Patterns of funding allocation for tuberculosis control in fragile states.

OBJECTIVE: To assess recent (2006-2010) tuberculosis (TB) funding patterns in conflict and non-conflict-affected fragile states to inform global policy. METHODS: The Creditor Reporting System was analysed for official development assistance funding disbursements towards TB control in 11 conflict-affected states, 17 non-conflict-affected fragile states and 38 comparable non-fragile states. The amounts of funding, funding relative to burden, funding relative to malaria and human immunodeficiency virus (HIV) control, disbursements relative to commitments, sources of funding as well as funding activities were extracted and analysed. RESULTS: Fragile states received on average more per capita for TB control relative to non-fragile states (US0.159 vs. US0.079). However conflict-affected fragile states received on average less per capita than non-conflict-affected states (US0.144 vs. US0.203), despite worse development indicators. Conflict-affected fragile states also received on average only 70% of TB funds already committed. Analysis by burden revealed the least disparity in funding in highest prevalence settings. Analysis of funding activities suggests increasing importance of TB-HIV integration, multidrug-resistant TB and research in both fragile and non-fragile states. Relative to non-conflict-affected fragile states, conflict-affected fragile states received approximately two thirds the per capita funding for TB. CONCLUSIONS: This study revealed disparities in TB control funding between fragile and non-fragile as well as between conflict and non-conflict-affected fragile states. Findings suggest possible avenues for improving the allocation of global TB funding.

Monocytoid B cells: an enigmatic B cell subset showing evidence of extrafollicular immunoglobulin gene somatic hypermutation.

Monocytoid B cells are IgM(+) , IgD(-/+) , CD27(-) B cells, localized in the perisinusoidal area of the lymph node. These cells are especially prominent in infections such as those caused by toxoplasma and HIV. The ontogeny of monocytoid B cells with respect to B cell maturation is incompletely known. We analysed clonal expansion, somatic hypermutation and expression of activation-induced cytidine deaminase (AID) in monocytoid B cells. Sequence analysis of the rearranged immunoglobulin heavy chain genes amplified from microdissected monocytoid B cell zones with a high proportion of proliferating cells reveals the presence of multiple clones with low-level ongoing mutations (mean frequency: 0.46 × 10(-2) per bp). Mutation analysis of these ongoing mutations reveals strand bias, a preference of transitions over transversions as well as the occurrence of small deletions, as observed for somatically mutated immunoglobulin genes in the human germinal centre. Proliferation, ongoing mutation as well as expression of AID, combined, is evidence that monocytoid B cells acquire the mutations in the extrafollicular perisinusoidal area of the lymph node and pleads against a postgerminal centre B cell origin.

Therapeutic efficacy of chloroquine and sulfadoxine/pyrimethamine against Plasmodium falciparum infection in Somalia.

OBJECTIVE: To assess the efficacy of chloroquine and sulfadoxine/pyrimethamine in the treatment of uncomplicated Plasmodium falciparum infections in Somalia. METHODS: Patients with clinical malaria in Merca, an area of high transmission of the disease, were treated with the standard regimens of chloroquine (25 mg/kg) or sulfadoxine/pyrimethamine (25 mg sulfadoxine and 1.25 mg pyrimethamine per kg). Similar patients in Gabiley, an area of low transmission, received the standard regimen of chloroquine. The clinical and parasitological responses were monitored for 14 days. FINDINGS: Chloroquine treatment resulted in clinical failure in 33% (n = 60) and 51% (n = 49) of the patients in Merca and Gabiley respectively. There were corresponding parasitological failures of 77% RII/RIII and 35% RII/RIII. Patients who experienced clinical failure had significantly higher initial parasitaemia than those in whom there was an adequate clinical response, both in Merca (t = 2.2; P t = 2.8; P n = 50) of the patients achieved an adequate clinical response despite a parasitological failure rate of 76% RII/RIII. CONCLUSION: Chloroquine should no longer be considered adequate for treating clinical falciparum malaria in vulnerable groups in the areas studied. Doubts about the therapeutic life of sulfadoxine/pyrimethamine in relation to malaria are raised by the high levels of resistance in the Merca area and underline the need to identify suitable alternatives.

Characterization of a gene encoding a Pichia pastoris protein disulfide isomerase.

Protein disulphide isomerases belong to the thioredoxin superfamily of protein-thiol oxidoreductases that have two double-cysteine redox-active sites and take part in protein folding in the endoplasmic reticulum (ER). We report here the cloning of a Pichia pastoris genomic DNA fragment (2919 bp) that encodes the full length of a protein disulphide isomerase (PpPDI). The deduced amino acid sequence of PDI consists of 517 residues and carries the two characteristic PDI-type redox-active domains -CGHC-, separated by 338 residues, and two potential N-glycosylation sites. The N-terminal end forms a putative signal sequence, and an acidic C-terminal region represents a possible calcium-binding domain. Together with the -HDEL ER retrieval sequence at the C-terminus, these features indicate that the gene encodes a redox-active ER-resident protein disulphide isomerase. The nucleotide sequence, which also contains two other open reading frames, has been submitted to the EMBL Nucleotide Sequence Database, Accession No. AJ302014.