Robust clinical and laboratory response to hydroxyurea using pharmacokinetically guided dosing for young children with sickle cell anemia

Hydroxyurea is FDA-approved and now increasingly used for children with sickle cell anemia (SCA), but dosing strategies, pharmacokinetic (PK) profiles, and treatment responses for individual patients are highly variable. Typical weight-based dosing with step-wise escalation to maximum tolerated dose (MTD) leads to predictable laboratory and clinical benefits, but often takes 6 to 12 months to achieve. The Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154) was a single-center study designed to prospectively validate a novel personalized PK-guided hydroxyurea dosing strategy with a primary endpoint of time to MTD. Enrolled participants received a single oral 20 mg/kg dose of hydroxyurea, followed by a sparse PK sampling approach with three samples collected over three hours. Analysis of individual PK data into a population PK model generated a starting dose that targets the MTD. The TREAT cohort (n = 50) was young, starting hydroxyurea at a median age of 11 months (IQR 9-26 months), and PK-guided starting doses were high (27.7 ± 4.9 mg/kg/d). Time to MTD was 4.8 months (IQR 3.3-9.3), significantly shorter than comparison studies (p < 0.0001), thus meeting the primary endpoint. More remarkably, the laboratory response for participants starting with a PK-guided dose was quite robust, achieving higher hemoglobin (10.1 ± 1.3 g/dL) and HbF (33.3 ± 9.1%) levels than traditional dosing. Though higher than traditional dosing, PK-guided doses were safe without excess hematologic toxicities. Our data suggest early initiation of hydroxyurea, using a personalized dosing strategy for children with SCA, provides laboratory and clinical response beyond what has been seen historically, with traditional weight-based dosing.     

Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial

Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open‐label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9·8 ± 2·9 years), predominantly female (60:40), and previously treated with transfusions (4·1 ± 2·4 years) and iron chelation (3·1 ± 2·1 years). Liver iron concentration (LIC; 9·0 ± 6·6 mg/g dry weight) and serum ferritin were moderately elevated (2696 ± 1678 μg/l), but transferrin was incompletely saturated (47·2 ± 23·6%). Spleen R2* was 509 ± 399 Hz (splenic iron ~13·9 mg/g) and correlated with LIC (r² = 0·14, P = 0·0008). Pancreas R2* was increased in 38·3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80·7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin‐creatinine ratios. Extra‐hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin.     

Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia

Glomerular hyperfiltration and microalbuminuria/proteinuria are early manifestations of sickle nephropathy. The effects of hydroxyurea therapy on these renal manifestations of sickle cell anemia (SCA) are not well defined. Our objective was to investigate the effects of hydroxyurea on glomerular filtration rate (GFR) measured by ^99mTc‐DTPA clearance, and on microalbuminuria/proteinuria in children with SCA. Hydroxyurea study of long‐term effects (HUSTLE) is a prospective study (NCT00305175) with the goal of describing the long‐term cellular, molecular, and clinical effects of hydroxyurea therapy in SCA. Glomerular filtration rate, urine microalbumin, and serum cystatin C were measured before initiating hydroxyurea therapy and then repeated after 3 years. Baseline and Year 3 values for HUSTLE subjects were compared using the Wilcoxon Signed Rank test. Associations between continuous variables were evaluated using Spearman correlation coefficient. Twenty‐three children with SCA (median age 7.5 years, range, 2.5–14.0 years) received hydroxyurea at maximum tolerated dose (MTD, 24.4 ± 4.5 mg/kg/day, range, 15.3–30.6 mg/kg/day). After 3 years of treatment, GFR measured by ^99mTc‐DTPA decreased significantly from 167 ± 46 mL/min/1.73 m² to 145 ± 27 mL/min/1.73 m² (P = 0.016). This decrease in GFR was significantly associated with increase in fetal hemoglobin (P = 0.042) and decrease in lactate dehydrogenase levels (P = 0.035). Urine microalbumin and cystatin C levels did not change significantly. Hydroxyurea at MTD is associated with a decrease in hyperfiltration in young children with SCA. Am. J. Hematol., 88:116–119, 2013. © 2012 Wiley Periodicals, Inc.     

