NT-proBNP as a marker of cardiopulmonary status in sickle cell anaemia in Africa.

N-terminal (NT) pro-brain natriuretic peptide (proBNP) > or =160 ng/l has a 78% positive predictive value for pulmonary hypertension and is associated with increased mortality in US sickle cell disease patients, but the importance in sickle cell disease patients in Africa is not known. In a cross-sectional study at Ahmadu Bello University Teaching Hospital, Shika-Zaria, Nigeria, we studied 133 hydroxycarbamide-naïve Nigerian sickle cell anaemia patients aged 18-52 years at steady-state and 65 healthy controls. Twenty-six percent of patients versus 5% of controls had NT-proBNP > or =160 ng/l (P = 0.0006). By logistic regression among the patients, human immunodeficiency virus seropositivity, higher serum ferritin and lower haemoglobin or higher lactate dehydrogenase independently predicted elevated NT-proBNP. After adjustment for haemoglobin concentration, elevated NT-proBNP concentration was associated with an estimated 7.8-fold increase in the odds of severe functional impairment, defined as an inability to walk more than 300 m in 6 min (95% confidence interval 1.5-32.6; P = 0.005). Similarly, elevated tricuspid regurgitation velocity was associated with an estimated 5.6-fold increase in the odds of functional impairment (95% confidence interval 1.5-21.0; P = 0.011). In conclusion, NT-proBNP elevation is common and is associated with markers of anaemia, inflammation and iron status and with severe functional impairment among sickle cell anaemia patients in Nigeria.

Prevalence and risk factors for pulmonary artery systolic hypertension among sickle cell disease patients in Nigeria.

Pulmonary artery systolic hypertension is common and associated with increased mortality among adult sickle cell disease (SCD) patients in the United States. Although the prevalence of SCD is highest in sub-Saharan Africa, the frequency of pulmonary artery systolic hypertension and the risk factors for the development of pulmonary hypertension have not been reported from Africa. We studied 208 hydroxyurea naïve Nigerian SCD patients at steady state and 94 healthy controls. Pulmonary artery systolic hypertension was defined prospectively as tricuspid regurgitant jet velocity > or =2.5 m/sec. Results were compared with a previously published US prospective SCD cohort. Only 7% of Nigerians compared with 46% of US adults with SCD were >35 years. Tricuspid regurgitant jet velocity was > or =2.5 m/sec in 25% of Nigerian SCD patients. Higher jet velocity was associated with greater serum globulin (P = 0.002), blood urea nitrogen (P = 0.019) and lactate dehydrogenase concentrations (P = 0.026) and with inability to walk >300 m in 6 min (P = 0.042). Compared with the US cohort, Nigerian patients had more hemolysis as indicated by lower hemoglobin and higher lactate dehydrogenase concentrations (P < or = 0.003). Pulmonary hypertension is common among Nigerian SCD patients. The public health implication of this finding is significant considering the potential number of individuals at risk for this complication. Better understanding of the long term outcome of pulmonary hypertension and causes of death in SCD and the institution of preventive measures are major public health challenges for Africa. The inclusion of African sites in sickle cell pulmonary hypertension clinical trials should be encouraged.

Cis-vaccenic acid induces differentiation and up-regulates gamma globin synthesis in K562, JK1 and transgenic mice erythroid progenitor stem cells.

Gamma globin induction remains a promising pharmacological therapeutic treatment mode for sickle cell anemia and beta thalassemia, however Hydroxyurea remains the only FDA approved drug which works via this mechanism. In this regard, we assayed the γ-globin inducing capacity of Cis-vaccenic acid (CVA). CVA induced differentiation of K562, JK1 and transgenic mice primary bone marrow hematopoietic progenitor stem cells. CVA also significantly up-regulated γ-globin gene expression in JK-1 and transgenic mice bone marrow erythroid progenitor stem cells (TMbmEPSCs) but not K562 cells without altering cell viability. Increased γ-globin expression was accompanied by KLF1 suppression in CVA induced JK-1 cells. Erythropoietin induced differentiation of JK-1 cells 24h before CVA induction did not significantly alter CVA induced differentiation and γ-globin expression in JK-1 cells. Inhibition of JK-1 and Transgenic mice bone marrow erythroid progenitor stem cells Fatty acid elongase 5 (Elovl5) and Δ(9) desaturase suppressed the γ-globin inductive effects of CVA. CVA treatment failed to rescue γ-globin expression in Elovl5 and Δ(9)-desaturase inhibited cells 48 h post inhibition in JK-1 cells. The data suggests that CVA directly modulates differentiation of JK-1 and TMbmEPSCs, and indirectly modulates γ-globin gene expression in these cells. Our findings provide important clues for further evaluations of CVA as a potential fetal hemoglobin therapeutic inducer.

