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Justin McArthur

Publications and source records attributed to Justin McArthur.

8 recordsLinked to original sources
PubMed2006

Molecular programming of endothelin-1 in HIV-infected brain: role of Tat in up-regulation of ET-1 and its inhibition by statins.

Human Immune Deficiency Virus-1 (HIV-1) infection can induce severe and debilitating neurological problems, including behavioral abnormalities, motor dysfunction, and dementia. HIV can persistently infect astrocytes, during which viral accessory proteins are produced that are unaffected by current antiretroviral therapy. The effect of these proteins on astrocyte function remains unknown. Astrocytes are the predominant cells within the brain; thus, disruption of astrocyte function could influence the neuropathogenesis of HIV infection. To explore further these effects, we constitutively expressed HIV-Tat protein in astrocytes. Since the nuclear presence of Tat protein leads to alteration of host gene expression, we further analyzed the effects of Tat on host gene transcripts. Endothelin-1 (ET-1) was a significantly elevated transcript as verified by reverse transcription-polymerase chain reaction (RT-PCR), and it was subsequently released extracellularly in Tat-expressing and HIV-infected astrocytes. ET-1 expression was also prominent in reactive astrocytes and neurons in brain tissues from basal ganglia and frontal lobes of HIV encephalitic patients. HIV-Tat regulated ET-1 at the transcriptional level through NF-kappaB (NF-kappaB)-responsive sites in the ET-1 promoter. Intriguingly, simvastatin (10 microM) down-regulated HIV-Tat-induced ET-1 and also inhibited activation of NF-kappaB in astrocytes. Our findings suggest that ET-1 may be critical in mediating the neuropathogenesis of HIV dementia and that statins may have therapeutic potential in these patients.

Astrocytes↗
PubMed2006

Therapy Insight: CNS manifestations of HIV-associated immune reconstitution inflammatory syndrome.

The introduction of combination antiretroviral therapy for HIV infection has prolonged the lives of patients with AIDS. It is increasingly being recognized, however, that following initiation of this therapy some patients can develop a paradoxical neurological deterioration, despite dramatic improvements in HIV viral load and CD4+ T-cell counts. This immune reconstitution inflammatory syndrome (IRIS) in the CNS is emerging as an important neurological complication, particularly as antiretroviral therapy is now becoming readily available worldwide. Currently, there are no guidelines for prevention, diagnosis or treatment of the CNS manifestations of IRIS. Even in patients with an acute presentation, the diagnosis can be challenging. Furthermore, it is possible that more-chronic forms of the syndrome exist but remain unrecognized. Here, we review the various clinical presentations of CNS IRIS, and discuss options for their management.

AIDS-Related Opportunistic Infections↗
PubMed2004

A randomized controlled trial of 5% lidocaine gel for HIV-associated distal symmetric polyneuropathy.

OBJECTIVE: To investigate the analgesic efficacy and safety of 5% lidocaine gel in painful HIV-associated distal sensory polyneuropathy (DSP). BACKGROUND: Painful DSP, the most common neurologic complication in HIV infection, is difficult to treat. Lidocaine 5% gel was effective in alleviating neuropathic pain in an open-label study of HIV DSP. METHODS: In a double-blind, placebo-controlled, crossover, multi-center study, 64 subjects were randomized to receive 5% lidocaine or vehicle gel for 2 weeks (phase A). A washout period of 2 weeks was followed by a crossover to the alternate agent for another 2 weeks (phase B). The primary outcome was difference in average pain scores (Gracely pain scale) between the 2 groups during the second week of each treatment period. Secondary outcomes included differential effect of the first treatment, difference in global pain relief, and pain response by neurotoxin exposure. RESULTS: The baseline pain scores of the 2 groups were similar. The average pain scores during the second week of each phase of the lidocaine gel group did not differ from those of the placebo group (phase A: lidocaine 1.09, placebo 1.15; phase B: lidocaine 1.16, placebo 1.10). There also was no difference noted in secondary outcomes. The pain responses of lidocaine gel-treated subjects with current exposure to neurotoxic antiretrovirals (1.18) did not differ compared with those without (1.10) (P = 0.358). There were no significant adverse effects. CONCLUSION: Lidocaine 5% gel is a safe but ineffective agent in the treatment of pain in HIV-associated DSP.

Anesthetics, Local↗
PubMed2004

The reliability of skin biopsy with measurement of intraepidermal nerve fiber density.

Intraepidermal nerve fiber density (IENFD) is a sensitive measure of small fiber injury, and holds promise as a clinical trial endpoint measure. A total of 48 punch biopsies were obtained from 22 patients. Tissue was sectioned and stained with PGP9.5. The relative intertrial variability (RIV) of IENFD measurements for each section and punch made by two different observers was determined (interobserver variability). Intraobserver variability (same observer measuring twice) was determined for 50% of the sections and punches. Sections from 12 punch biopsies were also stained at a second laboratory. The effect of the number of sections counted and processing site on reproducibility was investigated. A total of 223 sections were analyzed. The mean IENFD was 6.7 fibers/mm. Mean (+/-standard deviation) interobserver variability was 9.6%+/-9.4 for each biopsy site and 10.2%+/-11.9 for individual sections. Mean intraobserver variability was 9.6%+/-8.9 for biopsies, and 8.8%+/-9.0 for sections. There was no significant difference in IENFD for tissue stained at different laboratories. Intraclass correlation coefficients were greater than 0.98 for each comparison. There was no relationship between absolute IENFD and reproducibility. Reproducibility was highest when four sections were counted. IENFD measurement is highly reproducible. At least four sections should be analyzed. Reliability does not vary with severity of disease. These findings suggest IENFD may be a useful endpoint measure in future neuropathy treatment trials.

Biopsy↗
PubMed2003

New insights into diabetic polyneuropathy.

Patients with complaints of numbness, tingling, and dysesthesias in the toes and feet are frequently referred to neurologists. Often, the only objective evidence for peripheral nerve dysfunction in these patients is limited to small-caliber sensory nerve fibers. On examination these patients may have reduced distal pinprick sensation, and distal leg skin biopsies show loss of small-caliber nerve fibers. Studies focusing on small-caliber nerve fibers have led to a growing impression that neuropathy can be associated with early diabetes or impaired glucose tolerance (IGT). Often, neuropathy can be the presenting symptom of either diabetes or IGT. Furthermore, the oral glucose tolerance test appears to be a more sensitive measure of glucose dysmetabolism in these patients than levels of fasting blood glucose or glycated hemoglobin. Patients with IGT-associated neuropathy may represent an attractive target population for future regenerative studies given that their neuropathy is less severe and presumably more easily reversed than neuropathy occurring in patients with diabetes.Historically, small-caliber fibers have not been extensively evaluated due to a lack of objective measures. Several measures to evaluate these fibers are emerging, including skin biopsy with visualization of epidermal nerve fibers. The accessibility of epidermal nerve fibers makes them an attractive target for nerve injury models, which have potential for development as novel outcome measures. Such approaches may address some of the challenges of past diabetic polyneuropathy trials.

Biopsy↗