Effectiveness and Long-Term Safety of Thiazolidinediones and Metformin in Renal Transplant Recipients

ObjectiveTo investigate the long-term safety and effectiveness of thiazolidinediones and metformin in renal transplant recipients with posttransplant diabetes mellitus (PTDM) or preexisting diabetes mellitus (DM).MethodsRetrospective chart review was performed for renal transplant recipients with PTDM or preexisting DM followed up during the years 2000-2006. Data collected included baseline characteristics; glomerular filtration rate (GFR); creatinine; hemoglobin A_1c; and development of congestive heart failure, edema, and liver function abnormalities. GFR was calculated using the Modification of Diet in Renal Disease study equation calculator.ResultsThirty-two patients comprised the metformin group (PTDM = 21, preexisting DM = 11), and 46 patients were included in the TZD group (PTDM = 33, preexisting DM = 13). Only 24 patients taking metformin and 31 patients taking TZDs were included for effectiveness analysis since the others required additional medications to control their DM. Mean follow-up was 16.4 months (range, 1-55 months) for patients treated with metformin and 37.1 months (range, 6-72 months) for patients treated with TZDs. GFR was decreased from baseline in all patients, but the only significant change was in patients with preexisting DM. While there was a significant change in creatinine levels in the metformin group, only 5 patients had to discontinue the drug because of this elevation (3 in preexisting DM group, 2 in PTDM group). Change in hemoglobin A_1c from baseline was not significant in either study group. Development of congestive heart failure or liver function abnormalities was not observed.ConclusionsMetformin appears to be safe in the renal transplant population for a mean duration of 16 months, although caution should be exercised using close monitoring in patients with preexisting DM. TZDs appear to be safe for a mean duration of 37 months after renal transplant. (Endocr Pract. 2008;14:979-984)     

Efficacy and Safety of Biodegradable Polymer Biolimus-Eluting Stents versus Durable Polymer Drug-Eluting Stents: A Meta-Analysis

Backgrounds

Drug-eluting stents (DES) with biodegradable polymers have been developed to address the risk of thrombosis associated with first-generation DES. We aimed to determine the efficacy and safety of biodegradable polymer biolimus-eluting stents (BES) versus durable polymer DES.

Methods

Systematic database searches of MEDLINE (1950 to June 2013), EMBASE (1966 to June 2013), the Cochrane Central Register of Controlled Trials (Issue 6 of 12, June 2013), and a review of related literature were conducted. All randomized controlled trials comparing biodegradable polymer BES versus durable polymer DES were included.

Results

Eight randomized controlled trials investigating 11,015 patients undergoing percutaneous coronary interventions were included in the meta-analysis. The risk of major adverse cardiac events did not differ significantly between the patients treated with the biodegradable polymer BES and the durable polymer DES (Relative risk [RR], 0.970; 95% CI, 0.848–1.111; p = 0.662). However, biodegradable polymer BES was associated with reduced risk of very late ST compared with the durable polymer DES, while the risk of early or late ST was similar (RR for early or late ST, 1.167; 95% CI 0.755–1.802; p = 0.487; RR 0.273; 95% CI 0.115–0.652; p = 0.003; p for interaction = 0.003).

Conclusions

In this meta-analysis of randomized controlled trials, treatments with biodegradable polymer BES did not significantly reduce the risk of major adverse cardiac events, but demonstrated a significantly lower risk of very late ST when compared to durable polymer DES. This conclusion requires confirmation by further studies with long-term follow-up.

PROSPERO register number

http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013004364#.UnM2lfmsj6J     

Optimization of Drug Delivery by Drug-Eluting Stents

Drug-eluting stents (DES), which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the endothelial healing process. To this end, we have developed a computational model of fluid flow and drug transport in stented arteries and have used this model to establish a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that allows identification of optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Paclitaxel-eluting stents perform optimally by releasing their drug either very rapidly (within a few hours) or very slowly (over periods of several months up to one year) at concentrations considerably lower than current DES. In contrast, sirolimus-eluting stents perform optimally only when drug release is slow. The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices.     

Lesion Length Impacts Long Term Outcomes of Drug-Eluting Stents and Bare Metal Stents Differently

Background

Long lesions have been associated with adverse outcomes in percutaneous coronary interventions with bare metal stents (BMS). However, the exact impact of lesion length on the short- and long-term outcomes of drug-eluting stent (DES) implantations is not as clear.

