Monitoring toxicity associated with parenteral sodium stibogluconate in the day-case management of returned travellers with New World cutaneous leishmaniasi

Background

Patients with New World cutaneous leishmaniasis (NWCL) caused by Leishmania Viannia are treated with parenteral sodium stibogluconate (SbV) to reduce the risk of development of mucocutanous leishmaniasis. Our centre manages patients with NWCL on an outpatient-basis. This study was conducted to assess the safety and efficacy of this approach.

Methodology

We reviewed records of 67 consecutive NWCL patients, aged 17–61 years, treated as day-cases with 20 mg/kg/day SbV for up to 28 days at our UK centre. Data had been collected in a standardised format at the time of treatment using a care-record tool. Patients reported adverse-effects daily using a structured questionnaire. Blood tests and electrocardiograms were performed twice weekly to monitor for toxicity.

Principal Findings

Parenteral SbV treatment was associated with an early, significant suppression of mean lymphocyte and platelet counts. By day four of treatment, lymphocytes reduced by 0.53×10⁹/L (CI 0.29×10⁹/L to 0.76×10⁹/L, p<0.001), and platelets by 31,000/µL (CI 16,000/µL to 46,000/µL, p<0.001). SbV was further associated with significant elevation of serum alanine transaminase concentrations, with a mean peak rise of 107 iu/L by day 13 (CI 52 iu/L to 161 iu/L, p<0.001). These disturbances were temporary and did not result in adverse clinical events. Patient-described symptoms were cumulative and at three weeks of treatment, 59.6% of patients experienced myalgia and 29.8% malaise. Treatment adherence and clinical outcomes were comparable to inpatient treatment studies. A total of 1407 individual doses of SbV resulted in only 26 nights'' hospital admission, a saving of 1381 bed-days compared to inpatient treatment.

Conclusions/Significance

In specialist centres, NWCL patients aged below 65 years and without co-morbidities can be safely and effectively treated without hospital admission. This reduces the cost of treatment, and is much preferred by patients. Twice weekly blood and electrocardiographic monitoring may be surplus to requirement in clinically well, low-risk patients.     

Competing phytoplankton undermines allelopathy of a bloom-forming dinoflagellate

Biotic interactions in the plankton can be both complex and dynamic. Competition among phytoplankton is often chemically mediated, but no studies have considered whether allelopathic compounds are modified by biotic interactions. Here, we show that compounds exuded during Karenia brevis blooms were allelopathic to the cosmopolitan diatom Skeletonema costatum, but that bloom allelopathy varied dramatically among collections and years. We investigated several possible causes of this variability and found that neither bloom density nor concentrations of water-borne brevetoxins correlated with allelopathic potency. However, when we directly tested whether the presence of competing phytoplankton influenced bloom allelopathy, we found that S. costatum reduced the growth-inhibiting effects of bloom exudates, suggesting that S. costatum has a mechanism for undermining K. brevis allelopathy. Additional laboratory experiments indicated that inducible changes to K. brevis allelopathy were restricted to two diatoms among five sensitive phytoplankton species, whereas five other species were constitutively resistant to K. brevis allelopathy. Our results suggest that competitors differ in their responses to phytoplankton allelopathy, with S. costatum exhibiting a previously undescribed method of resistance that may influence community structure and alter bloom dynamics.     

Brugia malayi Antigen (BmA) Inhibits HIV-1 Trans-Infection but Neither BmA nor ES-62 Alter HIV-1 Infectivity of DC Induced CD4+ Th-Cells

One of the hallmarks of HIV-1 disease is the association of heightened CD4⁺ T-cell activation with HIV-1 replication. Parasitic helminths including filarial nematodes have evolved numerous and complex mechanisms to skew, dampen and evade human immune responses suggesting that HIV-1 infection may be modulated in co-infected individuals. Here we studied the effects of two filarial nematode products, adult worm antigen from Brugia malayi (BmA) and excretory-secretory product 62 (ES-62) from Acanthocheilonema viteae on HIV-1 infection in vitro. Neither BmA nor ES-62 influenced HIV-1 replication in CD4⁺ enriched T-cells, with either a CCR5- or CXCR4-using virus. BmA, but not ES-62, had the capacity to bind the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) thereby inhibiting HIV-1 trans-infection of CD4⁺ enriched T-cells. As for their effect on DCs, neither BmA nor ES-62 could enhance or inhibit DC maturation as determined by CD83, CD86 and HLA-DR expression, or the production of IL-6, IL-10, IL-12 and TNF-α. As expected, due to the unaltered DC phenotype, no differences were found in CD4⁺ T helper (Th) cell phenotypes induced by DCs treated with either BmA or ES-62. Moreover, the HIV-1 susceptibility of the Th-cell populations induced by BmA or ES-62 exposed DCs was unaffected for both CCR5- and CXCR4-using HIV-1 viruses. In conclusion, although BmA has the potential capacity to interfere with HIV-1 transmission or initial viral dissemination through preventing the virus from interacting with DCs, no differences in the Th-cell polarizing capacity of DCs exposed to BmA or ES-62 were observed. Neither antigenic source demonstrated beneficial or detrimental effects on the HIV-1 susceptibility of CD4⁺ Th-cells induced by exposed DCs.     

Linkage studies with 17q and 18q markers in a breast/ovarian cancer family.