A prospective newborn screening and treatment program for sickle cell anemia in Luanda,Angola

Over 300,000 infants are born annually with sickle cell anemia (SCA) in sub‐Saharan Africa, and >50% die young from infection or anemia, usually without diagnosis of SCA. Early identification by newborn screening (NBS), followed by simple interventions dramatically reduced the mortality of SCA in the United States, but this strategy is not yet established in Africa. We designed and implemented a proof‐of‐principle NBS and treatment program for SCA in Angola, with focus on capacity building and local ownership. Dried bloodspots from newborns were collected from five birthing centers. Hemoglobin identification was performed using isoelectric focusing; samples with abnormal hemoglobin patterns were analyzed by capillary electrophoresis. Infants with abnormal FS or FSC patterns were enrolled in a newborn clinic to initiate penicillin prophylaxis and receive education, pneumococcal immunization, and insecticide‐treated bed nets. A total of 36,453 infants were screened with 77.31% FA, 21.03% FAS, 1.51% FS, and 0.019% FSC. A majority (54.3%) of affected infants were successfully contacted and brought to clinical care. Compliance in the newborn clinic was excellent (96.6%). Calculated first‐year mortality rate for babies with SCA compares favorably to the national infant mortality rate (6.8 vs. 9.8%). The SCA burden is extremely high in Angola, but NBS is feasible. Capacity building and training provide local healthcare workers with skills needed for a functional screening program and clinic. Contact and retrieval of all affected SCA infants remains a challenge, but families are compliant with clinic appointments and treatment. Early mortality data suggest screening and early preventive care saves lives. Am. J. Hematol. 88:984–989, 2013. © 2013 Wiley Periodicals, Inc.     

A dose‐escalation phase IIa study of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer,in sickle cell disease

2,2‐dimethylbutyrate (HQK‐1001), an orally‐bioavailable promoter‐targeted fetal globin gene‐inducing agent, was evaluated in an open‐label, randomized dose‐escalation study in 52 subjects with hemoglobin SS or S/β⁰ thalassemia. HQK‐1001 was administered daily for 26 weeks at 30 mg/kg (n = 15), 40 mg/kg (n = 18) and 50 mg/kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 31). The most common drug‐related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose‐limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non‐compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases ≥4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8–3.2%] in 21 subjects receiving HQK‐1001 alone and 2.7% (95% CI, 1.7–3.8%) in 31 subjects receiving HQK‐1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5–1.0 g/dL), and 13 subjects (25%) had increases ≥1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK‐1001 in sickle cell disease. Am. J. Heamtol. 88:E255–E260, 2013. © 2013 Wiley Periodicals, Inc.     

The clinical epidemiology of sickle cell anemia In Africa

Sickle cell anemia (SCA) is the commonest severe monogenic disorders of humans. The disease has been highly characterized in high‐income countries but not in sub‐Saharan Africa where SCA is most prevalent. We conducted a retrospective cohort study of all children 0–13 years admitted from within a defined study area to Kilifi County Hospital in Kenya over a five‐year period. Children were genotyped for SCA retrospectively and incidence rates calculated with reference to population data. Overall, 576 of 18,873 (3.1%) admissions had SCA of whom the majority (399; 69.3%) were previously undiagnosed. The incidence of all‐cause hospital admission was 57.2/100 person years of observation (PYO; 95%CI 52.6–62.1) in children with SCA and 3.7/100 PYO (95%CI 3.7–3.8) in those without SCA (IRR 15.3; 95%CI 14.1–16.6). Rates were higher for the majority of syndromic diagnoses at all ages beyond the neonatal period, being especially high for severe anemia (hemoglobin <50 g/L; IRR 58.8; 95%CI 50.3–68.7), stroke (IRR 486; 95%CI 68.4–3,450), bacteremia (IRR 23.4; 95%CI 17.4–31.4), and for bone (IRR 607; 95%CI 284–1,300), and joint (IRR 80.9; 95%CI 18.1–362) infections. The use of an algorithm based on just five clinical features would have identified approximately half of all SCA cases among hospital‐admitted children with a number needed to test to identify each affected patient of only fourteen. Our study illustrates the clinical epidemiology of SCA in a malaria‐endemic environment without specific interventions. The targeted testing of hospital‐admitted children using the Kilifi Algorithm provides a pragmatic approach to early diagnosis in high‐prevalence countries where newborn screening is unavailable.     

Lymphomas in sub‐Saharan Africa – what can we learn and how can we help in improving diagnosis,managing patients and fostering translational research?

