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Background: Iron deficiency, the most common micronutrient disorder and cause of anaemia globally, impairs growth, cognition, behaviour and resistance to infection. Methods/Results: As part of a national survey of inherited haemoglobin variants in 7526 students from 72 secondary schools purposefully selected from the 25 districts of Sri Lanka, we studied 5912 students with a normal haemoglobin genotype. Median age was 16.0 (IQR 15.0–17.0) years and 3189 (53.9%) students were males. Most students were Sinhalese (65.7%), with fewer Tamils (23.1%) and Muslims (11.2%). Anaemia occurred in 470 students and was more common in females (11.1%) than males (5.6%). Haemoglobin, serum ferritin, transferrin receptor and iron were determined in 1196 students with low red cell indices and a structured sample of those with normal red cell indices (n = 513). The findings were weighted to estimate the frequencies of iron deficiency and iron deficiency anaemia classified according to WHO criteria. Iron depletion (serum ferritin 28.1 nmol/l) in 11.6% students. Iron deficiency anaemia (cellular iron deficiency with low haemoglobin) occurred in only 130/2794 (4.6%) females and 28/2789 (1.0%) males. Iron biomarkers were normal in 83/470 (14.6%) students with anaemia. In multiple regression analysis, the odds for iron depletion and cellular iron deficiency were about one-third in males compared with females, and the odds for iron deficiency anaemia were about one fifth in males compared to females. Tamil ethnicity and age Conclusions: Low iron status and anaemia remain common problems in Sri Lankan secondary school students especially females, younger students and the socioeconomically disadvantaged Tamil population. More research is needed to identify factors other than low iron status that contribute to anaemia in adolescents.

Studies of the frequency of heterozygous carriers for common inherited diseases of haemoglobin in over 7500 adolescent children in 25 districts in Sri Lanka have disclosed a highly significant variation over very short geo- graphical distances. A further analysis of these findings, including their relationship to the past frequency and distribution of malaria, climatic vari- ation, altitude, ethnic origin and consanguinity rates, have provided evi- dence regarding the evolutionary basis for the variable distribution of these conditions over short distances. It is likely that the complex interplay between malaria and the environment, together with related ethnic and social issues, exists in many countries across the tropical belt. Hence, these observations emphasise the importance of micromapping heterozygote dis- tributions in high-frequency countries in order to define their true burden and the facilities required for the prevention and management of the homozygous and compound heterozygous disorders that result from their interaction.

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10(-4) with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

Anemia affects over 800 million women and children globally. Measurement of hepcidin as an index of iron status shows promise, but its diagnostic performance where hemoglobinopathies are prevalent is unclear. We evaluated the performance of hepcidin as a diagnostic test of iron deficiency in adolescents across Sri Lanka. We selected 2273 samples from a nationally representative cross‐sectional study of 7526 secondary schoolchildren across Sri Lanka and analyzed associations between hepcidin and participant characteristics, iron indices, inflammatory markers, and hemoglobinopathy states. We evaluated the diagnostic accuracy of hepcidin as a test for iron deficiency with estimation of the AUCROC, sensitivity/specificity at each hepcidin cutoff, and calculation of the Youden Index to find the optimal threshold. Hepcidin was associated with ferritin, sTfR, and hemoglobin. The AUCROC for hepcidin as a test of iron deficiency was 0.78; hepcidin outperformed Hb and sTfR. The Youden index‐predicted cutoff to detect iron deficiency (3.2 ng/mL) was similar to thresholds previously identified to predict iron utilization and identify deficiency in African populations. Neither age, sex, nor α‐ or β‐thalassemia trait affected diagnostic properties of hepcidin. Hepcidin pre‐screening would prevent most iron‐replete thalassemia carriers from receiving iron whilst still ensuring most iron deficient children were supplemented. Our data indicate that the physiological relationship between hepcidin and iron status transcends specific populations. Measurement of hepcidin in individuals or populations could establish the need for iron interventions.

OBJECTIVE. We investigated occupational therapy faculty beliefs about and perceptions of interprofessional education (IPE) and to identify differences in faculty positions on IPE between programs affiliated with an on-campus academic health care center (AHC) and programs not affiliated with an on-campus AHC. METHOD. Online surveys were distributed by email to 1,466 faculty at programs accredited by the Accreditation Council for Occupational Therapy Education. The results were described using descriptive statistics and cross-tabulations. RESULTS. Faculty responses supported the need for IPE. Ethics was ranked as the most important IPE competency among both the AHC and the non-AHC groups. IPE was more commonly included in the curriculum of programs with an on-campus AHC than in the curriculum of those without an AHC. CONCLUSION. The majority of occupational therapy faculty supported the need for IPE; however, many reported limitations with faculty or time constraints as barriers to IPE.

