Domestic and peridomestic transmission of American cutaneous leishmaniasis: changing epidemiological patterns present new control opportunities

Predictions that deforestation would reduce American cutaneous leishmaniasis incidence have proved incorrect. Presentations at a recent international workshop, instead, demonstrated frequent domestication of transmission throughout Latin America. While posing new threats, this process also increases the effectiveness of vector control in and around houses. New approaches for sand fly control and effective targeting of resources are reviewed.     

Extreme differences in rates of molecular evolution of foraminifera revealed by comparison of ribosomal DNA sequences and the fossil record

Foraminifera have one of the best known fossil records among the unicellular eukaryotes. However, the origin and phylogenetic relationships of the extant foraminiferal lineages are poorly understood. To test the current paleontological hypotheses on evolution of foraminifera, we sequenced about 1,000 base pairs from the 3' end of the small subunit rRNA gene (SSU rDNA) in 22 species representing all major taxonomic groups. Phylogenies were derived using neighbor- joining, maximum-parsimony, and maximum-likelihood methods. All analyses confirm the monophyletic origin of foraminifera. Evolutionary relationships within foraminifera inferred from rDNA sequences, however, depend on the method of tree building and on the choice of analyzed sites. In particular, the position of planktonic foraminifera shows important variations. We have shown that these changes result from the extremely high rate of rDNA evolution in this group. By comparing the number of substitutions with the divergence times inferred from the fossil record, we have estimated that the rate of rDNA evolution in planktonic foraminifera is 50 to 100 times faster than in some benthic foraminifera. The use of the maximum-likelihood method and limitation of analyzed sites to the most conserved parts of the SSU rRNA molecule render molecular and paleontological data generally congruent.      

Successful immunotherapy with matrix metalloproteinase-derived peptides in adjuvant arthritis depends on the timing of peptide administration

We have recently found that matrix metalloproteinases (MMPs) are targets for T-cell and B-cell reactivity in experimental arthritis. In the present article, we investigate whether modulation of MMP-specific T-cell responses could influence the course of adjuvant arthritis (AA). Lewis rats were treated nasally with MMP peptides prior to or after AA induction. Administration of the MMP-10 or the MMP-16 peptide prior to AA induction reduced the arthritic symptoms. In contrast, administration of the MMP-10 peptide after AA induction aggravated the arthritic symptoms. The present study shows the possible usefulness of MMP peptides for immunotherapy. However, a clear understanding of proper timing of peptide administration is crucial for the development of such therapies.     

Quantification of protein transcytosis in the human colon carcinoma cell line CaCo-2

The transepithelial absorption of food-type proteins has been shown to proceed by endocytosis along two functional pathways: a minor direct pathway allowing transport of intact protein and a major lysosomal degradative pathway. The human colon carcinoma cell line CaCo-2 grown on Millipore filters was used here further to characterize these pathways by measuring HRP transport across the cell monolayer in Ussing chambers. In the apical-basal direction, this transport mainly occurred along the degradative pathway and was inhibited at 4 degrees C (7.41 +/- 1.26 pmoles/h.cm2 vs. 27.40 +/- 8.91 at 37 degrees C). The amount conveyed via the direct pathway was very small (0.89 +/- 0.35 pmoles/h.cm2) and did not diminish at 4 degrees C (1.43 +/- 0.59 pmoles/h.cm2). In the basal-apical direction, HRP transport along the degradative pathway at 37 degrees C was similar to the apical-basal value and was inhibited at 4 degrees C (16.40 +/- 4.05 vs. 2.72 +/- 2.52 pmoles/h.cm2), but along the direct pathway, it was eight times the apical-basal value (8.36 +/- 3.11 pmoles/h.cm2) and was inhibited at 4 degrees C (2.43 +/- 0.78 pmoles/h.cm2). Intact HRP fluxes were not correlated with the electrical resistance of the filters, indicating transport via a transcellular route. Monensin at 10(-5) M did not affect direct or degradative transport in the apical-to-basal direction. These results suggest that in CaCo-2 cells HRP undergoes bidirectional transcytosis by a fluid-phase mechanism, but the extent of degradation during that transport varies according to the membrane (apical or basal) where it is presented.     

