHODS: We analyzed cerebrospinal fluid (CSF) samples from 29 patients with MS or clinically isolated syndromes (CIS), 27 patients with transverse myelitis (TM), 50 patients with human immunodeficiency virus (HIV) infection, and 27 patients with other neurological diseases (ONDs) by surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy. RESULTS: We found a unique protein of 12.5 kDa that was 100% specific for MS/CIS compared with TM or OND. Low levels of this protein were found in some patients with HIV infection. Tandem mass spectroscopy of a tryptic digest of this 12.5 kDa protein identified it as a cleavage product of full-length cystatin C (13.4 kDa), an important inhibitor of cysteine proteases including the cathepsins. Although total cystatin C levels in the MS patients was not different compared with controls, the patients with the highest 12.5/13.4 peak ratios also had the greatest cathepsin B inhibitory activity. INTERPRETATION: This suggests that cleavage of cystatin C may be an adaptive host response and may identify a subgroup of patients with MS.

Adolescent↗
PubMed2006

Saving the clinician-scientist: report of the ANA long range planning committee.

Daunting obstacles to the development of careers in academic medicine represent the most important threat to the future of academic neurology. The Long Range Planning Committee of the American Neurological Association has for the past 2 years considered what practical methods might be undertaken to enhance the attractiveness of careers as neurologist investigators and to ensure that aspiring clinician-scientists are encouraged and retained. The deliberations have resulted in several recommendations. First, a plan has been developed to introduce flexibility during residency training in neurology. This will permit trainees who plan careers in academic medicine to have a substantial exposure to research during residency, shortening the subsequent transition to independent careers. Second, the American Neurological Association will create an annual course in clinical neuroscience research, to be held each summer for academically oriented residents. Improved mentoring and career guidance was identified as a third priority, addressed in part by the development of several new courses for trainees and mentors. Finally, planning is under way for a new postresidency training program in clinical research that will link small and large departments of neurology. Beyond these recommendations, the entire continuum of training for physician-scientists should be reexamined, from the first days of college to the successful launch as independent investigators. The development of additional demonstration projects to improve the quality and reduce the total length of training would be highly desirable.

Education, Medical, Graduate↗
PubMed2006

Enzyme replacement therapy and intraepidermal innervation density in Fabry disease.

We prospectively evaluated the effect of enzyme replacement therapy (ERT) on the intraepidermal nerve fiber density (IENFD) and thermal threshold in patients with Fabry disease, an X-linked disorder associated with a painful small-fiber neuropathy and decreased linear IENFD in a length-dependent pattern. Twenty-five hemizygous male patients with Fabry disease were enrolled in a 6-month, randomized, placebo-controlled ERT trial of 0.2 mg/kg of alpha-galactosidase A (agalsidase-alfa) every 2 weeks followed by an additional 12 months of open-label ERT for both populations. IENFD and thermal threshold were measured in the distal thigh at baseline, 6 months, and 18 months from initiation of the trial. We found no significant difference in IENFD between the treatment groups at 6 months. After an additional year of ERT, there was a significant reduction in IENFD in the patient group as a whole, attributable to the declining glomerular filtration rate. Thermal thresholds remained unchanged. We conclude that epidermal nerve fiber regeneration, as measured in the distal thigh, does not occur in this patient population after 12-18 months of ERT.

Adult↗
PubMed2006

Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues.

The importance of astrocytes as a reservoir of human immunodeficiency virus type 1 (HIV-1) in the brain remains elusive. By combining immunohistochemistry, laser capture microdissection, and triple-nested Alu-PCR, we demonstrate integrated HIV-1 in astrocytes and macrophages isolated directly from autopsy brain tissues of HIV-1-infected subjects. The ability of HIV-1 to integrate in terminally differentiated astrocytes suggests a permanent reservoir of provirus in brain that will impact the development and likely success of strategies aimed at eradicating HIV-1.

AIDS Dementia Complex↗
PubMed2006

Prevalence of human immunodeficiency virus-associated cognitive impairment in a group of Hispanic women at risk for neurological impairment.

