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Chimeric Allografts Induced by Short-Term Treatment with Stem Cell Mobilizing Agents Result in Long-term Kidney Transplant Survival without Immunosuppression: II Study in Miniature Swine. - American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Transplantation is now lifesaving therapy for patients with end stage organ failure but requires lifelong immunosuppression with resultant morbidity. Current immunosuppressive strategies inhibit T cell activation and prevent donor-recipient engagement. Therefore, it is not surprising that few host cells are demonstrated in donor grafts. However, our recent small animal studies found large numbers of recipient stem cells present after transplant and pharmacological mobilization resulting in a chimeric, repopulated organ. We now confirm these findings in a well characterized large animal preclinical model. Here we show that AMD3100 (A) and FK506 (F) mobilization of endogenous stem cells immediately post kidney transplant combined with repeat therapy at 1, 2, and 3 months led to drug free long term survival in maximally immunologically mismatched swine. Three long term recipients have stable chimeric transplants, preserved anti-donor skin graft responses, and normal serum creatinine despite withdrawal of all medication for 3 years. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
The Ecological Dynamics of Fecal Contamination and Salmonella Typhi and Salmonella Paratyphi A in Municipal Kathmandu Drinking Water. - PLoS neglected tropical diseases
One of the UN sustainable development goals is to achieve universal access to safe and affordable drinking water by 2030. It is locations like Kathmandu, Nepal, a densely populated city in South Asia with endemic typhoid fever, where this goal is most pertinent. Aiming to understand the public health implications of water quality in Kathmandu we subjected weekly water samples from 10 sources for one year to a range of chemical and bacteriological analyses. We additionally aimed to detect the etiological agents of typhoid fever and longitudinally assess microbial diversity by 16S rRNA gene surveying. We found that the majority of water sources exhibited chemical and bacterial contamination exceeding WHO guidelines. Further analysis of the chemical and bacterial data indicated site-specific pollution, symptomatic of highly localized fecal contamination. Rainfall was found to be a key driver of this fecal contamination, correlating with nitrates and evidence of S. Typhi and S. Paratyphi A, for which DNA was detectable in 333 (77%) and 303 (70%) of 432 water samples, respectively. 16S rRNA gene surveying outlined a spectrum of fecal bacteria in the contaminated water, forming complex communities again displaying location-specific temporal signatures. Our data signify that the municipal water in Kathmandu is a predominant vehicle for the transmission of S. Typhi and S. Paratyphi A. This study represents the first extensive spatiotemporal investigation of water pollution in an endemic typhoid fever setting and implicates highly localized human waste as the major contributor to poor water quality in the Kathmandu Valley.
Acute liver failure associated with Garcinia cambogia use. - Annals of hepatology
Millions of Americans regularly use herbal supplements, but many are unaware of the potential hidden dangers. Numerous supplements have been associated with hepatotoxicity and, indeed dietary/herbal supplements represent an increasingly common source of acute liver injury. We report a case of acute liver failure requiring liver transplantation associated with the use of Garcinia cambogia, a supplement widely promoted for weight loss. When patients present with acute hepatitis or liver failure from an unknown etiology, a careful history of supplement use should be performed.
16S rRNA assessment of the influence of shading on early-successional biofilms in experimental streams. - FEMS microbiology ecology
Elevated nutrient levels can lead to excessive biofilm growth, but reducing nutrient pollution is often challenging. There is therefore interest in developing control measures for biofilm growth in nutrient-rich rivers that could act as complement to direct reductions in nutrient load. Shading of rivers is one option that can mitigate blooms, but few studies have experimentally examined the differences in biofilm communities grown under shaded and unshaded conditions. We investigated the assembly and diversity of biofilm communities using in situ mesocosms within the River Thames (UK). Biofilm composition was surveyed by 454 sequencing of 16S amplicons (âˆ¼400 bp length covering regions V6/V7). The results confirm the importance of sunlight for biofilm community assembly; a resource that was utilized by a relatively small number of dominant taxa, leading to significantly less diversity than in shaded communities. These differences between unshaded and shaded treatments were either because of differences in resource utilization or loss of diatom-structures as habitats for bacteria. We observed more co-occurrence patterns and network interactions in the shaded communities. This lends further support to the proposal that increased river shading can help mitigate the effects from macronutrient pollution in rivers.Â© FEMS 2015.
