Comparative molecular modeling of Anopheles gambiae CYP6Z1, a mosquito P450 capable of metabolizing DDT

One of the challenges faced in malarial control is the acquisition of insecticide resistance that has developed in mosquitoes that are vectors for this disease. Anopheles gambiae, which has been the major mosquito vector of the malaria parasite Plasmodium falciparum in Africa, has over the years developed resistance to insecticides including dieldrin, 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), and pyrethroids. Previous microarray studies using fragments of 230 An. gambiae genes identified five P450 loci, including CYP4C27, CYP4H15, CYP6Z1, CYP6Z2, and CYP12F1, that showed significantly higher expression in the DDT-resistant ZAN/U strain compared with the DDT-susceptible Kisumu strain. To predict whether either of the CYP6Z1 and CYP6Z2 proteins might potentially metabolize DDT, we generated and compared molecular models of these two proteins with and without DDT docked in their catalytic sites. This comparison indicated that, although these two CYP6Z proteins share high sequence identity, their metabolic profiles were likely to differ dramatically from the larger catalytic site of CYP6Z1, potentially involved in DDT metabolism, and the more constrained catalytic site of CYP6Z2, not likely to metabolize DDT. Heterologous expressions of these proteins have corroborated these predictions: only CYP6Z1 is capable of metabolizing DDT. Overlays of these models indicate that slight differences in the backbone of SRS1 and variations of side chains in SRS2 and SRS4 account for the significant differences in their catalytic site volumes and DDT-metabolic capacities. These data identify CYP6Z1 as one important target for inhibitor design aimed at inactivating insecticide-metabolizing P450s in natural populations of this malarial mosquito.     

Contribution of rickettsioses in Sri Lankan patients with fever who responded to empirical doxycycline treatment

Twenty-eight febrile Sri Lankan patients with undiagnosed fever for 7 days after hospital admission, who responded to empirical treatment with doxycycline, were retrospectively investigated using microimmunofluorescence assay to verify whether they had rickettsial infection. Eleven (39%) patients were confirmed as having spotted fever group rickettsioses and 10 (36%) as having Orientia tsutsugamushi. Seven were negative for all tests. This suggests that greater use of doxycycline appears justified for patients with undiagnosed fever in settings where rickettsial diseases are endemic or re-emerging with inadequate diagnostic facilities.     

Quality of life following surgery for recurrent fistula-in-ano

Background  

The management of fistula-in-ano remains a major surgical challenge and carries a significant morbidity affecting the quality of life (QOL) due to the disease and repeated operations. The aim of the study was to assess the QOL before and after successful surgical treatment of recurrent fistula-in-ano using the gastrointestinal quality of life index (GIQLI) which is a validated instrument consisting of 36 questions for measuring quality of life in patients with gastrointestinal disorders including fistula-in-ano.     

A Randomised Trial of Text Message Support for Reducing Weight Regain Following Sleeve Gastrectomy

Introduction

Sleeve gastrectomy (SG) is a common bariatric procedure with high rates of weight regain (WR). Clinicians and patients have identified a lack of follow-up support and maladaptive lifestyle behaviours as potential causes for WR. While text message support has been shown to be effective for weight loss in non-surgical patients, it has not been investigated for reducing WR in bariatric patients.

Purpose

To determine the effectiveness of text message support in reducing weight regain following sleeve gastrectomy.

Methods

A text message intervention was designed. The effectiveness of the intervention was investigated by a randomised trial powered to detect a 15% difference in the primary outcome of percent excess weight loss (84 participants required). Secondary outcomes were the Bariatric Analysis and Reporting System (BAROS) score and patient satisfaction. Outcomes were assessed at 6 and 12 months.

Results

Ninety-five participants were randomised to either standard care or text message support (daily text message for 1 year). While there was no significant difference in the primary outcome at 6 or 12 months, patients who received the intervention tended to have less WR and a significantly better BAROS score at 12 months. Participants who received text message support found it beneficial, would have liked the messages to continue, and felt WR was reduced by having the text message support.

Conclusion

Text message support following SG is feasible, may reduce weight regain, improves the BAROS score and is valued by patients.

Trial Registration

NCT02341001

     

Retinal venular calibre dilatation after intravitreal ranibizumab treatment for neovascular age-related macular degeneration

Background: To describe the changes in retinal vascular calibre in response to intravitreal ranibizumab injections in patients with neovascular age‐related macular degeneration. Design: Prospective interventional case series. Participants: Treatment naïve patients with neovascular age‐related macular degeneration were recruited over a 1‐year period. Methods: Each patient received three monthly intravitreal injections according to a ‘loading dose’. Retinal arteriolar and venular calibre was measured from digital fundus photographs and summarized as central retinal artery equivalent and central retinal vein equivalent at baseline and 3 months. Main Outcome Measure: Central retinal artery equivalent and central retinal vein equivalent changes from baseline to 3 months. Results: Seventy‐four eyes of 71 patients had good quality images for grading vessel calibre at baseline and at 3 months in treated (study) eyes and 51 eyes of 51 patients had good quality images in fellow (control) eyes. Over 3 months, in study eyes treated with ranibizumab, there was a significant increase in central retinal vein equivalent over baseline (+6.20 µm, P = 0.005), but no significant change in central retinal artery equivalent (+0.86 µm, P = 0.55). In control eyes, there was no change in central retinal vein equivalent (?0.82 µm, P = 0.70) or central retinal artery equivalent (0.34 µm, P = 0.75). Conclusion: Intravitreal ranibizumab has a significant vasodilational effect on retinal venular calibre in eyes treated for neovascular age‐related macular degeneration. The reason for this change is unclear, but may relate to changes in blood flow or inflammatory changes within the retina.