Pattern of serum cytokine expression and T-cell subsets in sickle cell disease patients in vaso-occlusive crisis.

The pathogenesis of sickle vaso-occlusive crisis (VOC) in sickle cell disease (SCD) patients involves the accumulation of rigid sickle cells and the stimulation of an ongoing inflammatory response, as well as the stress of infections. The immune response, via cytokine imbalances and deregulated T-cell subsets, also has been proposed to contribute to the development of VOC. In this study, a panel of high-sensitivity cytokine kits was used to investigate cytokines in the sera of SCD patients in VOC. The results were compared primarily with those for stable SCD patients and secondarily with those for normal healthy people who served as controls. The cytokines studied included interleukin-2 (IL-2), IL-4, and IL-10. Lymphocyte subsets of patients with VOC were also studied and were compared with those of both control groups (20 stable patients without crisis [SCD group] and 20 normal healthy controls [NHC]). The VOC group was notable for remarkably elevated levels of IL-4, among the three cytokines tested, compared with those for the SCD and NHC groups. Patients with VOC also differed from stable SCD patients and NHC by having notably lower IL-10 levels, as well as the lowest ratio of CD4(+) to CD8(+) T cells (0.7). The patterns of the proinflammatory cytokine IL-2 did not differ between VOC and stable SCD patients, but NHC had significantly lower IL-2 levels than both the VOC and SCD groups. Our results demonstrate coexisting levels, both high and low, of TH1- and TH2-type cytokines, as well as diminished levels of T-cell subsets in VOC. These results are discussed in an effort to better understand the importance of the immune system profile in the pathogenesis of sickle cell VOC. Since the possibility that a cytokine imbalance is implicated in the pathogenesis of sickle cell crisis has been raised, our results should prompt further investigation of the host immune response in terms of TH1 and TH2 balance in sickle cell crisis.

Severe depression following á-interferon usage in a patient with chronic myeloid leukemia.

BACKGROUND: Chronic myeloid leukaemia (CML), with a median age of 40 years, is one of the commonest haematological malignancies in Nigeria. Cytoreductive agents, which were hitherto the mainstay of treatment, neither induce cytogenetic nor haematologic remission. Alphainterferon (á-IFN), an endogenous glycoprotein with cytotoxic and natural killer cell enhancer effects has been found to induce haematologic and cytogenetic remission in patients with CML, but neuro-psychiatric complications of á -interferon (á-IFN) usage were not reported in Nigeria. OBJECTIVE: To report a case of deliberate self-harm in University Lecturer as a side effect of á-IFN in the treatment of CML METHOD: Clinical and laboratory follow up of a patient receiving á-IFN in the management of CML from the time of diagnosis of CML to the point of loss of contact. RESULT: Severe depression is a complication that may adversely influence the clinical outcome of á-IFN usage CONCLUSIONS/RECOMMENDATIONS: Although interferon related depression is uncommon, it is suggested that pre-therapy interferon assays and neuro-psychiatric assessment are carried out in prospective users of á-IFN.

Sickle cell disease and pulmonary hypertension in Africa: a global perspective and review of epidemiology, pathophysiology, and management.

Secondary pulmonary hypertension (PAH) has been shown to have a prevalence of 30% in patients with sickle cell disease (SCD) with mortality rates of 40% at 40 months after diagnosis in the United States. The burden of SCD is highest in sub-Saharan Africa, especially in Nigeria (West Africa), where approximately 6 million people are afflicted. The true global incidence, prevalence, and burden of SCD and its associated end organ complications however remain unknown. Chronic hemolysis represents a prominent mechanistic pathway in the pathogenesis of SCD-associated pulmonary hypertension via a nitric oxide (NO) scavenging and abrogation of NO salutatory effects on vascular function, including smooth muscle relaxation, downregulation of endothelial adhesion molecules and inhibition of platelet activation. Many known infectious risk factors for PAH are also hyperendemic in Africa, including Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS), chronic hepatitis B and C, and possibly malaria. Interactions between these infectious complications and SCD-related hemolysis could yield an even higher prevalence of pulmonary hypertension and compound the existing global health systems challenges in managing SCD. Indeed, our preliminary analysis of African immigrants currently in the United States suggests that pulmonary hypertension represents a significant complication of SCD in the African subcontinent. There is clearly a need to include Africa and other parts of the world with high SCD prevalence in future comprehensive studies on the epidemiology and treatment of end organ complications of an aging SCD population world-wide.