Approximately 30 000 cases of non‐Hodgkin lymphoma (NHL) occur in the equatorial belt of Africa each year. Apart from the fact that Burkitt lymphoma (BL) is very common among children and adolescents in Africa and that an epidemic of human immunodeficiency virus (HIV) infection is currently ongoing in this part of the world, very little is known about lymphomas in Africa. This review provides information regarding the current infrastructure for diagnostics in sub‐Saharan Africa. The results on the diagnostic accuracy and on the distribution of different lymphoma subsets in sub‐Saharan Africa were based on a review undertaken by a team of lymphoma experts on 159 fine needle aspirate samples and 467 histological samples during their visit to selected sub‐Saharan African centres is presented. Among children (<18 years of age), BL accounted for 82% of all NHL, and among adults, diffuse large B‐cell lymphoma accounted for 55% of all NHLs. Among adults, various lymphomas other than BL, including T‐cell lymphomas, were encountered. The review also discusses the current strategies of the International Network of Cancer Treatment and Research on improving the diagnostic standards and management of lymphoma patients and in acquiring reliable clinical and pathology data in sub‐Saharan Africa for fostering high‐quality translational research.     

Pain and other non‐neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: Results from the SWiTCH clinical trial

To compare the non‐neurological events in children with sickle cell anemia (SCA) and previous stroke enrolled in SWiTCH. The NHLBI‐sponsored Phase III multicenter randomized clinical trial stroke with transfusions changing to hydroxyurea (SWiTCH) ( ClinicalTrials.gov NCT00122980) compared continuation of chronic blood transfusion/iron chelation to switching to hydroxyurea/phlebotomy for secondary stroke prevention and management of iron overload. All randomized children were included in the analysis (intention to treat). The Fisher's Exact test was used to compare the frequency of subjects who experienced at least one SCA‐related adverse event (AE) or serious adverse event (SAE) in each arm and to compare event rates. One hundred and thirty three subjects, mean age 13 ± 3.9 years (range 5.2–19.0 years) and mean time of 7 years on chronic transfusion at study entry, were randomized and treated. Numbers of subjects experiencing non‐neurological AEs were similar in the two treatment arms, including SCA‐related events, SCA pain events, and low rates of acute chest syndrome and infection. However, fewer children continuing transfusion/chelation experienced SAEs (P = 0.012), SCA‐related SAEs (P = 0.003), and SCA pain SAEs (P = 0.016) as compared to children on the hydroxyurea/phlebotomy arm. The timing of phlebotomy did not influence SAEs. Older age at baseline predicted having at least 1 SCA pain event. Patients with recurrent neurological events during SWiTCH were not more likely to experience pain. In children with SCA and prior stroke, monthly transfusions and daily iron chelation provided superior protection against acute vaso‐occlusive pain SAEs when compared to hydroxyurea and monthly phlebotomy. Am. J. Heamtol. 88:932–938, 2013. © 2013 Wiley Periodicals, Inc.     

Type 2 diabetes mellitus and obesity in sub‐Saharan Africa

While communicable diseases such as human immunodeficiency virus/acquired immune deficiency syndrome, malaria, and tuberculosis have continued to pose greater threats to the public health system in sub‐Saharan Africa (SSA), it is now apparent that non‐communicable diseases such as diabetes mellitus are undoubtedly adding to the multiple burdens the peoples in this region suffer. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes (90–95%), exhibiting an alarming prevalence among peoples of this region. Its main risk factors include obesity, rapid urbanization, physical inactivity, ageing, nutrition transitions, and socioeconomic changes. Patients in sub‐Saharan Africa also show manifestations of β‐cell dysfunction and insulin resistance. However, because of strained economic resources and a poor health care system, most of the patients are diagnosed only after they have overt symptoms and complications. Microvascular complications are the most prevalent, but metabolic disorders and acute infections cause significant mortality. The high cost of treatment of T2DM and its comorbidities, the increasing prevalence of its risk factors, and the gaps in health care system necessitate that solutions be planned and implemented urgently. Aggressive actions and positive responses from well‐informed governments appear to be needed for the conducive interplay of all forces required to curb the threat of T2DM in sub‐Saharan Africa. Despite the varied ethnic and transitional factors and the limited population data on T2DM in sub‐Saharan Africa, this review provides an extensive discussion of the literature on the epidemiology, risk factors, pathogenesis, complications, treatment, and care challenges of T2DM in this region. Copyright © 2010 John Wiley & Sons, Ltd.     

