Publications

Analgesic efficacy varies depending on the pain syndrome being treated. One reason for this may be a differential effect of individual pain syndromes on the function of the endogenous pain control circuits at which these drugs act to produce analgesia. To test this hypothesis, we examined the effects of diverse (i.e., ongoing inflammatory, neuropathic, or chronic widespread) pain syndromes on analgesia induced by activation of an opioid-mediated, noxious stimulus-induced endogenous pain control circuit. This circuit was activated by subdermal capsaicin injection at a site remote from the site of nociceptive testing. Analgesia was not affected by carrageenan-induced inflammatory pain or the early phase of oxaliplatin neuropathy (a complication of cancer chemotherapy). However, the duration of analgesia was markedly shorter in the late phase of oxaliplatin neuropathy and in alcoholic neuropathy. A model of fibromyalgia syndrome produced by chronic unpredictable stress and proinflammatory cytokines also shortened analgesia duration, but so did the same stress alone. Therefore, since chronic pain can activate neuroendocrine stress axes, we tested whether they are involved in the attenuation of analgesic duration induced by these pain syndromes. Rats in which the sympathoadrenal axis was ablated by adrenal medullectomy showed normal duration pain-induced analgesia in groups with either late-phase oxaliplatin neuropathy, alcoholic neuropathy, or exposure to sound stress. These results support the suggestion that pain syndromes can modulate activity in endogenous pain control circuits and that this effect is sympathoadrenal dependent.

BACKGROUND

Many resource-constrained countries now train non-physician clinicians in HIV/AIDS care, a strategy known as 'task-shifting.' There is as yet no evidence-based international standard for training these cadres. In 2007, the Mozambican Ministry of Health (MOH) conducted a nationwide evaluation of the quality of care delivered by non-physician clinicians (técnicos de medicina, or TMs), after a two-week in-service training course emphasizing antiretroviral therapy (ART).

METHODS

Forty-four randomly selected TMs were directly observed by expert clinicians as they cared for HIV-infected patients in their usual worksites. Observed clinical performance was compared to national norms as taught in the course.

RESULTS

In 127 directly observed patient encounters, TMs assigned the correct WHO clinical stage in 37.6%, and correctly managed co-trimoxazole prophylaxis in 71.6% and ART in 75.5% (adjusted estimates). Correct management of all 5 main aspects of patient care (staging, co-trimoxazole, ART, opportunistic infections, and adverse drug reactions) was observed in 10.6% of encounters.The observed clinical errors were heterogeneous. Common errors included assignment of clinical stage before completing the relevant patient evaluation, and initiation or continuation of co-trimoxazole or ART without indications or when contraindicated.

CONCLUSIONS

In Mozambique, the in-service ART training was suspended. MOH subsequently revised the TMs' scope of work in HIV/AIDS care, defined new clinical guidelines, and initiated a nationwide re-training and clinical mentoring program for these health professionals. Further research is required to define clinically effective methods of health-worker training to support HIV/AIDS care in Mozambique and similarly resource-constrained environments.

BACKGROUND

The gut is a major reservoir for human immunodeficiency virus (HIV) in patients receiving antiretroviral therapy (ART). We hypothesized that distinct immune environments within the gut may support varying levels of HIV.

METHODS

In 8 HIV-1-positive adults who were receiving ART and had CD4(+) T cell counts of >200 cells/μL and plasma viral loads of <40 copies/mL, levels of HIV and T cell activation were measured in blood samples and endoscopic biopsy specimens from the duodenum, ileum, ascending colon, and rectum.

RESULTS

HIV DNA and RNA levels per CD4(+) T cell were higher in all 4 gut sites compared with those in the blood. HIV DNA levels increased from the duodenum to the rectum, whereas the median HIV RNA level peaked in the ileum. HIV DNA levels correlated positively with T cell activation markers in peripheral blood mononuclear cells (PBMCs) but negatively with T cell activation markers in the gut. Multiply spliced RNA was infrequently detected in gut, and ratios of unspliced RNA to DNA were lower in the colon and rectum than in PBMCs, which reflects paradoxically low HIV transcription, given the higher level of T cell activation in the gut.

CONCLUSIONS

HIV DNA and RNA are both concentrated in the gut, but the inverse relationship between HIV DNA levels and T cell activation in the gut and the paradoxically low levels of HIV expression in the large bowel suggest that different processes drive HIV persistence in the blood and gut.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT00884793 (PLUS1).

BACKGROUND

Macrophages contribute to the progression and acute complications of atherosclerosis. Macrophage imaging may serve as a biomarker to identify subclinical inflamed lesions, to predict future risk, and to aid in the assessment of novel therapies.

METHODS AND RESULTS

To test the hypothesis that nanoparticle-enhanced, high-resolution magnetic resonance imaging (MRI) can measure plaque macrophage accumulation, we used 3-T MRI with a macrophage-targeted superparamagnetic nanoparticle preparation (monocrystalline iron oxide nanoparticles-47 [MION-47]) in cholesterol-fed New Zealand White rabbits 6 months after balloon injury. In vivo MRI visualized thickened abdominal aortas on both T1- and T2-weighted spin-echo images (T1 spin echo, 20 axial slices per animal; T2 spin echo, 28 slices per animal). Seventy-two hours after MION-47 injection, aortas exhibited lower T2 signal intensity compared with before contrast imaging (signal intensity ratio, aortic wall/muscle: before, 1.44 ± 0.26 versus after, 0.95 ± 0.22; 164 slices; P<0.01), whereas T1 spin echo images showed no significant change. MRI on ex vivo specimens provided similar results. Histological studies colocalized iron accumulation with immunoreactive macrophages in atheromata. The magnitude of signal intensity reduction on T2 spin echo in vivo images further correlated with macrophage areas in situ (150 slices; r=0.73). Treatment with rosuvastatin for 3 months yielded diminished macrophage content (P<0.05) and reversed T2 signal intensity changes (P<0.005). Signal changes in rosuvastatin-treated rabbits correlated with reduced macrophage burden (r=0.73). In vitro validation studies showed concentration-dependent MION-47 uptake by human primary macrophages.

CONCLUSION

The magnitude of T2 signal intensity reduction in high-resolution MRI after administration of superparamagnetic phagocytosable nanoparticles can assess macrophage burden in atheromata, providing a clinically translatable tool to identify inflamed plaques and to monitor therapy-mediated changes in plaque inflammation.