Design of the Endobronchial Valve for Emphysema Palliation Trial (VENT): a non-surgical method of lung volume reduction

Background

Lung volume reduction surgery is effective at improving lung function, quality of life, and mortality in carefully selected individuals with advanced emphysema. Recently, less invasive bronchoscopic approaches have been designed to utilize these principles while avoiding the associated perioperative risks. The Endobronchial Valve for Emphysema PalliatioN Trial (VENT) posits that occlusion of a single pulmonary lobe through bronchoscopically placed Zephyr^® endobronchial valves will effect significant improvements in lung function and exercise tolerance with an acceptable risk profile in advanced emphysema.

Methods

The trial design posted on Clinical trials.gov, on August 10, 2005 proposed an enrollment of 270 subjects. Inclusion criteria included: diagnosis of emphysema with forced expiratory volume in one second (FEV₁) < 45% of predicted, hyperinflation (total lung capacity measured by body plethysmography > 100%; residual volume > 150% predicted), and heterogeneous emphysema defined using a quantitative chest computed tomography algorithm. Following standardized pulmonary rehabilitation, patients were randomized 2:1 to receive unilateral lobar placement of endobronchial valves plus optimal medical management or optimal medical management alone. The co-primary endpoint was the mean percent change in FEV₁ and six minute walk distance at 180 days. Secondary end-points included mean percent change in St. George's Respiratory Questionnaire score and the mean absolute changes in the maximal work load measured by cycle ergometry, dyspnea (mMRC) score, and total oxygen use per day. Per patient response rates in clinically significant improvement/maintenance of FEV₁ and six minute walk distance and technical success rates of valve placement were recorded. Apriori response predictors based on quantitative CT and lung physiology were defined.

Conclusion

If endobronchial valves improve FEV₁ and health status with an acceptable safety profile in advanced emphysema, they would offer a novel intervention for this progressive and debilitating disease.

Trial Registration

ClinicalTrials.gov: NCT00129584     

Association between pygmy right whales (Caperea marginata) and areas of high marine productivity off Australia and New Zealand

Abstract

Opportunistic sightings and strandings of Caperea marginata (n=196) from the vicinity of Australia and New Zealand (1884 to early 2007) were used to relate geographic and temporal patterns to oceanographic and broad-scale climatic variability. Records were not uniformly distributed along the coast and more (69%) were from Australia than New Zealand. Seven coastal whale ‘hotspots’ were identified which accounted for 61% of records with locality data. Half of the hotspot records were from southeast (37) and northwest (20) Tasmania—others each had 9–15 events. Upwelling and/or high zooplankton abundance has been documented near all whale hotspots. Records of C. marginata occurred in all months, with 75% in spring and summer. Inter-annual variability showed broad agreement between increased whale records (usually in spring/summer) and strongly positive ‘Niño 3.4’ during 1980–1995 but not thereafter. Coastal upwelling and productivity increase during climatic phenomena such as El Niño and are likely to be quickly beneficial to plankton-feeding whales such as C. marginata.     

Portable light transmission measuring system for preserved corneas

Background  

The authors have developed a small portable device for the objective measurement of the transparency of corneas stored in preservative medium, for use by eye banks in evaluation prior to transplantation.     

Effects of cholera toxin on cellular and paracellular sodium fluxes in rabbit ileum

