Time Series Analysis of Trends in Malaria Cases and Deaths at Hospitals and the Effect of Antimalarial Interventions, 2001–2011, Ethiopia

Background

The Government of Ethiopia and its partners have deployed artemisinin-based combination therapies (ACT) since 2004 and long-lasting insecticidal nets (LLINs) since 2005. Malaria interventions and trends in malaria cases and deaths were assessed at hospitals in malaria transmission areas during 2001–2011.

Methods

Regional LLINs distribution records were used to estimate the proportion of the population-at-risk protected by LLINs. Hospital records were reviewed to estimate ACT availability. Time-series analysis was applied to data from 41 hospitals in malaria risk areas to assess trends of malaria cases and deaths during pre-intervention (2001–2005) and post-interventions (2006–2011) periods.

Findings

The proportion of the population-at-risk potentially protected by LLINs increased to 51% in 2011. The proportion of facilities with ACTs in stock exceeded 87% during 2006–2011. Among all ages, confirmed malaria cases in 2011 declined by 66% (95% confidence interval [CI], 44–79%) and SPR by 37% (CI, 20%–51%) compared to the level predicted by pre-intervention trends. In children under 5 years of age, malaria admissions and deaths fell by 81% (CI, 47%–94%) and 73% (CI, 48%–86%) respectively. Optimal breakpoint of the trendlines occurred between January and June 2006, consistent with the timing of malaria interventions. Over the same period, non-malaria cases and deaths either increased or remained unchanged, the number of malaria diagnostic tests performed reflected the decline in malaria cases, and rainfall remained at levels supportive of malaria transmission.

Conclusions

Malaria cases and deaths in Ethiopian hospitals decreased substantially during 2006–2011 in conjunction with scale-up of malaria interventions. The decrease could not be accounted for by changes in hospital visits, malaria diagnostic testing or rainfall. However, given the history of variable malaria transmission in Ethiopia, more data would be required to exclude the possibility that the decrease is due to other factors.     

Stimulation of platelet apoptosis by peptidoglycan from Staphylococcus aureus 113

Peptidoglycan (PGN), a component of bacterial cell wall and belonging to "Microbe-Associated Molecular Patterns" (MAMP) triggers host reactions contributing to the pathophysiology of infectious disease. Host cell responses to PGN exposure include apoptosis. Bacterial infections may result in activation of blood platelets and thrombocytopenia. The present study explored, whether HPLC-purified fractions of PGNs from Staphylococcus aureus 113 triggers apoptosis of platelets. To this end platelets were exposed to PGN fractions and annexin-V binding determined to depict cell membrane scrambling, DiOC6 fluorescence to estimate depolarization of mitochondrial potential, Fluo-3AM staining for intracellular Ca(2+) activity ([Ca(2+)](i)) and immunofluorescence to quantify protein abundance of active caspase-3. As a result, a 30?min exposure to monomeric fraction (mPGN) (≥50?ng/ml) was followed by annexin-V binding, paralleled by increase of [Ca(2+)](i), mitochondrial depolarization, caspase-3 activation and integrin α(IIb)β(3) upregulation. The annexin-V binding was significantly blunted by anti-TLR-2 antibodies, in absence of extracellular Ca(2+), and by pancaspase inhibitor zVAD-FMK (1?μM). In conclusion, PGN triggers apoptosis of platelets in activation-dependent manner, characterized by mitochondrial depolarization, caspase-3 activation and cell membrane scrambling.     

The SET8 H4K20 protein lysine methyltransferase has a long recognition sequence covering seven amino acid residues

The SET8 histone lysine methyltransferase, which monomethylates the histone 4 lysine 20 residue plays important roles in cell cycle control and genomic stability. By employing peptide arrays we have shown that it has a long recognition sequence motif covering seven amino acid residues, viz. R¹⁷–H¹⁸–(R¹⁹KY)–K²⁰–(V²¹ILFY)–(L²²FY)–R²³. Celluspots peptide array methylation studies confirmed specific monomethylation of H4K20 and revealed that the symmetric and asymmetric methylation on R¹⁷ of the H4 tail inhibits methylation on H4K20. Similarly, dimethylation of the R located at the −3 position also reduced methylation of p53 K382 which had been shown previously to be methylated by SET8. Based on the derived specificity profile, we identified 4 potential non-histone substrate proteins. After relaxing the specificity profile, we identified several more candidate substrates and showed efficient methylation of 20 novel non-histone peptides by SET8. However, apart from H4 and p53 none of the identified novel peptide targets was methylated at the protein level. Since H4 and p53 both contain the target lysine in an unstructured part of the protein, we conclude that the long recognition sequence of SET8 makes it difficult to methylate a lysine in a folded region of a protein, because amino acid side chains essential for recognition will be buried.     

Urocortins and the regulation of gastrointestinal motor function and visceral pain

Urocortin (Ucn) 1, 2 and 3 are corticotropin-releasing factor (CRF)-related peptides recently characterized in mammals. Urocortin 1 binds with high affinity to CRF type 1 (CRF1) and type 2 (CRF2) receptors while Ucn 2 and Ucn 3 are selective CRF2 ligands. They also have a distinct pattern of distribution, both in the brain and the gastrointestinal tract, compatible with a role mediating, with CRF, the response to stress. In rats and mice, Ucn 1 injected centrally or peripherally inhibited gastric emptying and stimulated colonic propulsive motor function, mimicking the effects of stress or exogenous CRF. Centrally administered Ucn 2 inhibited gastric emptying with similar potency as CRF, while Ucn 1 and Ucn 3 were less potent. However, after peripheral administration, Ucn 1 and Ucn 2 were more potent than CRF. In mice, centrally administered Ucn 1 and 2 stimulated colonic motility with lower potency than CRF, and Ucn 3 was inactive. Studies with selective CRF1 and CRF2 antagonists demonstrated that the gastric-inhibitory and colonic-stimulatory effects of exogenously administered Ucns are mediated through CRF2 and CRF1 receptors, respectively. In addition, Ucn 2 showed visceral anti-nociceptive activity associated with the selective activation of CRF2 receptors. These observations suggest that, acting centrally and peripherally, Ucns might play a significant role in the modulation of gastrointestinal motor and pain responses during stress and stress-related pathophysiological conditions.     