Genes on chromosomes 17q and 18q have been shown to code for putative tumor suppressors. By a combination of allele-loss studies on sporadic ovarian carcinomas and linkage analysis on a breast/ovarian cancer family, we have investigated the involvement of such genes in these diseases. Allele loss occurred in sporadic tumors from both chromosome 17p, in 18/26 (69%) cases, and chromosome 17q, in 15/22 (68%) cases. In the three familial tumors studied, allele loss also occurred on chromosome 17 (in 2/3 cases for 17p markers and in 2/2 cases for a 17q allele). Allele loss on chromosome 18q, at the DCC (deleted in colorectal carcinomas) locus, was not as common (6/16 cases [38%]) in sporadic ovarian tumors but had occurred in all three familial tumors. The results of linkage analysis on the breast/ovarian cancer family suggested linkage between the disease locus and 17q markers, with a maximum lod score of 1.507 obtained with Mfd188 (D17S579) polymorphism at 5% recombination. The maximum lod score for DCC was 0.323 at 0.1% recombination. In this family our results are consistent with a predisposing gene for breast/ovarian cancer being located at chromosome 17q21.     

Individual Odors in Djungarian Hamsters (Phodopus campbelli)

The sources of scent in Djungarian hamsters (Phodopus campbelli) that may be individually discriminated were investigated using an habituation paradigm. Male Djungarian hamsters were exposed to five presentations of a particular scent from one individual, and then to the same scent from a novel individual. Increased investigation of the scent from the novel individual indicated discrimination of scents from different individuals. Male hamsters distinguished individual differences in scents of other males from the midventral gland, urine, feces, mouth, and the corner of the mouth, which includes the sacculi; they did not discriminate among odors of different individuals when the scents were from the genital region, hindfeet, fur from behind ears or fur from the back. The results indicate that Djungarian hamsters have a repertoire of individually distinctive scents that are located in specific places on the body; these scents are not actively distributed to, nor passively picked up on, other parts of the body. The fact that scents from some areas do not contain individually distinctive information suggests that some sources may be specialized for producing individually distinctive scents.     

Fine structure and metabolism of multiply innervated fast muscle fibres in teleost fish

Summary Both the fast and slow muscle fibres of advanced teleost fish are multiply innervated. The fraction of slow-fibre volume occupied by mitochondria is 31.3%, 25.5% and 24.6%, respectively, for the myotomal muscles of brook trout (Salvelinus fontinalis), crucian carp (Carassius carassius), and plaice (Pleuronectes platessa), respectively. The corresponding figures for the fast muscles of these species are 9.3%, 4.6% and 2.0%, respectively. Cytochrome-oxidase and citrate-synthetase activities in the fast muscles of 9 species of teleost range from 0.20–0.93 moles substrate utilised, g wet weight muscle^-1 min^-1 (at 15° C) or around 4–17% of that of the corresponding slow fibres. Ultrastructural analyses reveal a marked heterogeneity within the fast-fibre population. For example, the fraction of fibres with <1% or >10% mitochondria is 0,4,42% and 36, 12 and 0%, respectively, for trout, carp and plaice. In general, small fibres (<500 m²) have the highest and large fibres (>1,500 m²) the lowest mitochondrial densities. The complexity of mitochondrial cristae is reduced in fast compared to slow fibres.Hexokinase activities range from 0.4–2.5 in slow and from 0.08–0.7 moles, g wet weight^-1 min^-1 in fast muscles, indicating a wide variation in their capacity for aerobic glucose utilisation. Phosphofructokinase activities are 1.2 to 3.6 times higher in fast than slow muscles indicating a greater glycolytic potential. Lactate dehydrogenase activities are not correlated with either the predicted anaerobic scopes for activity or the anoxic tolerances of the species studied. The results indicate a considerable variation in the aerobic capacities and principal fuels supporting activity among the fast muscles of different species. Brook trout and crucian carp are known to recruit fast fibres at low swimming speeds. For these species the aerobic potential of the fast muscle is probably sufficient to meet the energy requirements of slow swimming.     

Spatial and temporal genetic structure of Symbiodinium populations within a common reef‐building coral on the Great Barrier Reef

The dinoflagellate photosymbiont Symbiodinium plays a fundamental role in defining the physiological tolerances of coral holobionts, but little is known about the dynamics of these endosymbiotic populations on coral reefs. Sparse data indicate that Symbiodinium populations show limited spatial connectivity; however, no studies have investigated temporal dynamics for in hospite Symbiodinium populations following significant mortality and recruitment events in coral populations. We investigated the combined influences of spatial isolation and disturbance on the population dynamics of the generalist Symbiodinium type C2 (ITS1 rDNA) hosted by the scleractinian coral Acropora millepora in the central Great Barrier Reef. Using eight microsatellite markers, we genotyped Symbiodinium in a total of 401 coral colonies, which were sampled from seven sites across a 12‐year period including during flood plume–induced coral bleaching. Genetic differentiation of Symbiodinium was greatest within sites, explaining 70–86% of the total genetic variation. An additional 9–27% of variation was explained by significant differentiation of populations among sites separated by 0.4–13 km, which is consistent with low levels of dispersal via water movement and historical disturbance regimes. Sampling year accounted for 6–7% of total genetic variation and was related to significant coral mortality following severe bleaching in 1998 and a cyclone in 2006. Only 3% of the total genetic variation was related to coral bleaching status, reflecting generally small (8%) reductions in allelic diversity within bleached corals. This reduction probably reflected a loss of genotypes in hospite during bleaching, although no site‐wide changes in genetic diversity were observed. Combined, our results indicate the importance of disturbance regimes acting together with limited oceanographic transport to determine the genetic composition of Symbiodinium types within reefs.