Methods and Results

This study compared the impact of lesion length on angiographic and clinical outcomes of BMS and DES in a single-center prospective registry. Lesion length was divided into tertiles. The primary endpoints were angiographically defined binary in-stent restenosis (ISR) rate and major adverse cardiac event (MACE). Of the 4,312 de novo lesions in 3,447 consecutive patients in the CAPTAIN registry, 2,791 lesions (of 2,246 patients) received BMS, and the remaining 1,521 lesions (of 1,201 patients) received DES. The mean follow-up duration was 4.5 years. The longer the lesion, the higher the ISR rate (14%, 18%, and 29%, p<0.001) and the lower the MACE-free survivals (p = 0.007) in the BMS group. However, lesion length showed no such correlation with ISR rates (4.7%, 3.3%, and 7.8%, p = 0.67) or MACE-free survivals (p = 0.19) in the DES group.

Conclusions

In our single-center prospective registry, lesion length defined in tertiles has no impact on the short-term (ISR) or long-term (MACE) outcomes of patients implanted with DES. In contrast, longer lesion correlates with higher ISR and MACE rates in BMS group.     

Mild Renal Impairment and the Efficacy and Safety of Liraglutide

ObjectiveTo determine the effect of mild renal impairment (RI) on the efficacy and safety of liraglutide in patients with type 2 diabetes mellitus.MethodsIn this meta-analysis, we examined the 6 LEAD (Liraglutide Effect and Action in Diabetes) studies. Data from patients with type 2 diabetes who had normal renal function, mild RI, or moderate or severe RI were pooled for analysis. Renal function was measured by creatinine clearance as determined by the Cockcroft-Gault equation: normal renal function = creatinine clearance > 89 mL/min; mild RI = 60 mL/min ≤ creatinine clearance ≤ 89 mL/min; and moderate or severe RI = creatinine clearance < 60 mL/min. The meta-analysis included patients administered once-daily liraglutide (1.2 or 1.8 mg) or placebo as either monotherapy or in combination with oral antidiabetic drugs for 26 weeks. In addition, a pooled analysis of all phase 2 and 3 liraglutide trials was done to examine rates of altered renal function.ResultsMild RI did not affect the estimated treatment differences in hemoglobin A_1c. Patients with normal renal function demonstrated decreases in body weight and systolic blood pressure with either dosage of liraglutide, whereas patients in either RI group also demonstrated a decrease in body weight and systolic blood pressure, but these differences were not significant compared with differences observed in the placebo group. Liraglutide treatment vs placebo was safe and well tolerated in patients with mild RI, as there were no significant differences in rates of renal injury, minor hypoglycemia, or nausea. A trend towards increased nausea was observed in patients with moderate or severe RI receiving liraglutide, although the number of patients in this treatment group was too low to determine significance.ConclusionMild RI, as determined by the CockcroftGault equation, had no effect on the efficacy and safety of liraglutide in this meta-analysis. (Endocr Pract. 2011; 17:345-355)     

Additive Effect of Anemia and Renal Impairment on Long-Term Outcome after Percutaneous Coronary Intervention

Introduction

Anemia and renal impairment are important co-morbidities among patients with coronary artery disease undergoing Percutaneous Coronary Intervention (PCI). Disease progression to eventual death can be understood as the combined effect of baseline characteristics and intermediate outcomes.

Methods

Using data from a prospective cohort study, we investigated clinical pathways reflecting the transitions from PCI through intermediate ischemic or hemorrhagic events to all-cause mortality in a multi-state analysis as a function of anemia (hemoglobin concentration <120 g/l and <130 g/l, for women and men, respectively) and renal impairment (creatinine clearance <60 ml/min) at baseline.

