Desketoneoenactin-siderophore conjugates for Candida: evidence of iron transport-dependent species selectivity

We investigated the inhibitory activity of synthetic isocyanurate-based as well as linear mono- and trihydroxamate siderophore-drug conjugates against Candida spp. The conjugated drug was 13C-desketoneoenactin (DE). The MICs of siderophore-drug conjugates were determined in the absence and presence of 2,2'-dipyridyl to restrict iron availability. The ability of various siderophore types to promote growth in an iron-restricted medium was also assayed. Addition of a siderophore portion to the drug strongly impaired the inhibitory activity of DE. However, the activity of the drug conjugates was increased by up to 16-fold in iron-depleted medium for species having their growth strongly promoted by most hydroxamate-type siderophores (C. albicans, C. stellatoidea, and C. pseudotropicalis). The uptake of (55)Fe from ferrichrome and from two siderophore-drug conjugates was improved when C. albicans cells were grown in a low-iron medium. In the same assay, unlabeled ferrichrome was able to compete with the uptake of (55)Fe from both conjugates, indicating a common mechanism of uptake. A C. albicans strain lacking the siderophore transporter CaSit1/CaArn1 was not able to use ferrichrome or the synthetic ornithine-based trihydroxamate siderophore for growth promotion and was much less susceptible to the siderophore-drug conjugates than its isogenic parent strain. In summary, the ability of some Candida spp. to use ferrichrome-like siderophores for growth promotion explains the selective activity of hydroxamate-drug conjugates, and this activity seems to be related to the presence, in C. albicans, of the siderophore transporter CaSit1/CaArn1. New conjugate designs are necessary to fully restore or improve the initial DE activity.     

Studies on the mechanism whereby acidemia stimulates collecting duct hydrogen ion secretion in vivo

The purpose of these studies was to elucidate the mechanism whereby collecting duct hydrogen ion secretion was augmented by acidemia. The urine minus blood PCO2 difference in alkaline urine (U-B PCO2) was used to evaluate this parameter. In dogs with a normal ECF volume, the U-B PCO2 factored was high, and there was no significant relationship between the U-B PCO2 factored for the urine bicarbonate concentration and the blood hydrogen ion concentrations unless amiloride, an agent that abolishes the transtubular potential difference, was present. In this latter case, the U-B PCO2 was a linear function of the urine bicarbonate concentration, and the U-B PCO2 factored for the urine bicarbonate concentration was directly proportional to the blood hydrogen ion concentration. To extend the pH range considerably, we used lysine to induce bicarbonaturia in dogs with an expanded ECF volume. Amiloride now caused only a small decrease in the U-B PCO2 at any urine bicarbonate concentration, and furthermore, it did not influence the linear relationship between the U-B PCO2 factored for the urine bicarbonate concentration and the blood hydrogen ion concentration. These results suggests that acidemia stimulates collecting duct hydrogen ion secretion by a mechanism that appears to be independent of the amiloride-sensitive component of the U-B PCO2. We speculate that the mechanism might involve an increased intracellular hydrogen ion concentration during acidemia.     

Deep vein thrombosis: a rare complication of thalidomide therapy in recurrent erythema nodosum leprosum

A case of deep-vein thrombosis is reported in a female patient with multibacillary leprosy who received pulses of dexamethasone and cyclophosphamide for recurrent ENL that had not responded to prednisone and thalidomide.     

Treatment of femoral neck and trochanteric simple bone cysts

Introduction Problems associated with common treatment modalities of bone cysts located in the proximal femur include a high blood loss, infection, lack of stability, donor-site morbidity, restriction to normal activity, and high recurrence rate.Materials and methods Twelve patients with a simple bone cyst of the proximal femur were treated with retrograde flexible nailing. Six showed a pathological fracture. Mean age at surgery was 10.4 years, mean follow-up was 57 months. Radiographs were classified as healed, healed with residuals, recurred, or no response.Results The mean healing period was 38.8 months. Two cysts healed completely, nine healed with residuals. There was no recurrence or non-responder. In a fractured cyst a perforation of a nail through the cyst occurred 4 months after nailing.Conclusion The method is less invasive and offers early stability to the bone without the need for cast immobilization.None of the authors received financial support for this study.This study was conducted at the Department of Paediatric Orthopaedic Surgery, Medical University, Graz, Austria.A. Roposch is the recipient of the Research Training Competition Award, Population Health Sciences Program, Hospital for Sick Children, Toronto, Canada.     

Should laparoscopic cholecystectomy be performed in patients with thick-walled gallbladder?

Background/Purpose Laparoscopic cholecystectomy is the procedure of choice for patients with symptomatic cholelithiasis. This procedure is contraindicated in patients with gall-bladder cancer (GBC) because of fear of dissemination of the disease. One of the findings raising the suspicion of GBC is a thick-walled gallbladder (TWGB).Methods A prospective study of patients with TWGB was done over a period of 10 months at a tertiary-level referral hospital in northern India. We studied the clinical profiles, investigations (ultrasound [US] and computerized tomography [CT]) and management plans in these patients.Results A total of 60 patients were included in the study. After cholecystectomy, histopathology of gallbladders showed GBC in 2 (3.3%) patients. The remaining 58 patients had chronic cholecystitis, of whom 28 (48%) had xanthogranulomatous variant chronic cholecystitis. Cholecystectomy by the laparoscopic method was attempted in 46 (77%) patients and by open technique in the remaining 14 (23%) patients. Laparoscopic cholecystectomy was successful in 40 of the 46 (87%) patients in whom it was attempted. Obscure anatomy, suspicion of GBC, and bile duct injury were the causes of conversion, in the remaining 13% (6/46). None of the 11 patients who had a CT examination because of clinical or US suspicion of malignancy turned out to have GBC at final histology. Both the cases of GBC in this study were incidental findings on final histopathology.Conclusions Laparoscopic cholecystectomy can be successfully performed in the majority of patients with diffuse TWGB, with appropriate selection. There is, however, an increased chance of conversion to open cholecystectomy in these patients. If there is an intraoperative suspicion of GBC, early conversion to open cholecystectmy and frozen section/imprint cytology will help to decide the further treatment during surgery.     

Reversal of pancytopenia following kidney transplantation in a patient of primary hyperoxaluria with bone marrow involvement

Combined liver and kidney transplantation is the ideal treatment for patients with end-stage renal failure secondary to primary hyperoxaluria and systemic oxalosis, with a functioning liver providing replacement of the deficient enzyme and a functioning kidney providing the route of excretion for the oxalate crystals. Pancytopenia from bone marrow infiltration of oxalate crystals is a rare complication of primary hyperoxaluria, and its reversal following transplant has not been described. We report the first case of pancytopenia from marrow infiltration by oxalate crystals reversing following a successful kidney transplant alone. Although kidney alone transplants do not provide the best chance of survival or quality of life as compared to a combined kidney and liver transplant, a well functioning kidney transplant is able to take care of the systemic oxalate load and ameliorate, at least for a period of time, the systemic complications of oxalosis.