Glucose homeostasis after simultaneous pancreas and kidney transplantation: a comparison of subjects with C-peptide-positive non-type 1 diabetes mellitus and type 1 diabetes mellitus. - Clinical transplantation
While simultaneous pancreas kidney transplant (SPKTx) is a therapeutic option for patients with type 1 diabetes (T1DM) and renal failure, few centers offer SPKTx to "select" non-T1DM patients. To address concerns that existing insulin resistance may limit the benefits of the pancreas allograft among non-T1DM, we compared several indices of glucose homeostasis, in "select" non-T1DM and T1DM patients who received SPKTx.Criteria for "select" non-T1DM included the following: positive C-peptide, BMI <30 kg/m(2) , treatment with oral agents before insulin initiation, and insulin at <1 unit/kg/d. We compared several indices of glucose homeostasis within 1 yr post-SPKTx among seven "select" patients with non-T1DM and nine patients with T1DM with similar age, BMI, and immunosuppression. Measurements of insulin resistance included the following: homeostatic model, insulin sensitivity index, and insulin-glucose ratio; insulin secretion measures included the following: corrected insulin response.Non-T1DM had similar pre-transplant metabolic (fasting glucose, HbA1c, blood pressure, and lipid) parameters to the T1DM cohort. There were no significant differences in the various measures of insulin resistance and secretion between T1DM and "select" non-T1DM patients.Our results suggest SPKTx should be considered in the therapeutic armamentarium among carefully select non-T1DM with features of minimal insulin resistance; however, a larger cohort with longer follow-up is needed to confirm our results.Â© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Public health safety and transplant with increased-risk organs: striking the balance. - Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation
There is significant variability amongst transplant centers, Organ Procurement Organizations (OPO), members of public, and patients about organs from Public Health Service increased risk donors. This has therefore required regulatory bodies like Centers for Disease Control and Prevention to formulate policies for transplant centers and OPOs to minimize risk of infectious transmission to recipients of solid-organ transplants from such donors.
Validated predictive modelling of the environmental resistome. - The ISME journal
Multi-drug-resistant bacteria pose a significant threat to public health. The role of the environment in the overall rise in antibiotic-resistant infections and risk to humans is largely unknown. This study aimed to evaluate drivers of antibiotic-resistance levels across the River Thames catchment, model key biotic, spatial and chemical variables and produce predictive models for future risk assessment. Sediment samples from 13 sites across the River Thames basin were taken at four time points across 2011 and 2012. Samples were analysed for class 1 integron prevalence and enumeration of third-generation cephalosporin-resistant bacteria. Class 1 integron prevalence was validated as a molecular marker of antibiotic resistance; levels of resistance showed significant geospatial and temporal variation. The main explanatory variables of resistance levels at each sample site were the number, proximity, size and type of surrounding wastewater-treatment plants. Model 1 revealed treatment plants accounted for 49.5% of the variance in resistance levels. Other contributing factors were extent of different surrounding land cover types (for example, Neutral Grassland), temporal patterns and prior rainfall; when modelling all variables the resulting model (Model 2) could explain 82.9% of variations in resistance levels in the whole catchment. Chemical analyses correlated with key indicators of treatment plant effluent and a model (Model 3) was generated based on water quality parameters (contaminant and macro- and micro-nutrient levels). Model 2 was beta tested on independent sites and explained over 78% of the variation in integron prevalence showing a significant predictive ability. We believe all models in this study are highly useful tools for informing and prioritising mitigation strategies to reduce the environmental resistome.