Human immunodeficiency virus (HIV)-associated cognitive impairment, a significant cause of morbidity, affects up to 30% of HIV-infected people. Its prevalence doubled as patients began to live longer after the introduction of highly active retroviral therapy. Women are now one of the fastest growing groups with acquired immunodeficiency syndrome (AIDS) in the United States and Puerto Rico, but relatively little is known about the prevalence and characteristics of cognitive dysfunction in HIV-infected women. In this study the authors investigated its prevalence in a group of HIV-1-seropositive Hispanic women in Puerto Rico. Forty-nine women with a nadir CD4 cell count of < or = 500 cells/mm3 were enrolled. Cognitive impairment was defined according to the American Academy of Neurology criteria for HIV dementia as modified to identify an "asymptomatic cognitively impaired" group. Observed prevalence was compared with prevalence in other populations in United States, Europe, and Australia. Differences in clinical markers and neuropsychological test performance among the cohort stratified by cognitive impairment were tested. Cognitive impairment was observed in 77.6% (38/49) of cases; asymptomatic cognitive impairment in 32.7% (16/49); minor cognitive motor disorders in 16.3% (8/49); and HIV-associated dementia (HAD) in 28.6% (14/49). Cognitive impairment did not correlate with age, CD4 cell count, viral load, or treatment modality. The cross-sectional prevalence of HIV-associated cognitive impairment was 77.6% (28.6% for HAD). These findings should enhance awareness of the prevalence of HIV-associated cognitive impairment, both clinically apparent and "asymptomatic," in Hispanic women and lead to improvements in areas such as education and compliance and to reevaluation of treatment interventions.

Adult↗
PubMed2005

Evaluation of a clinical screening tool for HIV-associated sensory neuropathies.

OBJECTIVE: To evaluate the performance characteristics of a brief clinical neuropathy screening tool for use in sensory neuropathies complicating HIV infection. METHODS: The authors assessed 80 patients using the Brief Peripheral Neuropathy Screen (BPNS). Patients were defined as having neuropathy if they had both symptoms and signs consistent with this diagnosis. All subjects underwent sensory threshold testing and lower limb epidermal nerve fiber quantification using punch skin biopsy as objective measures. RESULTS: Individuals defined as having neuropathy using the BPNS (n = 37) performed less well on sensory threshold testing than other HIV-infected individuals (p < 0.0001 for warming, cooling, and vibration) and also had lower distal calf epidermal nerve fiber densities (p < 0.0001). Individuals who had symptoms but no neuropathic signs (n = 13) did not perform differently on any objective testing compared with neuropathy-free individuals, supporting the decision to require signs as well as symptoms as an operational criterion for the diagnosis of neuropathy. Of the symptoms listed in the screening tool, the presence of numbness had the greatest diagnostic efficiency for identifying those with neuropathy. CONCLUSION: The Brief Neuropathy Screening Tool (and the chosen definition of neuropathy) accurately detects those HIV-infected individuals with the greatest degree of peripheral nerve dysfunction and pathology. This is a valid neuropathy screening tool for use in the context of HIV infection, and is simple enough to be applicable in resource-limited settings.

Adult↗
PubMed2005

The International HIV Dementia Scale: a new rapid screening test for HIV dementia.

OBJECTIVE: HIV dementia is an important neurological complication of advanced HIV infection. The use of a cross-cultural screening test to detect HIV dementia within the international community is critical for diagnosing this condition. The objective of this study was to evaluate the sensitivity and specificity of a new screening test for HIV dementia, the International HIV Dementia Scale (IHDS) in cohorts from the US and Uganda. DESIGN: Two cross-sectional cohort studies designed to evaluate for the presence of HIV dementia. METHODS: Sixty-six HIV-positive individuals in the US and 81 HIV-positive individuals in Uganda received the IHDS and full standardized neurological and neuropsychological assessments. The sensitivity and specificity of varying cut-off scores of the IHDS were evaluated in the two cohorts. RESULTS: In the US cohort, the mean IHDS score for HIV-positive individuals without dementia and with dementia were 10.6 and 9.3 respectively (P < 0.001). Using the cut-off of < or = 10, the sensitivity and specificity for HIV dementia with the IHDS were 80% and 57% respectively in the US cohort, and 80% and 55% respectively in the Uganda cohort. CONCLUSIONS: The IHDS may be a useful screening test to identify individuals at risk for HIV dementia in both the industrialized world and the developing world. Full neuropsychological testing should then be performed to confirm a diagnosis of HIV dementia.

AIDS Dementia Complex↗
PubMed2005

A programmable prompting device improves adherence to highly active antiretroviral therapy in HIV-infected subjects with memory impairment.

