Medial arterial calcification is frequently seen in diabetic patients with severe diabetic neuropathy. Sixty patients (19 diabetic and 41 non-diabetic) were examined radiologically for typical Mönckeberg's sclerosis of feet arteries 6-8 years after uni- or bilateral lumbar sympathectomy. Fifty-five out of 60 patients (92%) revealed medial calcification. This calcification was observed in both feet of 93% of patients, who had undergone bilateral operation. After unilateral sympathectomy the incidence of calcified arteries on the side of operation was significantly higher than that on the contralateral side (88% versus 18%, p less than 0.01). Although diabetic patients showed longer stretches of calcification than non-diabetic subjects, the difference was not significant in terms of incidence and length. Of 20 patients who had no evidence of calcinosis pre-operatively, 11 developed medial calcification after unilateral operation exclusively on the side of sympathectomy. In seven patients calcinosis was detected in both feet after bilateral operation. In conclusion, sympathetic denervation is one of the causes of Mönckeberg's sclerosis regardless of diabetes mellitus.

After the introduction of highly active antiretroviral therapy (HAART) in 1995 it took 3 years to recognize the new syndrome of lipodystrophy as a long-term complication of HAART [1]. It was found to be a direct toxic consequence of the various drugs used in combination regimens. Another 2 years later, an additional syndrome was described in patients who recently initiated HAART-the immune reconstitution inflammatory syndrome (IRIS) [2-4]. Although already recognized in the pre-HIV era in patients with treatment for tuberculosis [5, 6] and leprosy [7], it became substantially more frequent in HIV-infected patients on HAART. The term IRIS describes a collection of different inflammatory disorders which are associated with paradoxical deterioration of various preexisting infectious processes following commencement of HAART in HIV-infected patients. These preexisting infections in individuals with IRIS may have been previously diagnosed and treated or may have been symptomless and later revealed by the patient's improved capacity to mount an inflammatory response.

ObjectivesApproximately 10% of HIV-infected patients fail to respond properly to highly active antiretroviral therapy (HAART). Among other factors, genetic variants of chemokine receptors have been shown to modify the course and outcome of HIV infection. Our objective was to investigate whether a failure of virological response is associated with polymorphisms of the chemokine receptors or cofactors. MethodsA total of 256 HIV-infected patients receiving HAART and 221 healthy controls were analysed for the chemokine receptor 5 (CCR5)-D32-bp, stromal derived factor 1 (SDF1)-3 0 A and chemokine receptor 2 (CCR2)-64I polymorphisms. Treatment failure was defined as failure to lower the viral load below 50 HIV-1 RNA copies/mL within the first year of treatment despite good adherence. Genomic DNA was extracted from peripheral blood lymphocytes (PBL) and amplified by polymerase chain reaction (PCR). ResultsSuccessful treatment was associated with heterozygosity for the CCR5-D32-bp variant found in 24 of 184 responders (13%) vs. one of 72 nonresponders (1.4%; P 5 0.004). Eighty-four of 184 responders (45.7%) vs. 25 of 72 nonresponders (34.7%) were heterozygous for the SDF1-3 0 A allele (P 5 0.073). The CCR2-64I polymorphism was rare in both groups: 4.9% in responders vs. 1.4% in nonresponders (P 5 0.175). The odds ratio for successful treatment was 4.7 for individuals who tested positive for at least one variant allele of the three polymorphisms. Comparison of genotype frequencies between HIV-infected and healthy individuals showed highly significant differences (Po0.001). ConclusionsChemokine receptor polymorphisms have a modifying effect on the virological response to HAART. Multivariate analysis demonstrated that heterozygosity for the CCR5-D32-bp variant is an independent prognostic factor for treatment outcome.

The acyclic nucleoside phosphonates (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) were evaluated for their efficacy and side effects in a double-blind placebo-controlled trial using naturally occurring feline immunodeficiency virus (FIV)-infected cats. This natural retrovirus animal model is considered highly relevant for the pathogenesis and chemotherapy of HIV in humans. Both PMEA and FPMPA proved effective in ameliorating the clinical symptoms of FIV-infected cats, as measured by several clinical parameters including the incidence and severity of stomatitis, Karnofsky's score, immunologic parameters such as relative and absolute CD4+ lymphocyte counts, and virologic parameters including proviral DNA levels in peripheral blood mononuclear cells (PBMC) of drug-treated animals. In contrast with PMEA, FPMPA showed no hematologic side effects at a dose that was 2.5-fold higher than PMEA.

It is unknown whether high levels of lactate result from enhanced production or decreased degradation. We therefore investigated differences in the kinetics of plasma lactic acid in HIV-infected patients receiving or not receiving highly active antiretroviral therapy (HAART) and in uninfected controls after submaximal ergometric exercise. MethodsTen healthy controls, 11 HIV-infected therapy-naïve patients, 15 HIV-infected patients on HAART with normal baseline lactate levels, and nine HIV-infected patients on HAART with elevated baseline lactate levels >2 mmol/L performed 10 min of ergometric exercise, with a heart rate of 200 beats/min minus age. Lactate levels were measured at baseline, at the end of exercise and 15, 30, 45, 60 and 120 min thereafter. ResultsMean baseline lactate levels were 1.4, 1.5, 1.5 and 2.8 mmol/L in the controls, the therapy-naïve patients, the patients on HAART with normal lactate levels and the patients on HAART with elevated lactate levels, respectively. Maximum lactate levels after exercise were similar in all groups (9.7, 9.4, 9.0 and 10.1 mmol/L, respectively). Significant differences were found in the slope of lactate decline between controls and untreated individuals (P 5 0.038) and between patients on HAART with normal baseline lactate and patients on HAART with elevated baseline lactate (P 5 0.028). ConclusionsDifferences in lactate metabolism do exist between healthy controls and HIV-infected therapy-naïve individuals. Thus, HIV infection in itself may influence lactate levels. Elevated baseline lactate levels are associated with a delayed decline of lactate after exercise. These results could be explained by impaired lactate clearance. Lactate production upon exercise does not seem to be affected by baseline lactate levels. Fig. 1).Mitochondria have a pivotal role in cellular energy homeostasis, producing adenosphine biphosphate (APT) by oxidative phosphorylation. Under normal aerobic conditions, glucose is metabolized to pyruvate, which is further degraded in the mitochondrion to CO 2 , H 2 O and ATP. Lactate production can be induced by anaerobic glycolysis, by a defect in the oxidative phosphorylation of peripheral tissue or as a result of defective mitochondrial DNA (mtDNA)-encoded proteins. The primary site of lactate clearance is the liver and, to a lesser extent, the kidney and the skeletal muscle itself. The sole pathway for lactate utilization leading to stable lactate concentrations of less than 2 mmol/L is conversion back to pyruvate and then to glucose in the Cori Cycle, which depends on ATP and sufficient oxidative phosphorylation. Thus, impaired lactate clearance may be the result of a mitochondrial dysfunction in the liver [8] or in other tissues, for example skeletal muscle.Skeletal muscle cells, which have high amounts of mitochondria and high oxidative requirements, are the most important producers of lactate, especially during exercise. Elevated lactate levels could also be caused by increased production (see Fig. 1). Whether hyperlactataemia associated w...