The XylR/NtrC-type regulator CbsR positively regulates upstream pathway of chlorobenzene degradation in Pandoraea pnomenusa.

AIMS: Pandoraea pnomenusa MCB032 completely degrades chlorobenzene, whose metabolic pathway is encoded by cbs and clc gene clusters. The putative regulatory factors ClcR and CbsR are predicted to regulate the cbs and clc gene clusters. This research aims to understand the function of ClcR and CbsR. METHODS AND RESULTS: RT-PCR analyses demonstrated that the cbsFAaAbAcAdB operon that encodes catabolic pathways for the degradation of chlorobenzene to chlorocatechol is located on an operon. Moreover, the clcABCDE operon is involved in the 3-chlorocatechol pathway. Gene knockout and transcriptional analysis showed that the transcription of the cbsFAaAbAcAdB operon is positively regulated by CbsR, whereas the clcABCDE operon is activated by ClcR. Primer extension analysis was used to locate the transcription start sites of the cbsFAaAbAcAdB and cbsR operons. Electrophoretic mobility shift assay analyses showed that CbsR is bound to the sites in the promoter regions of cbsFAaAbAcAdB and cbsR operons. CONCLUSION: The XylR/NtrC-type regulator CbsR positively regulates the transcription of the cbsFAaAbAcAdB operon encoding the upstream pathway of chlorobenzene catabolism, while the LysR-type regulator ClcR activates the clcABCDE operon encoding the downstream pathway.

Non-Vitamin K-Dependent Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With CKD: Pragmatic Considerations for the Clinician.

Management of atrial fibrillation (AF) in patients with advanced chronic kidney disease (CKD) poses a complex conundrum because of higher risks for both thromboembolic and bleeding complications compared to the general population. This makes it particularly important for clinicians to carefully weigh the risks versus benefits of anticoagulation therapy to determine the individualized net clinical benefit for every patient. During the past few years, 4 non-vitamin K-dependent oral anticoagulant (NOAC) agents have supplemented warfarin in the therapeutic armamentarium for the prevention of systemic thromboembolism in nonvalvular AF. However, the use of NOACs in CKD specifically mandates a nuanced understanding due to their varying dependence on renal clearance, with resultant safety implications related to either underdosing (thromboembolism) or excessive drug exposure (bleeding). This pragmatic review highlights unique considerations pertaining to accurate estimation and temporal monitoring of kidney function in the context of NOAC use with specific clinical deliberations and variables when determining whether an NOAC is appropriate for a patient with CKD. The dependence of NOACs on renal clearance and several troubling safety signals in the published literature suggest that it is vital for nephrologists to be active members of a multidisciplinary team caring for these high-risk patients with CKD and AF.

Impact of Obesity on Modality Longevity, Residual Kidney Function, Peritonitis, and Survival Among Incident Peritoneal Dialysis Patients.

BACKGROUND: The prevalence of severe obesity, often considered a contraindication to peritoneal dialysis (PD), has increased over time. However, mortality has decreased more rapidly in the PD population than the hemodialysis (HD) population in the United States. The association between obesity and clinical outcomes among patients with end-stage kidney disease remains unclear in the current era. STUDY DESIGN: Historical cohort study. SETTING & PARTICIPANTS: 15,573 incident PD patients from a large US dialysis organization (2007-2011). PREDICTOR: Body mass index (BMI). OUTCOMES: Modality longevity, residual renal creatinine clearance, peritonitis, and survival. RESULTS: Higher BMI was significantly associated with shorter time to transfer to HD therapy (P for trend < 0.001), longer time to kidney transplantation (P for trend < 0.001), and, with borderline significance, more frequent peritonitis-related hospitalization (P for trend = 0.05). Compared with lean patients, obese patients had faster declines in residual kidney function (P for trend < 0.001) and consistently achieved lower total Kt/V over time (P for trend < 0.001) despite greater increases in dialysis Kt/V (P for trend < 0.001). There was a U-shaped association between BMI and mortality, with the greatest survival associated with the BMI range of 30 to < 35kg/m2 in the case-mix adjusted model. Compared with matched HD patients, PD patients had lower mortality in the BMI categories of < 25 and 25 to < 35kg/m2 and had equivalent survival in the BMI category ≥ 35kg/m2 (P for interaction = 0.001 [vs < 25 kg/m2]). This attenuation in survival difference among patients with severe obesity was observed only in patients with diabetes, but not those without diabetes. LIMITATIONS: Inability to evaluate causal associations. Potential indication bias. CONCLUSIONS: Whereas obese PD patients had higher risk for complications than nonobese PD patients, their survival was no worse than matched HD patients.

