Globulin fraction and albumin: globulin ratio as a predictor of mortality in a South African multiple myeloma cohort.

Multiple myeloma, a hematological malignancy typified by the clonal expansion of bone marrow plasma cells, contributes to one percent of all malignancies worldwide. Despite myeloma only contributing to 10% of all hematological malignancies, it carries significant morbidity owing to its heterogenous presentation from orthopedic manifestations to renal sequelae. Patients with the disease can be risk stratified into high risk categories by the presence of various cytogenetic and other laboratory measures, albeit expensive. The albumin:globulin ratio and its inverse the globulin:albumin ratio is proposed as a means of predicting survival in this group of patients as a cheaper and more accessible marker of disease.

Tryptophan depletion in context of the inflammatory and general nutritional status of a low-income South African HIV-infected population.

BACKGROUND: The essential amino acid tryptophan cannot be synthesised in the body and must be acquired through dietary intake. Oxidation of tryptophan, due to immune induction of the enzyme indoleamine 2,3-dioxygenase (IDO), is considered to be the main cause of tryptophan depletion in HIV infection and AIDS. We examined plasma tryptophan levels in a low-income sub-Saharan HIV-infected population and compared it to that of developed countries. Tryptophan levels were further examined in context of the general nutritional and inflammatory status. METHODS: This cross-sectional study included 105 HIV-positive patients recruited from the Kalafong Hospital in Pretoria, South Africa, and 60 HIV-negative controls. RESULTS: Patient tryptophan levels were in general markedly lower than those reported for developed countries. In contrast to reports from developed countries that showed tryptophan levels on average to be 18.8 % lower than their control values, tryptophan levels in our study were 44.1 % lower than our controls (24.4 ± 4.1 vs. 43.6 ± 11.9 µmol/l; p < 0.001). Tryptophan levels correlated with both CD4 counts (r = 0.341; p = 0.004) and with pro-inflammatory activity as indicated by neopterin levels (r = -0.399; p = 0.0001). Nutritional indicators such as albumin and haemoglobin correlated positively with tryptophan and negatively with the pro-inflammatory indicators neopterin, interleukin 6 and C-reactive protein. The most probable causes of the lower tryptophan levels seen in our population are food insecurity and higher levels of inflammatory activity. CONCLUSIONS: We contend that inflammation-induced tryptophan depletion forms part of a much wider effect of pro-inflammatory activity on the nutritional profile of HIV-infected patients.

The kynurenine pathway activities in a sub-Saharan HIV/AIDS population.

BACKGROUND: Tryptophan is an essential amino acid for the synthesis of proteins and important metabolites such as serotonin, melatonin, tryptamine and niacin. After protein synthesis, more than 90 % of tryptophan catabolism occurs along the kynurenine pathway. The inflammation-inducible enzyme indoleamine 2,3 dioxygenase (IDO) is responsible for the first rate-limiting step in the kynurenine pathway, i.e., oxidation of tryptophan to kynurenine. Excessive IDO activity in conditions such as HIV/AIDS may lead to tryptophan depletion and accumulation of metabolites downstream from kynurenine. Little is known about the kynurenine pathway of HIV/AIDS patients in sub-Saharan regions. This study, in a low income sub-Saharan HIV/AIDS population, examined the effects of activities in the kynurenine pathway on plasma levels of tryptophan, kynurenine and the neurotoxin quinolinic acid, and on de novo synthesis of nicotinamide. METHODS: Plasma samples were obtained from a cohort of 105 HIV patients and 60 controls. Kynurenine pathway metabolites were analysed using gas chromatography - mass spectrometry. ELISA and flow cytometry were used to assess plasma inflammatory markers. RESULTS: IDO activity, depletion of tryptophan, as well as accumulation of kynurenine and the neurotoxin quinolinic acid, were not only significantly greater in the patients than in the controls, but also markedly greater than in HIV/AIDS patients from developed countries. Tryptophan levels were 12.3 % higher, kynurenine levels 16.2 % lower, quinolinic acid levels 43.2 % lower and nicotinamide levels 27,2 % lower in patients on antiretroviral treatment than in antiretroviral-naïve patients. Patients' kynurenine pathway metabolites correlated with the levels of inflammatory markers, including that of the major IDO-inducer, interferon-gamma. Indications are that the rate of de novo synthesis of nicotinamide in the kynurenine pathway correlates with increases in quinolinic acid levels up to a point where saturation of the enzyme quinolinate phosphoribosyl transferase occurs. CONCLUSIONS: Higher levels of inflammatory activity in this low income sub-Saharan HIV/AIDS population than in patients from developed countries lead to greater tryptophan depletion and greater accumulation of metabolites downstream from tryptophan with quinolinic acid levels often reaching levels associated with the development of HIV/AIDS-associated neurocognitive dysfunction. De novo synthesis of nicotinamide from quinolinic acid contributes to the maintenance of nicotinamide, and by implication NAD levels, in HIV/AIDS patients from low income populations. Antiretroviral treatment partially corrects disturbances in the kynurenine pathway.