Glucose, the predominant energy substrate of the central and peripheral nervous system, is delivered to neurons via a family of facilitative glucose transporters (GLUT). The majority of glucose is transported to the brain via glucose transporter 1 (GLUT1) located on epithelial cells of capillaries and on the astrocytes that wrap around them. Changes in neuronal activity are linked to increases in glucose demand and local cerebral glucose utilization. Current research has indicated a corresponding change in GLUT1 expression in response to increased metabolic demand in operant tasks. The purpose of this study was to examine, in the mouse brain, the effects of neuronal activation induced by voluntary running on the plastic expression of vascular GLUT1 and neuronal plasticity as measured by the microtubule protein beta-tubulin III (Tuj). The results showed that access to a running wheel for 48 h induced plastic changes in the expression of GLUT1, Tuj and GLUT1-associated estimate of astrocyte vascular endfeet in motor regions. The results tend to support the plastic association between mechanisms of energy supply and plastic reorganization of neurons following a new training experience.

The α-globin genes were studied in nine families with unexplained hypochromic anaemia and in 167 patients with HbE β thalassaemia in Sri Lanka. As well as the common deletion forms of α(+) thalassaemia three families from an ethnic minority were found to carry a novel form of α(0) thalassaemia, one family carried a previously reported form of α(0) thalassaemia, --(THAI), and five families had different forms of non-deletional thalassaemia. The patients with HbE β thalassaemia who had co-inherited α thalassaemia all showed an extremely mild phenotype and reduced levels of HbF and there was a highly significant paucity of α(+) thalassaemia in these patients compared with the normal population. Extended α gene arrangements, including ααα, αααα and ααααα, occurred at a low frequency and were commoner in the more severe phenotypes of HbE β thalassaemia. As well as emphasising the ameliorating effect of α thalassaemia on HbE β thalassaemia the finding of a novel form of α(0) thalassaemia in an ethnic minority, together with an unexpected diversity of forms of non-deletion α thalassaemia in Sri Lanka, further emphasises the critical importance of micro-mapping populations for determining the frequency of clinically important forms of the disease.

During investigations of the phenotypic diversity of hemoglobin (Hb) E β thalassemia, a patient was encountered with persistently high levels of methemoglobin associated with a left-shift in the oxygen dissociation curve, profound ascorbate deficiency, and clinical features of scurvy; these abnormalities were corrected by treatment with vitamin C. Studies of erythropoietin production before and after treatment suggested that, as in an ascorbate-deficient murine model, the human hypoxia induction factor pathway is not totally dependent on ascorbate levels. A follow-up study of 45 patients with HbE β thalassemia showed that methemoglobin levels were significantly increased and that there was also a significant reduction in plasma ascorbate levels. Haptoglobin levels were significantly reduced, and the high frequency of the 2.2 haptoglobin genotype may place an additional pressure on ascorbate as a free-radical scavenger in this population. There was, in addition, a highly significant correlation between methemoglobin levels, splenectomy, and factors that modify the degree of globin-chain imbalance. Because methemoglobin levels are modified by several mechanisms and may play a role in both adaptation to anemia and vascular damage, there is a strong case for its further study in other forms of thalassemia and sickle-cell anemia, particularly when splenic function is defective.

The thalassemias pose an increasing burden for health-care services in many Asian countries. In order to conserve rare resources, it is essential to determine the reasons for the remarkable phenotypic heterogeneity and natural history of these disorders so that the most cost-effective methods for their control and management can be established. A long-term observational study of patients with different forms of thalassemia in Sri Lanka suggests that in addition to the well-defined primary, secondary and tertiary genetic modifiers, environmental factors, particularly malaria, and variation in the ability to adapt to the profound anaemia which characterizes these conditions, may play a significant role in determining their clinical severity. These findings may have important implications for the control and management of thalassemia in Asian populations.