Background. Patients cite "forgetting" as a reason for nonadherence to highly active antiretroviral therapy (HAART). We measured the effect of a memory-prompting device on adherence to HAART in memory-intact and memory-impaired human immunodeficiency virus (HIV)-infected subjects.Methods. The study was a prospective, randomized, controlled trial involving 64 HIV-infected adults. The intervention was the Disease Management Assistance System (DMAS) device, combined with monthly adherence counseling. Control subjects received only adherence counseling. The DMAS was programmed with HAART regimen data to provide verbal reminders at dosing times. Adherence was measured for 24 weeks using electronic drug exposure monitor (eDEM) caps.Results. A total of 58 subjects completed the 24-week study period; 28 were HAART naive (12 DMAS users and 16 control subjects). Mean adherence scores did not differ significantly between DMAS users (80%) and control subjects (65%). Post hoc analysis of 31 memory-impaired subjects (14 DMAS users and 17 control subjects) revealed significantly higher adherence rates among DMAS users (77%), compared with control subjects (57%) (P=.001). However, analysis of memory-intact subjects showed that adherence was not significantly improved for DMAS users (83%), compared with control subjects (77%) (P=.25). At week twelve, 38% of the DMAS users and 14% of the control subjects had an undetectable plasma HIV RNA load (P=.014), and at week 24, the plasma HIV RNA load was undetectable for 34% of the DMAS users and 38% of the control subjects (P=.49). CD4(+) cell counts did not differ between the study arms. Virological and immunological responses were not related to DMAS use in memory-impaired subjects.Conclusion. The DMAS prompting device improved adherence for memory-impaired subjects but not for memory-intact subjects.

Anti-HIV Agents↗
PubMed2005

Undetectable cerebrospinal fluid HIV RNA and beta-2 microglobulin do not indicate inactive AIDS dementia complex in highly active antiretroviral therapy-treated patients.

OBJECTIVE: To assess whether nonelevated cerebrospinal fluid (CSF) markers could delineate inactive AIDS dementia complex (ADC) in patients receiving highly active antiretroviral therapy (HAART), using neuropsychologic performance change as an indicator of ADC stability. METHODS: We used data from the abacavir (ABC) ADC trial (n = 78) and examined the patients' neuropsychologic performance change with the Reliable Change Index according to 3 cutoff groups: (1) CSF viral load (VL) <100 copies/mL, (2) CSF beta-2 microglobulin (beta2m) <2.2 mg/L, and (3) CSF VL and CSF beta2m below cutoffs. RESULTS: CSF marker cutoff groups did not define neuropsychologic change. Linear regression showed that only CSF VL was a weak predictor of neuropsychologic performance change. CONCLUSION: HAART-treated ADC patients with baseline CSF markers of viral and immunologic inactivity did not necessarily have inactive ADC when followed over 12 weeks. More sensitive CSF markers to judge the activity of ADC are urgently needed, whereas the interpretation of these markers should be considered with caution in HAART-treated ADC patients.

AIDS Dementia Complex↗
PubMed2005

Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection.

Proteinase-activated receptors (PARs), a newly discovered subgroup of G-protein coupled receptors, are widely expressed by neural cells, but their roles in the nervous system remain uncertain. In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia. The inflammatory cytokines TNF-alpha and IL-1beta were also increased in HIV-1-associated dementia brains compared with patients without dementia (p < 0.05), but these same cytokines induced PAR-2 expression on neurons. Enhanced PAR-2 expression and subsequent activation prevented neuronal cell death and induction of the tumor suppressor, p53, caused by the HIV-encoded protein, Tat (p < 0.01). Intrastriatal implantation of a PAR-2 peptide agonist also inhibited Tat-induced neurotoxicity in a mouse model of HIV neuropathogenesis (p < 0.05). Moreover, PAR-2 null animals showed more severe neuroinflammation and neuronal loss caused by Tat neurotoxicity (p < 0.05). TNF-alpha protected wild-type neurons from Tat-related neurotoxicity, but in PAR-2-deficient neurons, the same concentrations of TNF-alpha were cytotoxic (p < 0.001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death.

AIDS Dementia Complex↗
PubMed2005

Peripheral nerve-derived HIV-1 is predominantly CCR5-dependent and causes neuronal degeneration and neuroinflammation.

HIV-related peripheral neuropathy is a major neurological complication of HIV infection, although little is known about its pathogenesis. We amplified HIV-1 C2V3 envelope sequences from peroneal nerves obtained from HIV/AIDS patients. Sequence analysis and infectious recombinant viruses containing peripheral nerve-derived C2V3 sequences indicated a predominance of CCR5-dependent and macrophage-tropic HIV-1, although dual tropic viruses using both CCR5 and CXCR4 were identified. The neuropathogenic effects of recombinant HIV-1 clones were investigated using a novel dorsal root ganglion culture system that was comprised of sensory neurons, macrophages and Schwann cells from transgenic rats expressing human CD4 and CCR5 on monocytoid cells. Despite restricted viral replication, HIV-1 infection caused a reduction in the percentage of neurons with neuritic processes together with significant neurite retraction, which was accompanied by induction of IL-1beta and TNF-alpha expression, depending on the individual virus. Our results suggest that HIV-1 infection of the peripheral nervous system causes axonal degeneration, possibly through the induction of pro-inflammatory cytokines.

Adult↗