Intra- and inter-pandemic variations of antiviral, antibiotics and decongestants in wastewater treatment plants and receiving rivers. - PloS one
The concentration of eleven antibiotics (trimethoprim, oxytetracycline, ciprofloxacin, azithromycin, cefotaxime, doxycycline, sulfamethoxazole, erythromycin, clarithromycin, ofloxacin, norfloxacin), three decongestants (naphazoline, oxymetazoline, xylometazoline) and the antiviral drug oseltamivir's active metabolite, oseltamivir carboxylate (OC), were measured weekly at 21 locations within the River Thames catchment in England during the month of November 2009, the autumnal peak of the influenza A[H1N1]pdm09 pandemic. The aim was to quantify the pharmaceutical response to the pandemic and compare this to drug use during the late pandemic (March 2010) and the inter-pandemic periods (May 2011). A large and small wastewater treatment plant (WWTP) were sampled in November 2009 to understand the differential fate of the analytes in the two WWTPs prior to their entry in the receiving river and to estimate drug users using a wastewater epidemiology approach. Mean hourly OC concentrations in the small and large WWTP's influent were 208 and 350 ng/L (max, 2070 and 550 ng/L, respectively). Erythromycin was the most concentrated antibiotic measured in Benson and Oxford WWTPs influent (max=6,870 and 2,930 ng/L, respectively). Napthazoline and oxymetazoline were the most frequently detected and concentrated decongestant in the Benson WWTP influent (1650 and 67 ng/L) and effluent (696 and 307 ng/L), respectively, but were below detection in the Oxford WWTP. OC was found in 73% of November 2009's weekly river samples (max=193 ng/L), but only in 5% and 0% of the late- and inter-pandemic river samples, respectively. The mean river concentration of each antibiotic during the pandemic largely fell between 17-74 ng/L, with clarithromycin (max=292 ng/L) and erythromycin (max=448 ng/L) yielding the highest single measure. In general, the concentration and frequency of detecting antibiotics in the river increased during the pandemic. OC was uniquely well-suited for the wastewater epidemiology approach owing to its nature as a prodrug, recalcitrance and temporally- and spatially-resolved prescription statistics.
Kidney Transplant Program at the Mayo Clinic in Arizona. - Clinical transplants
Since 1999, we have performed 2,302 kidney transplants at the Mayo Clinic in Arizona. Transplant volume has increased by 45% since 2010. Our center performed 269 kidney transplants in 2013. Our growth is related to multiple factors, including an experienced, committed team and strong support from our institution and referring nephrologists. Areas of program innovation at our center include: transplanting deceased donors with acute kidney injury, outcomes in older kidney transplant recipients, alemtuzumab induction with steroid avoidance, living donor paired kidney exchange-3 site experience, and other non-traditional deceased donor kidney transplants. Of the 162 acute kidney injury (AKI) donor transplants done at our program, 71% had severe AKI. The AKI donor kidneys had more delayed graft function; but graft survival, estimated glomerular filtration rate, and biopsy findings at 1 year were not different form the control group. We have transplanted 188 patients â‰¥ 70 years old at the time of transplantation. Graft survival at 1, 3, and 5 years was similar to that of patients < 70. Since 2008, 778 (37%) patients received alemtuzumab induction, therapy with excellent patient and graft survival. We have used steroid avoidance immunosuppression with excellent outcomes since 2003. Since starting kidney paired donation in 2009, it has resulted in 54 kidney transplants, including 4 compatible pairs. More than half of the deceased donor transplants done at our center are from non-traditional donors such as Public Health Service increased risk, donation after cardiac death, extended criteria donors/high kidney donor profile index, and pediatric en-bloc donors. One- and 3-year graft survival of the non-traditional deceased donor kidney transplants are not different than the traditional deceased donor kidney transplants.
Compliance to oseltamivir among two populations in Oxfordshire, United Kingdom affected by influenza A(H1N1)pdm09, November 2009--a waste water epidemiology study. - PloS one
Antiviral provision remains the focus of many pandemic preparedness plans, however, there is considerable uncertainty regarding antiviral compliance rates. Here we employ a waste water epidemiology approach to estimate oseltamivir (TamifluÂ®) compliance. Oseltamivir carboxylate (oseltamivir's active metabolite) was recovered from two waste water treatment plant (WWTP) catchments within the United Kingdom at the peak of the autumnal wave of the 2009 Influenza A (H1N1)pdm09 pandemic. Predictions of oseltamivir consumption from detected levels were compared with two sources of national government statistics to derive compliance rates. Scenario and sensitivity analysis indicated between 3-4 and 120-154 people were using oseltamivir during the study period in the two WWTP catchments and a compliance rate between 45-60%. With approximately half the collected antivirals going unused, there is a clear need to alter public health messages to improve compliance. We argue that a near real-time understanding of drug compliance at the scale of the waste water treatment plant (hundreds to millions of people) can potentially help public health messages become more timely, targeted, and demographically sensitive, while potentially leading to less mis- and un-used antiviral, less wastage and ultimately a more robust and efficacious pandemic preparedness plan.
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