Feasibility trial for primary stroke prevention in children with sickle cell anemia in Nigeria (SPIN trial)

The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence‐based guidelines for primary stroke prevention are lacking. In Kano, Nigeria, we conducted a feasibility trial to determine the acceptability of hydroxyurea therapy for primary stroke prevention in children with abnormal transcranial Doppler (TCD) measurements. Children with SCA and abnormal non‐imaging TCD measurements (≥200 cm/s) received moderate fixed‐dose hydroxyurea therapy (～20 mg/kg/day). A comparison group of children with TCD measurements <200 cm/s was followed prospectively. Approximately 88% (330 of 375) of families agreed to be screened, while 87% (29 of 33) of those with abnormal TCD measurements, enrolled in the trial. No participant elected to withdraw from the trial. The average mean corpuscular volume increased from 85.7 fl at baseline to 95.5 fl at 24 months (not all of the children who crossed over had a 24 month visit), demonstrating adherence to hydroxyurea. The comparison group consisted of initially 210 children, of which four developed abnormal TCD measurements, and were started on hydroxyurea. None of the monthly research visits were missed (n = total 603 visits). Two and 10 deaths occurred in the treatment and comparison groups, with mortality rates of 2.69 and 1.81 per 100 patient‐years, respectively (P = .67). Our results provide strong evidence, for high family recruitment, retention, and adherence rates, to undertake the first randomized controlled trial with hydroxyurea therapy for primary stroke prevention in children with SCA living in Africa.     

Alteration of lymphocyte phenotype and function in sickle cell anemia: Implications for vaccine responses

Individuals with sickle cell anemia (SCA) have increased susceptibility to infections, secondary to impairment of immune function. Besides the described dysfunction in innate immunity, including impaired opsonization and phagocytosis of bacteria, evidence of dysfunction of T and B lymphocytes in SCA has also been reported. This includes reduction in the proportion of circulating CD4+ and CD8+ T cells, reduction of CD4+ helper: CD8+ suppressor T cell ratio, aberrant activation and dysfunction of regulatory T cells (T_reg), skewing of CD4+ T cells towards Th2 response and loss of IgM‐secreting CD27 + IgM^highIgD^low memory B cells. These changes occur on the background of immune activation characterized by predominance of memory CD4+ T cell phenotypes, increased Th17 signaling and elevated levels of C‐reactive protein and pro‐inflammatory cytokines IL‐6 and TNF‐α, which may affect the immunogenicity and protective efficacy of vaccines available to prevent infections in SCA. Thus, in order to optimize the use of vaccines in SCA, a thorough understanding of T and B lymphocyte functions and vaccine reactivity among individuals with SCA is needed. Studies should be encouraged of different SCA populations, including sub‐Saharan Africa where the burden of SCA is highest. This article summarizes our current understanding of lymphocyte biology in SCA, and highlights areas that warrant future research. Am. J. Hematol. 91:938–946, 2016. © 2016 Wiley Periodicals, Inc.     

High Oxidative Stress Is Correlated with Frailty in Elderly Chinese

OBJECTIVES: To evaluate the relationship between oxidative stress and frailty in elderly people. DESIGN: Cross‐sectional study. SETTING: Community and hospital‐based outpatient clinic. PARTICIPANTS: Ninety participants aged 65 and older. MEASUREMENTS: Frailty status was determined according to the presence of weak handgrip strength, weight loss, slow walking speed, exhaustion, and low activity level and was classified as frail (≥3 criteria), prefrail (1 or 2 criteria), or robust (0 criteria). An oxidative stress marker (serum 8‐hydroxy‐2′‐deoxyguanosine, 8‐OHdG), metabolic markers (body mass index, waist–hip ratio, serum lipids, glucose, and albumin), an inflammatory marker (serum high‐sensitivity C‐reactive protein, hs‐CRP), demographic information, and comorbidities (diabetes mellitus, hypertension, congestive heart failure, osteoarthritis, overweight or obesity, impaired fasting plasma glucose, renal insufficiency, and depression) were assessed. RESULTS: Of the 90 participants, 21 (23.3%) were frail, 56 (62.2%) were prefrail, and 13 (14.4%) were robust. Frail subjects had higher median (range) serum 8‐OHdG (2.5 ng/mL (1.5–6.2 ng/mL) vs 2.3 ng/mL (0.5–8.1 ng/mL) and 1.0 ng/mL (0.5–5.3 ng/mL)) and serum hs‐CRP (2.5 mg/L (0.3–32.1 mg/L) vs 1.8 mg/L (0.3–50.5 mg/L) and 1.7 mg/L (0.3–4.0 mg/L)) levels, lower mean±standard deviation serum albumin levels (4.1±0.4 g/dL vs 4.4±0.4 g/dL and 4.6±0.2 g/dL) and higher mean waist–hip ratios (0.96±0.11 vs 0.91±0.07 and 0.89±0.05)) than prefrail and robust subjects, respectively (P<.05 for all). In multivariable regression analysis, high serum 8‐OHdG level was still significantly associated with frailty after adjusting for age, smoking status, comorbidities, waist–hip ratio, serum albumin level, and hs‐CRP level. CONCLUSION: High oxidative stress, characterized by high serum 8‐OHdG level, was independently associated with frailty in the selected sample of elderly Chinese.     