A non-specific biomarker of disease activity in HIV/AIDS patients from resource-limited environments.

BACKGROUND: A general non-specific marker of disease activity that could alert the clinician and prompt further investigation would be of value in patients with HIV/AIDS, especially in resource limited environments. OBJECTIVE: To investigate the potential of neopterin as non-specific biomarker in patients with advanced HIV/AIDS. METHODS: Cross-sectional study in 105 HIV positive patients (75 on highly active antiretroviral treatment (HAART). Neopterin was assessed by enzyme linked immune-absorbent assay and cytokines by flow cytometry. RESULTS: Neopterin levels were significantly higher (p<0.001) for the total patient than for the control group. Significant correlations between neopterin and plasma indicators of inflammation showed neopterin to be a good indicator of active inflammatory status and of the effect of HAART on the immune system. Neopterin was superior to C-reactive protein and to individual cytokines as indicator of immune deficiency. Increased neopterin levels were associated with a decline in albumin, haemoglobin and the albumin/globulin ratio, and with increases in red cell distribution width. CONCLUSIONS: Plasma neopterin is a good non-specific biomarker of disease activity in HIV/AIDS patients. It is a good indicator of inflammatory activity, perpetuation of inflammation-associated co-morbidities, degree of immune deficiency and has predictive value for underlying disease, and for monitoring the HAART response.

Expression of the H- and L-subunits of ferritin in bone marrow macrophages of patients with osteoarthritis.

Osteoarthritis is a disease characterized by an increase in the production of reactive oxygen species (ROS) in afflicted joints. Excess iron, due to its role in the production of ROS and crystal deposition in the joints, is implicated in the disease progression of osteoarthritis. Ferritin is a major regulator of the bioavailability of iron, and its functions are determined largely by the combination of H- and L-subunits present in its outer protein shell. The purpose of the study was to investigate the expression of the H- and L-subunits of ferritin in bone marrow macrophages of osteoarthritis patients. The cytokine profiles were assessed as cytokines play an important role in the expression of the ferritin subunits. The H-subunit of ferritin in the bone marrow macrophages was significantly higher (P value = 0.035) in the osteoarthritis patients compared with the controls (107.84; 69.25-167.94 counts/µm(2); n = 7 versus 71.07; 58.56-86.26 counts/µm(2); n = 19). A marginally significant increase (P value = 0.059) was shown for the expression of the L-subunit in the osteoarthritis patients compared with the controls (133.03; 104.04-170.10 counts/µm(2); n = 7 versus 104.23; 91.53-118.70 counts/µm(2); n = 19). The osteoarthritis and control groups had comparable C-reactive protein, as well as proinflammatory and anti-inflammatory cytokine concentrations. The major exception was for transforming growth factor-ß (TGF-ß), which was higher (P value = 0.014) in the plasma of the osteoarthritis patients (16.69; 13.09-21.28 ng/mL; n = 7 versus 8.60; 6.34-11.67 ng/mL; n = 19). Up-regulation of the ferritin subunits decreases the levels of bioavailable iron and provides protection against the unwarranted production of ROS and crystal deposition. A role for TGF-ß in the up-regulation of the expression of the H-subunit, and possibly the L-subunit, of ferritin is postulated in osteoarthritis.