Creatinine clearance, walking speed, and muscle atrophy: a cohort study.

BACKGROUND: Chronic kidney disease is associated with malnutrition and inflammation. These processes may lead to loss of skeletal muscle and reduced physical performance. Associations of kidney function with muscle composition and longitudinal measures of physical performance are unknown. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We evaluated 826 community-dwelling older adults enrolled in the Invecchiare in Chianti (InCHIANTI) Study who were free of baseline stroke or activities of daily living disability. PREDICTOR: Baseline creatinine clearance (Clcr) based on 24-hour urine collection. OUTCOMES: Cross-sectional and longitudinal trajectories of physical performance measured by 7-m usual gait speed, 400-m fast gait speed, and knee extension strength using isometric dynamometry. Calf muscle composition assessed by quantitative computed tomography. RESULTS: Mean age of participants was 74 ± 7 (SD) years, with 183 having Clcr < 60 mL/min/1.73 m(2). After adjustment, each 10-mL/min/1.73 m(2) decrement in Clcr was associated with 0.01 (95% CI, 0.004-0.017) m/s slower 7-m usual walking speed and 0.008 (95% CI, 0.002-0.014) m/s slower 400-m walking speed. Each 10-mL/min/1.73 m(2) decrement in Clcr was associated with 28 (95% CI, 0.8-55) mm(2) lower muscle area and 0.15 (95% CI, 0.04-0.26) mg/cm(3) lower muscle density. After adjustment, lower Clcr was associated with slower mean 7-m (P=0.005) and 400-m (P=0.02) walk and knee extension strength (P=0.001) during the course of follow-up. During a mean follow-up of 7.1 ± 2.5 years, each 10-mL/min/1.73 m(2) lower baseline Clcr was associated with 0.024 (95% CI, 0.01-0.037) kg/y greater decline in knee strength. LIMITATIONS: Single baseline measurement of Clcr and 3-year interval between follow-up visits may lead to nondifferential misclassification and attenuation of estimates. CONCLUSIONS: Among older adults, lower Clcr is associated with muscle atrophy, reduced walking speed, and more rapid declines in lower-extremity strength over time.

Effect of paracellular permeation enhancers on intestinal permeability of two peptide drugs, enalaprilat and hexarelin, in rats.

Transcellular permeation enhancers are known to increase the intestinal permeability of enalaprilat, a 349 Da peptide, but not hexarelin (887 Da). The primary aim of this paper was to investigate if paracellular permeability enhancers affected the intestinal permeation of the two peptides. This was investigated using the rat single-pass intestinal perfusion model with concomitant blood sampling. These luminal compositions included two paracellular permeation enhancers, chitosan (5 mg/mL) and ethylenediaminetetraacetate (EDTA, 1 and 5 mg/mL), as well as low luminal tonicity (100 mOsm) with or without lidocaine. Effects were evaluated by the change in lumen-to-blood permeability of hexarelin and enalaprilat, and the blood-to-lumen clearance of 51chromium-labeled EDTA (CLCr-EDTA), a clinical marker for mucosal barrier integrity. The two paracellular permeation enhancers increased the mucosal permeability of both peptide drugs to a similar extent. The data in this study suggests that the potential for paracellular permeability enhancers to increase intestinal absorption of hydrophilic peptides with low molecular mass is greater than for those with transcellular mechanism-of-action. Further, the mucosal blood-to-lumen flux of 51Cr-EDTA was increased by the two paracellular permeation enhancers and by luminal hypotonicity. In contrast, luminal hypotonicity did not affect the lumen-to-blood transport of enalaprilat and hexarelin. This suggests that hypotonicity affects paracellular solute transport primarily in the mucosal crypt region, as this area is protected from luminal contents by a constant water flow from the crypts.

Glycemic targets and medication limitations for type 2 diabetes mellitus in the older adult.