Bacteraemia in sickle cell anaemia is associated with low haemoglobin: a report of 890 admissions to a tertiary hospital in Tanzania

Bacteraemia is a leading cause of morbidity in sickle cell anaemia (SCA), but information from studies in Africa is limited. We evaluated 890 admissions from 648 SCA patients at a tertiary hospital in Tanzania. Bacteraemia was present in 43 admissions (4·8%); isolates included Staphylococcus aureus (12/43; 28%), non‐Typhi Salmonella (9/43; 21%), Streptococcus pneumoniae (3/43; 7%) and Salmonella Typhi (2/43; 5%). Compared to SCA patients without bacteraemia, SCA patients with bacteraemia had significantly lower haemoglobin [71 g/l vs. 62 g/l, odds ratio 0·72 (95% confidence interval 0·56–0·91), P < 0·01]. Further exploration is needed of the relationship between anaemia and bacterial infections in SCA in Africa.     

Hydroxyurea effectiveness in children and adolescents with sickle cell anemia: A large retrospective,population‐based cohort

The clinical efficacy of hydroxyurea in patients with sickle cell anemia (SCA) has been well established. However, data about its clinical effectiveness in practice is limited. We evaluated the clinical effectiveness of hydroxyurea in a large pediatric population using a retrospective cohort, pre‐post treatment study design to control for disease severity selection bias. The cohort included children with SCA (SS, Sβ⁰thalassemia) who received care at Children's Healthcare of Atlanta (CHOA) and who initiated hydroxyurea in 2009‐2011. Children on chronic transfusions, or children with inadequate follow up data and/or children who had taken hydroxyurea in the 3 years prior were excluded. For each patient healthcare utilization, laboratory values, and clinical outcomes for the 2‐year period prior to hydroxyurea initiation were compared to those 2 years after initiation. Of 211 children with SCA who initiated hydroxyurea in 2009–2011, 134 met eligibility criteria. After initiation of hydroxyurea, rates of hospitalizations, pain encounters, and emergency department visits were reduced by 47% (<0.0001), 36% (P = 0.0001) and 43% (P < 0.0001), respectively. Average hemoglobin levels increased by 0.7 g/dl (P < 0.0001). Hydroxyurea effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger children. Am. J. Hematol. 92:77–81, 2017. © 2016 Wiley Periodicals, Inc.     

Genetic modifiers of sickle cell anemia in the BABY HUG cohort: influence on laboratory and clinical phenotypes

The recently completed BABY HUG trial investigated the safety and efficacy of hydroxyurea in infants with sickle cell anemia (SCA). To investigate the effects of known genetic modifiers, genomic DNA on 190 randomized subjects were analyzed for alpha thalassemia, beta‐globin haplotype, polymorphisms affecting endogenous fetal hemoglobin (HbF) levels (XmnI, BCL11A, and HBS1L‐MYB), UGT1A1 promoter polymorphisms, and the common G6PD A^? mutation. At study entry, infants with alpha thalassemia trait had significantly lower mean corpuscular volume, total bilirubin, and absolute reticulocyte count. Beta‐globin haplotypes associated with milder disease had significantly higher hemoglobin and %HbF. BCL11A and XmnI polymorphisms had significant effects on baseline HbF, while UGT1A1 promoter polymorphisms significantly influenced baseline serum bilirubin. At study exit, subjects randomized to placebo still exhibited laboratory effects of alpha thalassemia and other modifiers, while those assigned hydroxyurea had treatment effects that exceeded most genetic influences. The pain phenotype was influenced by HbF modifiers in both treatment groups. These data document that genetic polymorphisms do modify laboratory and clinical phenotypes even in very young patients with SCA. The hydroxyurea effects are more potent, however, indicating that treatment criteria should not be limited to certain genetic subsets, and supporting the use of hydroxyurea for all young patients with SCA. Am. J. Hematol. 88:571–576, 2013. © 2013 Wiley Periodicals, Inc.     