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Hemoglobin E (HbE) β-thalassemia is the most common severe thalassemia syndrome across Asia, and millions of people are carriers. Clinical heterogeneity in HbE β-thalassemia is incompletely explained by genotype, and the interaction of phenotypic variation with hepcidin is unknown. The effect of thalassemia carriage on hepcidin is also unknown, but it could be relevant for iron supplementation programs aimed at combating anemia. In 62 of 69 Sri Lankan patients with HbE β-thalassemia with moderate or severe phenotype, hepcidin was suppressed, and overall hepcidin inversely correlated with iron accumulation. On segregating by phenotype, there were no differences in hepcidin, erythropoiesis, or hemoglobin between severe or moderate disease, but multiple linear regression showed that erythropoiesis inversely correlated with hepcidin only in severe phenotypes. In moderate disease, no independent predictors of hepcidin were identifiable; nevertheless, the low hepcidin levels indicate a significant risk for iron overload. In a population survey of Sri Lankan schoolchildren, β-thalassemia (but not HbE) trait was associated with increased erythropoiesis and mildly suppressed hepcidin, suggesting an enhanced propensity to accumulate iron. In summary, the influence of erythropoiesis on hepcidin suppression associates with phenotypic disease variation and pathogenesis in HbE β-thalassemia and indicates that the epidemiology of β-thalassemia trait requires consideration when planning public health iron interventions.

Vitamin D receptor (VDR) gene polymorphisms have been implicated in susceptibility to tuberculosis (TB), but reports have been inconsistent. We genotyped the VDR single-nucleotide polymorphisms (SNPs) FokI, BsmI, ApaI, and TaqI in 1139 case patients and control subjects and 382 families from The Gambia, Guinea, and Guinea-Bissau. The transmission-disequilibrium test on family data showed a significant global association of TB with SNP combinations FokI-BsmI-ApaI-TaqI and FokI-ApaI that were driven by the increased transmission to affected offspring of the FokI F and ApaI A alleles in combination. The ApaI A allele was also transmitted to affected offspring significantly more often than expected. Case-control analysis showed no statistically significant association between TB and VDR variants. BsmI, ApaI, and TaqI showed strong linkage disequilibrium. The significance of the family-based associations found between TB and FokI-BsmI-ApaI-TaqI and the FA haplotype supports a role for VDR haplotypes, rather than individual genotypes, in susceptibility to TB.

This Note begins by examining the facts of Republican Party of Minnesota v. White.Il Second, it examines the history of the judicial election system in Texas. Third, it examines the development of the Texas Code of Judicial Conduct and compares the American Bar Association's (ABA) past and current judicial codes with the Texas counterparts. Fourth, the Note analyzes the Supreme Court's decision and discusses the ramifications the White ruling will likely have on the judicial election process in Texas. Finally, this Note discusses possible alternatives to the electoral process in an effort to respond to the likely ramifications of White as well as improve the judiciary in Texas.

Guillain-Barn! syndrome is a subacute inflammatory demyelinating polyradicular neuropathy of the peripheral nerves. It is characterized by varying degrees of weakness, sensory abnormalities, and autonomic dysfunction. The cause of Guillain-Barre syndrome is not completely understood, but it is believed to be a postinfectious autoimmune disorder, because approximately two thirds of all cases are preceded by an infection, such as those caused by human immunodeficiency virus, cytomegalovirus, Epstein-Barr virus, and Campylobacter jejuni. Occasionally Guillain -Barre syndrome has been reported to come after vaccinations of various types. C jejuni infection, thought to be the most common antecedent infection to Guillain-Barre syndrome and the only bacterial infection that regularly precedes it, has been implicated in 50 to 75 percent of all cases. Culture studies have proved that a high proportion of patients with Guillain-Barre syndrome have C jejuni infection in their stools at the time of the onset of neurologic symptoms as well. We describe a case of Guillain-Barre syndrome associated with gastrointestinal C jejuni infection. This case not only highlights the clinical aspects of Guillain-Barre syndrome but also illustrates the severity of this neurologic syndrome and the lack of response to both plasmapheresis and immunoglobulin therapy.

Hemoglobin E β thalassemia is the commonest form of severe thalassemia in many Asian countries. Its remarkably variable clinical phenotype presents a major challenge to determining its most appropriate management. In particular, it is not clear why some patients with this condition can develop and function well at very low hemoglobin levels. Here, we demonstrate that patients with hemoglobin Eβ thalassemia have a significant decrease in the oxygen affinity of their hemoglobin, that is an increased P50 value, in response to anemia. This may in part reflect the lower level of hemoglobin F in this condition compared with other forms of β thalassemia intermedia. The ability to right-shift the oxygen dissociation curve was retained across the spectrum of mild and severe phenotypes, despite the significantly higher levels of hemoglobin F in the former, suggesting that efforts directed at producing a modest increase in the level of hemoglobin F in symptomatic patients with this disease should be of therapeutic value.