Results

Among 6029 patients undergoing PCI, anemia and renal impairment were observed isolated or in combination in 990 (16.4%), 384 (6.4%), and 309 (5.1%) patients, respectively. The most frequent transition was from PCI to death (6.7%, 95% CI 6.1–7.3), followed by ischemic events (4.8%, 95 CI 4.3–5.4) and bleeding (3.4%, 95% CI 3.0–3.9). Among patients with both anemia and renal impairment, the risk of death was increased 4-fold as compared to the reference group (HR 3.9, 95% CI 2.9–5.4) and roughly doubled as compared to patients with either anemia (HR 1.7, 95% CI 1.3–2.2) or renal impairment (HR 2.1, 95% CI 1.5–2.9) alone. Hazard ratios indicated an increased risk of bleeding in all three groups compared to patients with neither anemia nor renal impairment.

Conclusions

Applying a multi-state model we found evidence for a gradient of risk for the composite of bleeding, ischemic events, or death as a function of hemoglobin value and estimated glomerular filtration rate at baseline.     

The Long-Term Effectiveness of Methyldopa in Hypertension

A trial of methyldopa in hypertension was conducted in 60 patients for a mean time of 9.4 months. Initially, four different dosages of methyldopa were studied and blood pressure was significantly lowered in the supine and standing positions. Standing blood pressure was significantly reduced more than supine. An average of 5.2 visits passed before maintenance blood pressure was obtained. There was no significent evidence of deterioration during the duration of this study. Side effects were mild. Only two patients voluntarily requested discontinuance of this study. Tolerance to the drug occurred and approximately 50 per cent of the patients no longer had a significant blood pressure reduction to methyldopa alone by the end of the study. Methyldopa appears to be a significant addition to the drug therapy of hypertension.     

The Impact of Macroscopic Epistasis on Long-Term Evolutionary Dynamics

Genetic interactions can strongly influence the fitness effects of individual mutations, yet the impact of these epistatic interactions on evolutionary dynamics remains poorly understood. Here we investigate the evolutionary role of epistasis over 50,000 generations in a well-studied laboratory evolution experiment in Escherichia coli. The extensive duration of this experiment provides a unique window into the effects of epistasis during long-term adaptation to a constant environment. Guided by analytical results in the weak-mutation limit, we develop a computational framework to assess the compatibility of a given epistatic model with the observed patterns of fitness gain and mutation accumulation through time. We find that a decelerating fitness trajectory alone provides little power to distinguish between competing models, including those that lack any direct epistatic interactions between mutations. However, when combined with the mutation trajectory, these observables place strong constraints on the set of possible models of epistasis, ruling out many existing explanations of the data. Instead, we find that the data are consistent with a “two-epoch” model of adaptation, in which an initial burst of diminishing-returns epistasis is followed by a steady accumulation of mutations under a constant distribution of fitness effects. Our results highlight the need for additional DNA sequencing of these populations, as well as for more sophisticated models of epistasis that are compatible with all of the experimental data.     

Prognostic Impact of 9-Month High-Sensitivity C-Reactive Protein Levels on Long-Term Clinical Outcomes and In-Stent Restenosis in Patients at 9 Months after Drug-Eluting Stent Implantation

Introduction

The level of 9-month high-sensitivity C-reactive protein (hsCRP) in predicting cardiovascular outcomes is scanty in patients at 9 months after receiving drug-eluting stent (DES) implantations. This study aims to evaluate the relationship between 9-month follow-up hsCRP levels and long-term clinical outcomes in patients at 9 months after receiving DES.

Methods

A total of 1,763 patients who received 9-month follow-up angiography were enrolled and grouped according to hsCRP level 9 months after the DES implantation: group I (718 patients, hsCRP<1.0 mg/L), group II (639 patients, 1.0≦hsCRP≦3.0 mg/L), and group III (406 patients, hsCRP>3.0 mg/L).

Results

Group III patients had a lower cardiovascular event-free survival rate than group I or II patients during a follow-up of 64±45 months (64.5% vs. 71.6% vs. 72.8%, respectively, p = 0.012). Multivariate analysis showed that a follow-up hsCRP level <3.0 mg/L was an independent predictor of a major adverse cardiovascular event (cardiac death, reinfarction, target lesion revascularization, stenting in a new lesion, or coronary bypass surgery). Group III patients had a higher restenosis rate (11.3% vs. 5.8% vs. 6.6%, respectively, p = 0.002) and loss index (0.21±0.32 vs. 0.16±0.24 vs. 0.18±0.28, respectively, p = 0.001) than group I or II patients in 9-month follow-up angiography.