Antiretroviral therapy in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America

Objectives To describe temporal trends in baseline clinical characteristics, initial treatment regimens and monitoring of patients starting antiretroviral therapy (ART) in resource‐limited settings. Methods We analysed data from 17 ART programmes in 12 countries in sub‐Saharan Africa, South America and Asia. Patients aged 16 years or older with documented date of start of highly active ART (HAART) were included. Data were analysed by calculating medians, interquartile ranges (IQR) and percentages by regions and time periods. Not all centres provided data for 2006 and 2005 and 2006 were therefore combined. Results A total of 36 715 patients who started ART 1996–2006 were included in the analysis. Patient numbers increased substantially in sub‐Saharan Africa and Asia, and the number of initial regimens declined, to four and five, respectively, in 2005–2006. In South America 20 regimes were used in 2005–2006. A combination of 3TC/D4T/NVP was used for 56% of African patients and 42% of Asian patients; AZT/3TC/EFV was used in 33% of patients in South America. The median baseline CD4 count increased in recent years, to 122 cells/μl (IQR 53–194) in 2005–2006 in Africa, 134 cells/μl (IQR 72–191) in Asia, and 197 cells/μl (IQR 61–277) in South America, but 77%, 78% and 51%, respectively, started with <200 cells/μl in 2005–2006. In all regions baseline CD4 cell counts were higher in women than men: differences were 22cells/μl in Africa, 65 cells/μl in Asia and 10 cells/μl in South America. In 2005–2006 a viral load at 6 months was available in 21% of patients Africa, 8% of Asian patients and 73% of patients in South America. Corresponding figures for 6‐month CD4 cell counts were 74%, 77% and 81%. Conclusions The public health approach to providing ART proposed by the World Health Organization has been implemented in sub‐Saharan Africa and Asia. Although CD4 cell counts at the start of ART have increased in recent years, most patients continue to start with counts well below the recommended threshold. Particular attention should be paid to more timely initiation of ART in HIV‐infected men.     

Scarification in sub‐Saharan Africa: social skin,remedy and medical import

Various forms of body modification may be observed in sub‐Saharan Africa. Hypotheses and theories of scarification and tribal marking in sub‐Saharan Africa are described, plus the procedure of scarification, examples from several African countries, assumed effects in prevention and treatment of diseases, and the medical risks resulting from unsterile manipulation.     

Splenectomy reduces fibrosis and preneoplastic lesions with increased triglycerides and essential fatty acids in rat liver cirrhosis induced by a choline‐deficient L‐amino acid‐defined diet

Aim: This study investigated whether splenectomy is of significance in non‐alcoholic steatohepatitis (NASH). Methods: Five‐week‐old Wistar rats were fed a choline‐deficient diet for 8 weeks to create a NASH model. A sham‐operation or splenectomy was then performed, and rats were killed 4 weeks later. Results: Liver fibrosis and liver preneoplastic lesions were significantly reduced in the splenectomy group compared to the sham‐operation group, and α‐smooth muscle actin (SMA) expression was significantly inhibited (liver fibrosis area: sham 8.63 ± 4.09%, splenectomy 5.45 ± 3.69%, P < 0.01; preneoplastic lesion size: sham 6.56 ± 3.68 ×10⁶ µm²/cm², splenectomy 4.63 ± 3.27 ×10⁶ µm²/cm², P < 0.05; the number of preneoplastic lesions: sham 8.33 ± 3.96/cm², splenectomy 5.17 ± 1.80/cm², P < 0.01; α‐smooth muscle actin‐positive area: sham 4.41 ± 2.48%, splenectomy 2.75 ± 1.66%, P < 0.01) On the other hand, liver triglycerides and essential fatty acids were significantly increased in the splenectomy group (liver triglycerides: sham 182 ± 35.0 mg/g, splenectomy 230 ± 35.0 mg/g, P < 0.05; liver linoleic acid: sham 17.2 ± 4.9 mg/g, splenectomy 23.3 ± 6.9 mg/g, P < 0.05; liver α‐linolenic acid: sham 118 ± 36.6 µg/g, splenectomy 162 ± 51.4 µg/g, P < 0.05). In addition, expressions of hepatic fatty acid metabolism‐related genes (e.g. acyl‐CoA oxidase, liver carnitine palmitoyl‐CoA transferase I, cytochrome P450 4A, long‐chain acyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase) were significantly inhibited in the splenectomy group. Conclusion: These findings suggest that spleen plays an important regulatory role in the fibrosis, preneoplastic lesion and lipid metabolism of liver in a rat choline‐deficient L‐amino acid model.