In order to obtain an approximate assessment of the public health burden that will be posed by the inherited disorders of haemoglobin in southern Vietnam, several thousand individuals were screened for these conditions. A smaller sample was screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency. The important haemoglobin disorders identified were beta thalassaemia, haemoglobin E and a variety of different forms of alpha thalassaemia. There were sufficient G6PD-deficient individuals to materially affect malaria control programme design. The most remarkable finding was wide variation in the gene frequencies of these conditions among the ethnic groups sampled. The approximate number of babies expected to be born with clinically significant haemoglobin disorders in Vietnam was estimated from the gene-frequency data. This study emphasizes the importance of wide-scale population screening, including ethnic subgroups, to establish the requirements for inherited haemoglobin disorder programmes in resource-limited settings.

Background The heritable haemoglobinopathy α+-thalassaemia is caused by the reduced synthesis of α-globin chains that form part of normal adult haemoglobin (Hb). Individuals homozygous for α+-thalassaemia have microcytosis and an increased erythrocyte count. α+-Thalassaemia homozygosity confers considerable protection against severe malaria, including severe malarial anaemia (SMA) (Hb concentration < 50 g/l), but does not influence parasite count. We tested the hypothesis that the erythrocyte indices associated with α+-thalassaemia homozygosity provide a haematological benefit during acute malaria. Methods and Findings Data from children living on the north coast of Papua New Guinea who had participated in a case-control study of the protection afforded by α+-thalassaemia against severe malaria were reanalysed to assess the genotype-specific reduction in erythrocyte count and Hb levels associated with acute malarial disease. We observed a reduction in median erythrocyte count of ∼1.5 × 1012/l in all children with acute falciparum malaria relative to values in community children (p < 0.001). We developed a simple mathematical model of the linear relationship between Hb concentration and erythrocyte count. This model predicted that children homozygous for α+-thalassaemia lose less Hb than children of normal genotype for a reduction in erythrocyte count of >1.1 × 1012/l as a result of the reduced mean cell Hb in homozygous α+-thalassaemia. In addition, children homozygous for α+-thalassaemia require a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02) for Hb concentration to fall to 50 g/l, the cutoff for SMA. We estimated that the haematological profile in children homozygous for α+-thalassaemia reduces the risk of SMA during acute malaria compared to children of normal genotype (relative risk 0.52; 95% confidence interval [CI] 0.24–1.12, p = 0.09). Conclusions The increased erythrocyte count and microcytosis in children homozygous for α+-thalassaemia may contribute substantially to their protection against SMA. A lower concentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologically advantageous strategy against the significant reduction in erythrocyte count that occurs during acute infection with the malaria parasite Plasmodium falciparum. This haematological profile may reduce the risk of anaemia by other Plasmodium species, as well as other causes of anaemia. Other host polymorphisms that induce an increased erythrocyte count and microcytosis may confer a similar advantage., Karen Day and colleagues show that increased microcytic erythrocyte count may contribute substantially to the protection of α+-thalassaemia-homozygous children against severe malaria anaemia., Editors' Summary Background. Mutations (changes in the DNA that encodes proteins) continually arise within human populations. Harmful mutations that affect an individual's ability to reproduce usually disappear, but most other mutations persist at a low frequency. Some mutations, however, protect their human carriers against specific disease-causing organisms, and consequently occur at high frequencies in human populations that live in places where these organisms are common. For example, the inherited blood disorder α+-thalassemia, which is common in Africa and Southeast Asia, provides protection against malaria, a parasitic disease that occurs in tropical and subtropical parts of the world. α+-Thalassemia is