Conclusions

A high 9-month follow-up hsCRP level is an independent predictor of long-term clinical cardiovascular outcomes in patients at 9 months after DES implantation. It is also associated with a higher restenosis rate, larger late loss and loss index at 9 months after DES implantation.     

Long-Term Impact of Earthquakes on Sleep Quality

Purpose

We investigated the impact of the 6.3 magnitude 2009 L’Aquila (Italy) earthquake on standardized self-report measures of sleep quality (Pittsburgh Sleep Quality Index, PSQI) and frequency of disruptive nocturnal behaviours (Pittsburgh Sleep Quality Index-Addendum, PSQI-A) two years after the natural disaster.

Methods

Self-reported sleep quality was assessed in 665 L’Aquila citizens exposed to the earthquake compared with a different sample (n = 754) of L''Aquila citizens tested 24 months before the earthquake. In addition, sleep quality and disruptive nocturnal behaviours (DNB) of people exposed to the traumatic experience were compared with people that in the same period lived in different areas ranging between 40 and 115 km from the earthquake epicenter (n = 3574).

Results

The comparison between L’Aquila citizens before and after the earthquake showed a significant deterioration of sleep quality after the exposure to the trauma. In addition, two years after the earthquake L''Aquila citizens showed the highest PSQI scores and the highest incidence of DNB compared to subjects living in the surroundings. Interestingly, above-the-threshold PSQI scores were found in the participants living within 70 km from the epicenter, while trauma-related DNBs were found in people living in a range of 40 km. Multiple regressions confirmed that proximity to the epicenter is predictive of sleep disturbances and DNB, also suggesting a possible mediating effect of depression on PSQI scores.

Conclusions

The psychological effects of an earthquake may be much more pervasive and long-lasting of its building destruction, lasting for years and involving a much larger population. A reduced sleep quality and an increased frequency of DNB after two years may be a risk factor for the development of depression and posttraumatic stress disorder.     

Renal Denervation Suppresses Atrial Fibrillation in a Model of Renal Impairment

BackgroundA close association exists between renal impairment (RI) and atrial fibrillation (AF) occurrence. Increased activity of the sympathetic nervous system (SNS) may contribute to the development of AF associated with RI. Renal denervation (RDN) decreases central sympathetic activity.ObjectiveThe main objective of the study was to explore the effects of RDN on AF occurrence and its possible mechanisms in beagles with RI.MethodsUnilateral RI was induced in beagles by embolization of small branches of the renal artery in the right kidney using gelatin sponge granules in Model (n = 6) and RDN group (n = 6). The Sham group (n = 6) underwent the same procedure, except for embolization. Then animals in RDN group underwent radiofrequency ablation of the renal sympathetic nerve. Cardiac electrophysiological parameters, blood pressure, left ventricular end-diastolic pressure, and AF inducibility were investigated. The activity of the SNS, renin-angiotensin-aldosterone system (RAAS), inflammation and atrial interstitial fibrosis were measured.ResultsEmbolization of small branches of the renal artery in the right kidney led to ischemic RI. Heart rate, P wave duration and BP were increased by RI, which were prevented or attenuated by RDN. Atrial effective refractory period was shortened and AF inducibility was increased by RI, which were prevented by RDN. Antegrade Wenckebach point was shortened, atrial and ventricular rates during AF were increased by RI, which were attenuated or prevented by RDN. Levels of norepinephrine, renin and aldosterone in plasma, norepinephrine, angiotensin II, aldosterone, interleukin-6 and high sensitivity C-reactive protein in atrial tissue were elevated, and atrial interstitial fibrosis was enhanced by RI, which were attenuated by RDN.ConclusionsRDN significantly reduced AF inducibility, prevented the atrial electrophysiological changes in a model of RI by combined reduction of sympathetic drive and RAAS activity, and inhibition of inflammation activity and fibrotic pathway in atrial tissue.     