Distinct mechanisms contribute to immunity in the lantibiotic NAI‐107 producer strain Microbispora ATCC PTA‐5024

The investigation of self‐resistance in antibiotic producers is important to understand the emergence of antibiotic resistance in pathogens and to improve antibiotic production. Lantibiotics are ribosomally synthesized antibiotics that mostly target peptidoglycan biosynthesis. The actinomycete Microbispora ATCC PTA‐5024 produces the lantibiotic NAI‐107, which interferes with peptidoglycan biosynthesis by binding bactoprenol‐pyrophosphate‐coupled peptidoglycan precursors. In order to understand how Microbispora counteracts the action of its own antibiotic, its peptidoglycan composition was analysed in detail. Microbispora peptidoglycan consists of muropeptides with D‐Ala and Gly in similar proportion at the fourth position of the peptide stems and alternative 3‐3 cross‐links besides the classical 4‐3 cross‐links. In addition, the NAI‐107 biosynthetic gene cluster (mlb) was analysed for the expression of immunity proteins. We show that distinct immunity determinants are encoded in the mlb cluster: the ABC transporter MlbYZ acting cooperatively with the transmembrane protein MlbJ and the lipoprotein MlbQ. NMR structural analysis of MlbQ revealed a hydrophobic surface patch, which is proposed to bind the cognate lantibiotic. This study demonstrates that immunity in Microbispora is not only based on one determinant but on the action of the distinct immunity proteins MlbQ, MlbYZ and MlbJ.     

Identification of a single gene for seed coat impermeability in soybean PI 594619

Key message

Inheritance studies and molecular mapping identified a single dominant gene that conditions seed coat impermeability in soybean PI 594619.

Abstract

High temperatures during seed fill increase the occurrence of soybeans with impermeable seed coat, which is associated with non-uniform and delayed germination and emergence. This can be an issue in soybean production areas with excessively high-temperature environments. The objectives of the present study were to investigate the inheritance of impermeable seed coat under a high-temperature environment in the midsouthern United States and to map the gene(s) that affect this trait in a germplasm line with impermeable seed coat (PI 594619). Crosses were made between PI 594619 and an accession with permeable seed coat at Stoneville, MS in 2008. The parental lines and the segregating populations from reciprocal crosses were grown in Stoneville in 2009. Ninety-nine F_2:3 families and parents were also grown at Stoneville, MS in 2011. Seeds were assayed for percent impermeable seed coat using the standard germination test. Genetic analysis of the F₂ populations and F_2:3 families indicated that seed coat impermeability in PI 594619 is controlled by a single major gene, with impermeable seed coat being dominant to permeable seed coat. Molecular mapping positioned this gene on CHR 2 between markers Sat_202 and Satt459. The designation of Isc (impermeable seed coat) for this single gene has been approved by the Soybean Genetics Committee. Selection of the recessive form (isc) may be important in developing cultivars with permeable seed coat for high-heat production environments. The single-gene nature of impermeable seed coat may also have potential for being utilized in reducing seed damage caused by weathering and mold.     

Applications of the Poly-K Statistical Test to Life-Time Cancer Bioassay Studies

The statistical analysis of cancer bioassay data has historically depended on the pathological determination of the experimental animal's cause of death. The poly-k statistical test has provided a method of statistical analysis of animal bioassay data without the need for cause of death information. The test has been shown to have good statistical properties in the typical 2-year cancer bioassay. However, while the poly-k test has been applied to chronic lifetime animal studies, it has not been formally evaluated with respect to the operating characteristics of this statistical test when applied to such studies. Thus, our objective is to assess the performance of the poly-k test for lifetime studies and to make comparisons with other tests. We observed in one recent lifetime study of the gasoline additive methyl tertiary butyl ether (MTBE) that the application of the poly-k test was not statistically robust. Simulation studies were subsequently conducted for a limited number of scenarios of lifetime cancer bioassays. These simulations showed that the poly-k test is not statistically robust for testing effect of increasing dose in some lifetime cancer studies.     

Surfactant protein C: its unique properties and emerging immunomodulatory role in the lung

Surfactant protein C (SP-C) is a highly hydrophobic protein found in pulmonary surfactant. SP-C is synthesized exclusively in alveolar type II cells as a 21 kDa integral membrane precursor protein and subsequently proteolytically processed to a 3.7 kDa secretory protein. SP-C enhances the adsorption and spreading of phospholipids at the air-liquid interface thereby promoting the surface tension-lowering properties of surfactant. The importance of SP-C in normal lung function is underscored by the recent findings of inflammatory lung diseases associated both with absence of alveolar SP-C and with cellular expression of mutant SP-C isoforms. This review examines our current understanding of the role of SP-C in maintaining alveolar epithelial homeostasis and the potential role of abnormal SP-C expression in the development of lung diseases with particular emphasis on microbial pulmonary infection and inflammation.