caused by the loss of one or more of the genes that encode the α chains of hemoglobin, the red blood cell (erythrocyte) protein that carries oxygen around the body. These α chains are normally encoded by four genes, two on each Chromosome 16 (all chromosomes come in pairs). People with heterozygous α+-thalassemia lack one copy of the α chain gene and have a –α/αα genotype (genetic makeup). People with homozygous α+-thalassemia lack one copy of the gene on each chromosome (they have a –α/–α genotype) and have mild “microcytic anemia,” a condition characterized by increased numbers of abnormally small erythrocytes (microcytosis) that contain reduced amounts of hemoglobin. Why Was This Study Done? Paradoxically, although homozygous α+-thalassemia causes mild anemia, it provides protection against severe malarial anemia, a potentially fatal complication of malaria. Malaria parasites cause anemia because they multiply inside erythrocytes and rupture them. Scientists originally thought that α+-thalassemia protects against malaria by interfering with the parasite's ability to infect erythrocytes, but the evidence collected so far does not support this hypothesis. In this study, therefore, the researchers have investigated whether the microcytosis and increased erythrocyte count associated with α+-thalassemia might be responsible for the protection that this blood disorder provides against severe malarial anemia. Specifically, they asked whether this hematological (blood) profile protects against severe malarial anemia because people with the –α/–α genotype lose less hemoglobin for a given degree of malaria-induced erythrocyte loss than do those with the normal genotype. What Did the Researchers Do and Find? A study done in the mid 1990s in children living on the north coast of Papua New Guinea (where 68% of the population has α+-thalassemia) showed that homozygous α+-thalassemia protects against severe malaria. To investigate why, the researchers re-analyzed the genotype-specific reduction in erythrocyte counts and hemoglobin levels associated with acute malarial disease in these children and developed a simple mathematical model to predict hemoglobin levels after malaria infection. They found that when malarial infection reduced the number of erythrocytes per liter of blood by more than 1.1 × 1012 (the average measured loss of erythrocytes in this population because of malaria was 1.5 × 1012 per liter), children with homozygous α+-thalassemia lost less hemoglobin than did those with the normal genotype. Furthermore, children with homozygous α+-thalassemia needed a 10% greater reduction in their red blood cell count than children with the normal genotype for their hemoglobin levels to fall below the value that defines severe malarial anemia. What Do These Findings Mean? These findings suggest that the increased number of abnormally small erythrocytes associated with homozygous α+-thalassemia might be responsible for the protection against severe malarial anemia that this blood disorder provides, because more erythrocytes have to be destroyed by the parasite to reduce hemoglobin concentrations to a dangerous level than in people with the normal genotype. In other words, a lower concentration of hemoglobin per erythrocyte coupled with a larger population of erythrocytes might be advantageous in the face of the large reduction in erythrocyte numbers caused by infection with malaria parasites. The researchers note that their study population was infected with only one type of malaria parasite (Plasmodium falciparum), but speculate that the hematological profile associated with α+-thalassemia might also prevent other Plasmodium species causing anemia. Futhermore, they suggest, other mutations that increase the erythrocyte count and cause microcytosis might protect against severe malaria anemia in a similar fashion. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050056. The MedlinePlus encyclopedia contains pages on thalassemia and on malaria (in English and Spanish) Detailed information is available on thalassemia (including useful links to other resources) from the US National Heart Lung and Blood Institute, from the US National Human Genome Research Institute, from the Cooley's Anemia Foundation, and from MedlinePlus The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish) Information is also available from the World Health Organization on malaria (in English, Spanish, French, Russian, Arabic, and Chinese)