Application of Quality by Design (QbD) Approach to Ultrasonic Atomization Spray Coating of Drug-Eluting Stents

The drug coating process for coated drug-eluting stents (DES) has been identified as a key source of inter- and intra-batch variability in drug elution rates. Quality-by-design (QbD) principles were applied to gain an understanding of the ultrasonic spray coating process of DES. Statistically based design of experiments (DOE) were used to understand the relationship between ultrasonic atomization spray coating parameters and dependent variables such as coating mass ratio, roughness, drug solid state composite microstructure, and elution kinetics. Defect-free DES coatings composed of 70% 85:15 poly(dl-lactide-co-glycolide) and 30% everolimus were fabricated with a constant coating mass. The drug elution profile was characterized by a mathematical model describing biphasic release kinetics. Model coefficients were analyzed as a DOE response. Changes in ultrasonic coating processing conditions resulted in substantial changes in roughness and elution kinetics. Based on the outcome from the DOE study, a design space was defined in terms of the critical coating process parameters resulting in optimum coating roughness and drug elution. This QbD methodology can be useful to enhance the quality of coated DES.KEY WORDS: biodegradable polymers, coating, drug-eluting stents, processing, quality by design     

The Long-Term Impact of Physical and Emotional Trauma: The Station Nightclub Fire

Background

Survivors of physical and emotional trauma experience enduring occupational, psychological and quality of life impairments. Examining survivors from a large fire provides a unique opportunity to distinguish the impact of physical and emotional trauma on long-term outcomes. The objective is to detail the multi-dimensional long-term effects of a large fire on its survivor population and assess differences in outcomes between survivors with and without physical injury.

Methods and Findings

This is a survey-based cross-sectional study of survivors of The Station fire on February 20, 2003. The relationships between functional outcomes and physical injury were evaluated with multivariate regression models adjusted for pre-injury characteristics and post-injury outcomes. Outcome measures include quality of life (Burn Specific Health Scale–Brief), employment (time off work), post-traumatic stress symptoms (Impact of Event Scale–Revised) and depression symptoms (Beck Depression Inventory). 104 fire survivors completed the survey; 47% experienced a burn injury. There was a 42% to 72% response rate range. Although depression and quality of life were associated with burn injury in univariate analyses (p<0.05), adjusted analyses showed no significant relationship between burn injury and these outcomes (p = 0.91; p = .51). Post-traumatic stress symptoms were not associated with burn injury in the univariate (p = 0.13) or adjusted analyses (p = 0.79). Time off work was the only outcome in which physical injury remained significant in the multivariate analysis (p = 0.03).

Conclusions

Survivors of this large fire experienced significant life disruption, including occupational, psychological and quality of life sequelae. The findings suggest that quality of life, depression and post-traumatic stress outcomes are related to emotional trauma, not physical injury. However, physical injury is correlated with employment outcomes. The long-term impact of this traumatic event underscores the importance of longitudinal and mental health care for trauma survivors, with attention to those with and without physical injuries.     

药物引起肾功能损伤的研究进展

肾脏是人体血流量丰富,耗氧量最大的主要脏器之一。药物主要是帮助机体对抗疾病,同时药物也可以引起组织器官的损伤。由于大部分药物及其代谢产物经由肾脏排出体外,大大增加了药物对肾功能损伤的机率。因此,研究药物对肾脏的毒性作用并弄清药物所导致的肾损伤的作用机制,就显得尤为重要。这对于开发新药和临床合理用药均有着重要的意义。本文就目前引起肾损伤药物和引起损伤的相关机制进行综述。     

The Association of Metallothionein-4 Gene Polymorphism and Renal Function in Long-Term Lead-Exposed Workers

The goal of this study is to investigate if metallothionein (MT) gene polymorphism affects the susceptibility to lead as well as renal function parameters and blood pressures (BP) in workers exposed to lead for extended period of time. By means of real-time polymerase chain reaction, the MT4-216 A/G genotypes classified as rs396230 in the single nucleotide polymorphism database of the National Center for Biotechnology Information (database) were analyzed on 113 workers of a lead battery-recycling factory. Workers with G (mutant) allele were more susceptible to the toxic effects of lead on their systolic BP and serum renal function parameters. Their BP was 10 mmHg higher than those with wild-type (AA type) allele. Among subjects with the 3-genome, the GG mutant type subjects appear to be more susceptible to lead. Regression models of serum creatinine and BUN showed significant differences between the GG and GA types compared to AA type subjects. This cross-sectional study shows that workers with different MT-4 genotypes have different lead-induced adverse health effects. Those with the G allele have the greater susceptibility to lead so their exposure should be reduced.