The diarrhea observed in patients which cholera is known to be related to secretion of water and electrolytes into the intestinal lumen. However, the exact mechanisms involved in these secretory processes have remained unclear. Although it is clear that purified toxin acts on epithelial cell metabolism, its activity on Na⁺ transport across intestinal mucosa is equivocal: reported either to prevent net Na⁺ absorption or to cause net secretion of Na⁺ from serosa to mucosa. Since total transmural Na⁺ fluxes across “leaky” epithelia involve very significant movement via a paracellular shunt pathway, we studied the effects of cholera toxin on the cellular and paracellular pathways of Na⁺ movement. Unidirectional Na⁺ fluxes were examined as functions of applied potential in control tissues and in tissues from the same animal treated with purified cholera toxin. Treatment of rabbit ileum in vitro with toxin stimulated the cellular component of serosa-to-mucosa Na⁺ flux (from $\text{2.41 ± 0.49 μ}\text{equiv./h}$ per cm² under control conditions to $\text{4.71 ± 0.43 μ}\text{equiv./h}$ per cm² after treatment with toxin, $\text{P < 0.01}$). The effect of cholera toxin on Na⁺ movement through the cells from mucosa to serosa appeared to be insignificant. Finally, a marked decrease in the Na⁺ permeability ($\text{P < 0.01}$) and no detectable significant changes in transference number for Na⁺ of the paracellular shunt pathway were observed following treatment with cholera toxin. These results provide direct evidence for the hypothesis that purified cholera toxin stimulates active sodium secretion but has minimal effect on sodium absorption.     

Leishmaniasis worldwide and global estimates of its incidence

As part of a World Health Organization-led effort to update the empirical evidence base for the leishmaniases, national experts provided leishmaniasis case data for the last 5 years and information regarding treatment and control in their respective countries and a comprehensive literature review was conducted covering publications on leishmaniasis in 98 countries and three territories (see 'Leishmaniasis Country Profiles Text S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13, S14, S15, S16, S17, S18, S19, S20, S21, S22, S23, S24, S25, S26, S27, S28, S29, S30, S31, S32, S33, S34, S35, S36, S37, S38, S39, S40, S41, S42, S43, S44, S45, S46, S47, S48, S49, S50, S51, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S65, S66, S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S86, S87, S88, S89, S90, S91, S92, S93, S94, S95, S96, S97, S98, S99, S100, S101'). Additional information was collated during meetings conducted at WHO regional level between 2007 and 2011. Two questionnaires regarding epidemiology and drug access were completed by experts and national program managers. Visceral and cutaneous leishmaniasis incidence ranges were estimated by country and epidemiological region based on reported incidence, underreporting rates if available, and the judgment of national and international experts. Based on these estimates, approximately 0.2 to 0.4 cases and 0.7 to 1.2 million VL and CL cases, respectively, occur each year. More than 90% of global VL cases occur in six countries: India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil. Cutaneous leishmaniasis is more widely distributed, with about one-third of cases occurring in each of three epidemiological regions, the Americas, the Mediterranean basin, and western Asia from the Middle East to Central Asia. The ten countries with the highest estimated case counts, Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia, North Sudan, Costa Rica and Peru, together account for 70 to 75% of global estimated CL incidence. Mortality data were extremely sparse and generally represent hospital-based deaths only. Using an overall case-fatality rate of 10%, we reach a tentative estimate of 20,000 to 40,000 leishmaniasis deaths per year. Although the information is very poor in a number of countries, this is the first in-depth exercise to better estimate the real impact of leishmaniasis. These data should help to define control strategies and reinforce leishmaniasis advocacy.     

alpha-Tocopherol and protein kinase C inhibition enhance platelet-derived nitric oxide release.

Platelet activation is tightly regulated by products of the endothelium and platelets including nitric oxide (NO). Excess vascular oxidative stress has been associated with impaired NO release, and antioxidant status has been shown to alter endothelium-derived NO bioactivity. Although physiological levels of a-tocopherol are known to inhibit platelet function, the effect of a-tocopherol on platelet NO release is unknown. Loading platelets with physiologic levels of a-tocopherol increased platelet NO production approximately 1.5-fold (Pa-tocopherol, platelet NO release increased 50% (Pa-Tocopherol-loaded platelets also produced 74% less superoxide as compared with control (Pa-tocopherol inhibited PKC-dependent eNOS phosphorylation as determined by immunoprecipitation. Lastly, platelets isolated from NOS3-deficient mice released 80% less superoxide as compared with control animals (P=0.011), and incubation of NOS III-deficient platelets with 500 mM a-tocopherol only caused a modest additional decrease in platelet superoxide release (NS). Thus, a-tocopherol appears to enhance platelet NO release both in vitro and in vivo through antioxidant- and PKC-dependent mechanisms.