SETTING Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. Studies in a murine model of pulmonary TB have identified a role for Toll-like receptor 4 (TLR4) in the development of chronic lung infection with Mycobacterium tuberculosis. The Asp299Gly polymorphism in the human TLR4 gene is associated with in vivo hyporesponsiveness to lipopolysaccharide (LPS) in Caucasians. OBJECTIVE To determine whether TLR4 Asp299Gly influences LPS responses or susceptibility to pulmonary TB in humans in a Gambian population sample. DESIGN We compared whole blood monokine responses to LPS in 245 healthy blood donors stratified by TLR4 Asp299Gly genotype to assess whether this polymorphism was functional in this population. A case-control study of 640 subjects was conducted to investigate whether TLR4 Asp299Gly was associated with TB. RESULTS LPS-induced tumour necrosis factor, interleukin-1 beta and interleukin-10 production was not influenced by TLR4 Asp299Gly genotype. There was no association between TLR4 Asp299Gly and TB. CONCLUSION Our data suggest that TLR4 Asp299Gly has no influence on monocyte LPS responses or susceptibility to TB in Gambians and could be an ancient neutral polymorphism.

Introduction Worldwide the greatest burden of disease related to beta thalassemia resides in Asia and is largely represented by Hemoglobin E beta thalassemia (HbE/thal) [Weatherall DJ, Ann New York Acad Sci 2005, 1054:11-17]. HbE/thal is the most common serious form of beta thalassemia in many Asian populations. In Sri Lanka, over 17 years, we have characterized over 200 affected patients and had proposed [Olivieri, NF, et al., J Pediatr Hematol Oncol, 2000, 22:593-597], as now shown in less common forms of non-transfusion dependent thalassemia [Taher AT, et al., Br J Haematol 2010, 150:486-489], that non-transfusional iron accumulation (NTIA) is a potential complication in non-transfused patients with HbE/thal. In 2009, we implemented R2-MRI [St Pierre, TG, et al., Blood 2005, 105:855-861] in Sri Lanka. Here we report the variation and severity of non-transfusional iron accumulation (NTIA), in parallel with screening tests of organ dysfunction, in a first group of patients with HbE/thal. Methods Patients aged > 7 years with clinical evidence of iron overload (generally a serum ferritin > normal range in the absence of a history of regular transfusions) were recruited from The National Thalassaemia Centre (NTC), Kurunegala, Sri Lanka. LIC was measured using R2-MRI (FerriScan¨) with facilities situated a 6 hour return bus trip from the NTC. Liver function was evaluated using serum alanine transaminase (ALT). Fasting blood glucose (FBG), thyroid stimulating hormone (TSH), serum calcium and phosphate and serum ferritin (SF) were measured in local laboratories. Cardiac function was measured using echocardiography. Correlations between parameters were assessed using non-parametric (Spearman) analysis. Receiver operating characteristic (ROC) curve analysis was used to determine the optimum cut-off values of LIC and serum ferritin for predicting ALT values above the upper limit of the laboratory reference range. Results LIC measurements were successfully acquired for 110 of 112 enrolled subjects (45 male/ 67 female) with median age [range] 22.5 [7.8 – 61.5] years over 3 years. The variation in LIC was considerably, and unexpectedly, broad: median [range] LIC was 8.8 [0.7 – 65.0] mg Fe/g dw. LIC exceeded the threshold of risk established as 7.0 mg Fe/g dw [Olivieri NF, Brittenham GM, Blood 1997, 89:739-761] in a substantial proportion (57%) of patients. In parallel, organ dysfunction was observed: in a substantial group (52%), ALT was increased above normal range, while in 11%, ejection fraction was reduced (less than 56%). FBG and TSH were elevated above normal range in a substantial proportion of patients (6% and 30% respectively). Significant correlations were observed between LIC and serum ferritin concentration (r2=0.69, p Discussion This study of Asian patients with HbE/thal using R2-MRI, an FDA-approved non-invasive method of evaluation of LIC, reveals a wide range of NTIA and, in parallel, a significant proportion of patients with evidence of liver dysfunction. Our data suggest that the liver is at direct risk from NTIA in HbE/thal at a threshold of 6.35 mg Fe/g dry liver tissue. More robust correlations with dysfunction occurring in other organs may be expected to emerge during longitudinal studies which will be critical to understanding the evolution of organ damage occurring secondary to NTIA in this disorder. These studies are urgently needed to prevent morbidity and premature death in this most common form of beta thalassemia. Disclosures: St Pierre: Resonance Health Ltd: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Consultancy, Research Funding; Celgene: Consultancy; Shire: Consultancy.

Meningitis is an important cause of childhood mortality in sub-Saharan Africa. A case-control study investigating the role of the Toll-like receptor 4 gene in host susceptibility to Group A Neisseria meningitidis meningitis was conducted in 524 Gambian children. There was no association between a functional Toll-like receptor 4 gene polymorphism and meningitis, suggesting that this variant is not a major determinant of disease in this population.

Platelet-endothelial cell adhesion molecule 1 (PECAM-1/CD31) has been identified as an endothelial cell receptor of Plasmodium falciparum-infected erythrocytes. The significance of adhesion of infected erythrocytes to this receptor in malaria infection has not been determined. We have therefore studied the association of the functional mutation CTG-->GTG (Leu-->Val) in codon 125 of the Cd31 gene with severe disease in 2 case-control studies of malaria in Madang Hospital, Papua New Guinea, and in Kilifi District Hospital, Kenya. We analyzed data from 442 cases and controls from Papua New Guinea and data from 396 cases and controls from Kenya. The codon 125 polymorphism was not associated with severe malaria in either study. We conclude that the presence of CTG-->GTG (Leu-->Val) substitution in codon 125 in CD31 is not associated with protection from severe malaria, and we suggest that selective forces other than malaria may maintain this high-frequency polymorphism.