Salmonella typhimurium lacking ribose chemoreceptors localize in tumor quiescence and induce apoptosis

The effectiveness of most chemotherapeutics is limited by their inability to penetrate deep into tumor tissue and their ineffectiveness against quiescent cells. Motile Salmonella typhimurium, which are specifically attracted to compounds produced by quiescent cancer cells, could overcome this therapeutic barrier. We hypothesized that individual chemoreceptors target S. typhimurium to specific tumor microenvironments. To test this hypothesis, we used time-lapse fluorescent microscopy and tumor cylindroids to quantify the accumulation of chemotaxis machinery knockouts, including strains lacking individual cell surface chemoreceptors, chemotaxis signal transduction pathway enzymes, and the flagella and motor assemblies. To measure the extent of apoptosis induced by individual bacterial strains, caspase-3 activity was measured as a function of time. Our results showed how chemoreceptors directed bacterial chemotaxis within cylindroids: the aspartate receptor initiated chemotaxis toward cylindroids, the serine receptor initiated penetration, and the ribose/galactose receptor directed S. typhimurium toward necrosis. In addition, strains lacking proper flagella constructs, signal transduction proteins, or active motor function did not chemotax toward tumor cylindroids, indicating that directed chemotaxis is necessary to promote accumulation in tumors. By deleting the ribose/galactose receptor, bacterial accumulation localized to tumor quiescence and had a greater individual effect on inducing apoptosis than wild-type S. typhimurium. This new understanding of the mechanisms of Salmonella migration in tumors will allow for the development of bacterial therapies with improved targeting to therapeutically inaccessible regions of tumors.     

Oxidative stress as a major culprit in kidney disease in diabetes

It is postulated that localized tissue oxidative stress is a key component in the development of diabetic nephropathy. There remains controversy, however, as to whether this is an early link between hyperglycemia and renal disease or develops as a consequence of other primary pathogenic mechanisms. In the kidney, a number of pathways that generate reactive oxygen species (ROS) such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. In addition, a unifying hypothesis has been proposed whereby mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways. This postulate emphasizes the importance of mitochondrial dysfunction in the progression and development of diabetes complications including nephropathy. A mystery remains, however, as to why antioxidants per se have demonstrated minimal renoprotection in humans despite positive preclinical research findings. It is likely that the utility of current study approaches, such as vitamin use, may not be the ideal antioxidant strategy in human diabetic nephropathy. There is now an increasing body of data to suggest that strategies involving a more targeted antioxidant approach, using agents that penetrate specific cellular compartments, may be the elusive additive therapy required to further optimize renoprotection in diabetes.     

Transcatheter closure of high-risk muscular ventricular septal defects with the CardioSEAL occluder: initial report from the CardioSEAL VSD registry.

OBJECTIVES: The CardioSEAL VSD registry was created to track safety of the device to close high-risk Ventricular Septal Defect (VSD). BACKGROUND: This is the first report from the multi-centered CardioSEAL VSD registry reviewing demographics and initial results. METHODS: Centers recruited patients with VSD who were high-risk for surgery due to medical condition or anatomic features. RESULTS: 18 centers contributed data on 55 high-risk patients who had 61 VSD-occlusion procedures, with age of range of 5 days to 65 years and using one to six devices. Implantation approach was transvenous in 48, perventricular in five, and by combined approach in two patients. Ninety-two percent of intended VSD device implants were judged successful. Twenty-two patients had single VSD closed by single device in 18 and by two devices in four patients. All patients <8 kg underwent perventricular device implantation. Thirty-three patients had multiple VSDs which were closed by a single device in 23, and multiple devices in 10. At discharge echocardiography showed total residual flow through all VSDs in which devices were used was classified as "Small" or less in 74%, "More than small" in 11%, and "Uncertain" in 15%. Eight major adverse events occurred in 5/61 cases (8% event rate), with 3/81 devices embolized (4% embolization rate), 5/81 devices surgically explanted (6% explant rate), and no deaths judged to be procedure-related. CONCLUSION: This initial report from the multi-centered CardioSEAL VSD registry demonstrates the safety of the device to close high-risk VSDs.     

Informed consent in direct access colonoscopy

BACKGROUND AND AIM: Although direct access colonoscopy is a common practice, some consider the level of informed consent as inadequate, and therefore a medico-legal concern. The aim of this study was to assess the adequacy of informed consent from a patient perspective in a direct access colonoscopy service. METHODS: All patients having outpatient colonoscopy from May 2003 to February 2004 at a direct access colonoscopy service were considered for inclusion into the study. Information was obtained from patients by structured questionnaire administered either at the time of discharge from the day ward or mailed to their homes. RESULTS: Information was obtained from 346 direct access colonoscopy patients (172 male, 159 female; 226 >or= 50 years, 103 < 50 years), 80% of whom were referred by their family doctor. Colonoscopy was done for investigation of symptoms in 220 patients, and for screening and surveillance in 115 patients, with an indication not specified in 11 patients. The majority of patients were either very satisfied (70.5%) or satisfied (25.1%) with the consent process, with no demographic characteristics found to predict dissatisfaction. Thirty-seven patients expressed a preference to have seen a gastroenterologist prior to colonoscopy, and four of these patients reported the consent process to be unsatisfactory. Seventy (20.2%) patients reported that the most useful information about colonoscopy was received after they had completed bowel preparation. CONCLUSION: No demographic characteristics were found to predict the small fraction of patients dissatisfied with the informed consent process. Further medico-legal risk reduction may be facilitated by enhancing the provision of information prior to bowel preparation.     

Antiretroviral therapy in pregnancy: local practice in East London, UK

A review of antiretroviral prescribing, mode of delivery and pregnancy outcome was performed to assess local practice against the new British HIV Association guidelines. HIV status prior to pregnancy, antiretroviral medication, viral load, mode of delivery and pregnancy outcome were determined in 95 pregnancies recorded between 2004 and 2006 via retrospective case-note review. In total, 75% (n=71) of pregnancies resulted in live births; 56% (n=53) of pregnancies occurred in women who knew they were HIV positive prior to the current pregnancy; 49% (n=26) of them conceived on antiretroviral therapy (ART). Use of protease-inhibitor-based ART and number of normalvaginal delivery increased and the use of zidovudine (AZT) monotherapy and emergency caesarean section (CS) fell during the study period. In conclusion, there was an increase in vaginal deliveries and a reduction in the number of emergency CSs between 2004 and 2006.     

Oxidative stress in Niemann–Pick disease,type C

Niemann–Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder due to impaired intracellular cholesterol and lipid transport. Increased oxidative stress has been reported in human NPC1 mutant fibroblasts and in tissues from Npc1 mutant mice. However, oxidative stress in NPC patients has not been established. In this study, we demonstrated increased oxidative stress in NPC patients. Evaluation of serum from 37 NPC patients, compared to control values, showed significant decreases (p < .01) in both the fraction of reduced coenzyme Q10 (CoQ10) and trolox equivalent antioxidant capacity (TEAC). Both findings are consistent with increased oxidative stress in NPC. Supplementation with CoQ10 was not effective in correcting the decreased fraction of reduced CoQ10. Increased oxidative stress may be a contributing factor to the pathology of NPC, and demonstration of increased oxidative stress in NPC patients provides both a rationale and the biomarkers necessary to test the efficacy of antioxidant therapy in NPC.