Insights into the preclinical treatment of blood-stage malaria by the antibiotic borrelidin

Background and Purpose

Blood-stage Plasmodium parasites cause morbidity and mortality from malaria. Parasite resistance to drugs makes development of new chemotherapies an urgency. Aminoacyl-tRNA synthetases have been validated as antimalarial drug targets. We explored long-term effects of borrelidin and mupirocin in lethal P. yoelii murine malaria.

Experimental Approach

Long-term (up to 340 days) immunological responses to borrelidin or mupirocin were measured after an initial 4 day suppressive test. Prophylaxis and cure were evaluated and the inhibitory effect on the parasites analysed.

Key Results

Borrelidin protected against lethal malaria at 0.25 mg·kg⁻¹·day⁻¹. Antimalarial activity of borrelidin correlated with accumulation of trophozoites in peripheral blood. All infected mice treated with borrelidin survived and subsequently developed immunity protecting them from re-infection on further challenges, 75 and 340 days after the initial infection. This long-term immunity in borrelidin-treated mice resulted in negligible parasitaemia after re-infections and marked increases in total serum levels of antiparasite IgGs with augmented avidity. Long-term memory IgGs mainly reacted against high and low molecular weight parasite antigens. Immunofluorescence microscopy showed that circulating IgGs bound predominantly to late intracellular stage parasites, mainly schizonts.

Conclusions and Implications

Low borrelidin doses protected mice from lethal malaria infections and induced protective immune responses after treatment. Development of combination therapies with borrelidin and selective modifications of the borrelidin molecule to specifically inhibit plasmodial threonyl tRNA synthetase should improve therapeutic strategies for malaria.     

Emergency open cholecystectomy is associated with markedly lower incidence of postoperative nausea and vomiting (PONV) than elective open cholecystectomy: a retrospective cohort study

Background  

During a previous study to define and compare incidence risks of postoperative nausea and vomiting (PONV) for elective laparoscopic and open cholecystectomy at two hospitals in Jamaica, secondary analysis comparing PONV risk in elective open cholecystectomy to that after emergency open cholecystectomy suggested that it was markedly reduced in the latter group. The decision was made to collect data on an adequate sample of emergency open cholecystectomy cases and further explore this unexpected finding in a separate study.     

Interleukin-5 is at 5q31 and is deleted in the 5q- syndrome

Human interleukin-5 (IL-5) is a selective eosinophilopoietic and eosinophil-activating growth hormone. By in situ hybridization this gene is mapped to chromosome 5q23.3 to 5q32. It is shown to be deleted in two patients with the 5q-syndrome and in one patient previously diagnosed with myelodysplasia whose condition had progressed to acute myeloblastic leukemia. The clustering of other genes involved in hematopoiesis (IL-3, granulocyte-macrophage colony-stimulating factor, feline sarcoma viral oncogene homolog, colony-stimulating factor 1) to the same region as IL-5 suggests a nonrandom localization and raises interesting questions concerning the evolution and regulation of these genes.     

Erythropoietin and sexual dysfunction

BACKGROUND: Erythropoietin (rHuEpo) therapy has been shown to improve sexual function in the male dialysis population, with several studies suggesting a direct effect upon endocrine function, as well as correction of anaemia. Nevertheless many male dialysis patients receiving rHuEpo continue to complain of sexual dysfunction. METHODS: At a dedicated renal impotence clinic, 65 male dialysis patients were screened for endocrine disturbances. Baseline serum sex hormones were compared between those receiving and not receiving rHuEpo, using either the two-sample t test or the Mann-Whitney U test, after assessing for normality. Results from four patients were excluded on account of either medications (antiemetic phenothiazines), hepatic dysfunction, or carcinomatosis. RESULTS: Twenty-five patients (41.0%) were receiving rHuEpo, the recipients and non-recipients being well matched for haemoglobin (10.19 +/- 0.29 vs 10.55 +/- 0.25 g/dl, n.s.), age (51.1 +/- 1.9 vs 53.6 +/- 2.1 years, n.s.) and duration of sexual dysfunction (median, 3.0 vs 3.0 years, n.s.). The rHuEpo recipients had a higher median creatinine (1090 vs 972 micromol/l, P < 0.02), but similar nutritional status to the non-recipients (albumin 41.0 vs 39.0 g/l, n.s.). The total duration of rHuEpo therapy was 0.85 +/- 0.14 years. Prolactin levels were similar in both the rHuEpo recipients and non- recipients (440 vs 541 mu/l, n.s.), as were LH (11.0 vs 10.5 iu/l, n.s.) and FSH (8.0 vs 6.5 iu/l, n.s.). However, there were significant elevations of testosterone (19.8 +/- 1.3 vs 16.1 +/- 1.1 nmol/l, P < 0.05) and sex hormone binding globulin (SHBG) (40.5 vs 26.0 nmol/l, P < 0.01), with a trend toward elevated oestradiol (304 vs 248 pmol/l, P = 0.095) in the rHuEpo-treated group. Forty-eight subjects (78.7%) received peritoneal dialysis (PD), with the 19 rHuEpo recipients (39.6%) demonstrating increased serum testosterone (21.0 +/- 1.5 vs 16.6 +/- 1.3 nmol/l, P < 0.05), SHBG (40.5 vs 26.5 nmol/l, P < 0.01), LH (15.0 vs 10.0 iu/l, P < 0.01) and FSH (12.0 vs 5.3 iu/l, P < 0.05). These differences were not demonstrated in the 13 haemodialysis (HD) subjects. CONCLUSIONS: Male dialysis patients complaining of sexual dysfunction after correction of anaemia with rHuEpo are characterized by higher levels of serum testosterone and SHBG, but not suppression of hyperprolactinaemia or hyperoestrogenism. Male PD subjects receiving rHuEpo also demonstrated increased LH and FSH.      

A light-driven rhythm in neurotensin-like immunoreactivity in the chicken retina

Purpose: To determine if the pattern of release of neurotensin from the enkephalin-, neurotensin- and somatostatin-like immunoreactive amacrine cells in response to light and dark is the same as that of the enkephalins and somatostatin. Methods/Results: Both the enkephalins and somatostatin are released at high rates in the dark and at lower rates in the light, and these rate changes are reflected in increasing intracellular levels of the peptides in vivo in the light and decreasing levels in the dark The levels of neurotensin-like immunoreactivity show a similar diurnal light-driven and non-circadian rhythm in vivo. Conclusion: This implies that the actual release rates of neurotensin follow the same patterns as those demonstrated in vitro for the enkephalins and somatostatin.     

AN ATYPICAL CASE OF ATYPICAL PNEUMONIA

SUMMARY A 23-year-old man, previously fit and well, presented with an atypical pneumonia, associated with microangiopathic anaemia, thrombocytopenia, rhabdomyolysis and renal impairment. Despite administration of intravenous fluids and antibiotics, his condition rapidly deteriorated, and the possibility of an aggressive connective tissue disorder was raised. Thus he was treated with high-dose oral steroids and plasma exchange until autoantibodies were shown to be negative. At this stage it transpired that the patient had swallowed water from a stream three weeks earlier, and leptospira antibody titres were subsequently found to be elevated. Antibiotics were continued, and after a protracted course he made a full recovery. Leptospirosis should be remembered as a rare cause of atypical pneumonia, particularly if there is associated hepatic or renal impairment.