OBJECTIVE: To review the optimal management of type 2 diabetes mellitus (T2DM) in the older adult. DATA SOURCES: A PubMed search was completed to identify publications in the English language from 1947 to 2013 using combinations of the search terms: geriatrics, aged, diabetes mellitus, and type 2 diabetes mellitus. References of articles were also reviewed for inclusion if not identified in the PubMed search. STUDY SELECTION AND DATA EXTRACTION: Original studies, clinical reviews, and guidelines were identified and evaluated for clinical relevance. DATA SYNTHESIS: Although the number of older adults with T2DM is growing, evidence for the treatment of T2DM in this population is lacking. Barriers such as polypharmacy, comorbid conditions, economic limitations, cognitive impairment, and increased risk of hypoglycemia may limit optimal glycemic control in older adults. Several organizations provide recommendations for glycemic targets and recommend using standard glycemic goals in most healthy older adults. However, less stringent goals are necessary in certain older populations such as those patients with limited life expectancy and severe hypoglycemia. In general, glycemic goals should be individualized in older patients. Age-related pharmacokinetic and pharmacodynamic changes, comorbid conditions, adverse drug reactions, ease of medication administration, and cost of medications necessitate the need to individualize pharmacologic therapy. CONCLUSION: Glycemic targets and medication use for T2DM should be individualized in older adults.

Dabigatran for stroke prevention in nonvalvular atrial fibrillation: focus in the geriatric population.

OBJECTIVE: To evaluate the safety and efficacy of dabigatran for stroke prevention in the elderly population. DATA SOURCES: MEDLINE (1948-June 2013), Web of Science (1980-June 2013), and Google Scholar were used to identify relevant literature. Search terms included dabigatran, dabigatran etexilate, geriatric, elderly. STUDY SELECTION: All articles evaluating the use of dabigatran in the elderly were considered for inclusion. Data derived from controlled clinical studies were given priority for inclusion. DATA EXTRACTION: Only the Randomized Evaluation of Long-Term Anticoagulant Therapy trial has evaluated dabigatran etexilate for the prevention of stroke in nonvalvular atrial fibrillation. A post hoc analysis of this study was completed to identify the risks and benefits of therapy in patients 75 years of age and older. Numerous case reports and case series have been published that suggest an increased risk of bleeding in the elderly. Large observational studies, however, have not supported the hypotheses generated by these case reports. DATA SYNTHESIS: Since the approval of dabigatran etexilate, numerous case reports have suggested the potential dangers of bleeding complications, especially given that there is no known antidote. Observational studies have challenged these case reports and suggest that the increased risk of bleeding is similar or lower compared with warfarin therapy. The increased reporting of bleeding complications may be a result of reporting bias. CONCLUSIONS: Advanced age alone should not exclude the use of dabigatran. Clinicians should base their decision on patient characteristics and careful assessment of risk versus benefit.

Cellular senescence determines endothelial cell damage induced by uremia.

Renal dysfunction is closely associated with endothelial damage leading to cardiovascular disease. However, the extent to which endothelial damage induced by uremia is modulated by aging is poorly known. Aging can render endothelial cells more susceptible to apoptosis through an oxidative stress-dependent pathway. We examined whether senescence-associated to oxidative stress determines the injury induced by the uremia in endothelial cells. Human umbilical vein endothelial cells (HUVEC) was incubated with human uremic serum and, in the animal model, endothelial cells were obtained from aortas of uremic and no uremic rats. Vitamin C was used to prevent oxidative stress. Senescence, assessed by telomere length and enzyme-betagalactosidase (ß-gal), reactive oxygen species (ROS), mitochondrial depolarization (JC-1 probe), caspase 3, and apoptosis were determined by flow cytometry. NF-κB activity was determined by Western blot. Uremic serum increased ROS and NF-κB in young and aging HUVEC. However only in aging cells, uremic serum induced apoptosis (vs young HUVEC, p<0.01). The endothelial damage induced by uremia seems to be related with the increased oxidative stress, since in both HUVEC and in the experimental model of renal disease in rats, vitamin C prevents endothelial apoptosis. However, vitamin C did not decrease the oxidative stress associated to senescence. These results showed that as compared with young cells, senescent cells have high sensitivity to damage associated to the oxidative stress induced by the uremia. Consequently, protecting senescent endothelial cells from increased oxidative stress might be an effective therapeutic approach in the treatment of vascular disorders in chronic kidney diseases.