Examination of mortality rates in a retrospective cohort of patients treated with oral or implant naltrexone for problematic opiate use

Aims To examine and compare mortality rates in patients treated with oral and implant naltrexone. Design A retrospective cohort study. Setting A community not‐for‐profit drug treatment clinic. Participants Patients treated with oral naltrexone (n = 2155, 17 207 patient‐years) and implant naltrexone (n = 2389, 11 678 patient‐years) for problematic opiate use between August 1997 and December 2009. Measurements Crude gender, age, treatment period and cause‐specific mortality rates were calculated using data obtained from the National Death Index. Findings Crude mortality rates for patients treated with oral naltrexone [8.78 deaths per 1000 patient‐years (ptpy), 95% confidence interval (CI): 7.38–10.17] were significantly different to those treated with implant naltrexone (6.59 ptpy, 95% CI: 5.13–8.06) (P = 0.0339). During the first 4 months following treatment, differences in the two groups were particularly apparent, with a mortality rate of 26.28 ptpy in patients treated with oral naltrexone compared to 7.34 ptpy in patients treated with implant naltrexone (P = 0.0003). Differences in initial mortality rates following treatment were associated predominantly with high rates of opiate overdoses in oral naltrexone patients during the first 4 months following treatment (17.22 ptpy compared with 0.67 ptpy in implant naltrexone patients) (P < 0.0001). Conclusions The use of implant naltrexone can reduce all‐cause mortality and opiate overdose during the first 4 months following treatment compared with patients treated with oral naltrexone.     

Cardiac Outcomes Through Digital Evaluation (CODE) STEMI project: prehospital digitally-assisted reperfusion strategies

Background

Guidelines for reperfusion in ST-elevation myocardial infarction (STEMI) were recently adopted by the Canadian Cardiovascular Society. We have developed a blended model of prehospital thrombolytic (PHL) therapy or primary percutaneous coronary intervention (PPCI) activation, in order to achieve guideline times.

Methods

In our urban centre of 658,700 people, emergency medical services (EMS) were trained to perform and screen electrocardiograms (ECGs) for suspected STEMI. Suspected ECGs were transmitted to a physician's hand-held device. If the physician confirmed the diagnosis they coordinated initiation of either PHL or PPCI. In cases where physicians found the prehospital ECG negative for STEMI (PHENST), patients were transported to the closest emergency room.

Results

From July 21, 2008 to July 21, 2010, the Cardiac Outcomes Through Digital Evaluation (CODE) STEMI project received 380 transmitted calls. There were 226 confirmed STEMI by the on-call physician, 158 (70%) received PPCI, 48 (21%) received PHL, and 20 (9%) had angiography but no revascularization. The PPCI, median time from first medical contact to reperfusion was 76 minutes (interquartile range [IQR], 64-93). For PHL, median time from first medical contact to needle was 32 minutes (IQR, 29-39). The overall mortality rate for the STEMI patients was 8% (PHL = 4 [8.3%], PPCI = 8 [5%], medical therapy = 7 [35%]). There were 154 PHENST patients, 44% later diagnosed with acute coronary syndrome. The mortality rate for PHENST was 14%.

Conclusions

Through a model of EMS prehospital ECG interpretation, digital transmission, direct communication with a physician, and rapid coordinated service, we demonstrate that benchmark reperfusion times in STEMI can be achieved.     

Transcatheter aortic valve replacement: History and current status

Despite the poor prognosis associated with severe, symptomatic aortic stenosis, treatment options were limited for a large subgroup of patients deemed high risk for surgical replacement. The introduction of transcatheter aortic valve replacement (TAVR) over the past 10 years marks a new and exciting era in the treatment of valvular disease in these high-risk and inoperable patients. In this review, we outline the historical development, key clinical trials, current outcomes and future directions of TAVR.     

Alveolar macrophages from overweight/obese subjects with asthma demonstrate a proinflammatory phenotype

Rationale: Obesity is associated with increased prevalence and severity of asthma. Adipose tissue macrophages can contribute to the systemic proinflammatory state associated with obesity. However, it remains unknown whether alveolar macrophages have a unique phenotype in overweight/obese patients with asthma. Objectives: We hypothesized that leptin levels would be increased in the bronchoalveolar lavage fluid from overweight/obese subjects and, furthermore, that leptin would alter the response of alveolar macrophages to bacterial LPS. Methods: Forty-two subjects with asthma and 46 healthy control subjects underwent research bronchoscopy. Bronchoalveolar lavage fluid from 66 was analyzed for the level of cellular inflammation, cytokines, and soluble leptin. Cultured primary macrophages from 22 subjects were exposed to LPS, leptin, or leptin plus LPS. Cytokines were measured in the supernatants. Measurements and Main Results: Leptin levels were increased in overweight/obese subjects, regardless of asthma status (P = 0.013), but were significantly higher in overweight/obese subjects with asthma. Observed levels of tumor necrosis factor-α were highest in overweight/obese subjects with asthma. Ex vivo studies of primary alveolar macrophages indicated that the response to LPS was most robust in alveolar macrophages from overweight/obese subjects with asthma and that preexposure to high-dose leptin enhanced the proinflammatory response. Leptin alone was sufficient to induce production of proinflammatory cytokines from macrophages derived from overweight/obese subjects with asthma. Conclusions: Ex vivo studies indicate that alveolar macrophages derived from overweight/obese subjects with asthma are uniquely sensitive to leptin. This macrophage phenotype, in the context of higher levels of soluble leptin, may contribute to the pathogenesis of airway disease associated with obesity.     

Carotid intima-media thickness among human immunodeficiency virus-infected patients without coronary calcium

Subjects infected with human immunodeficiency virus (HIV) have increased risk for atherosclerosis. Carotid artery intima-media thickness (IMT) assessed using ultrasound and coronary artery calcium (CAC) detected using computed tomography predict cardiovascular risk in the general population; however, their usefulness and comparability in patients with HIV are less well defined. The purpose of this study was to compare IMT and CAC in the detection of atherosclerosis in subjects with HIV. CAC and IMT were measured in 253 HIV-infected and 58 uninfected adults. Associations among HIV-related factors, traditional risk factors, and CAC and IMT were evaluated. The distribution of IMT among subjects with and without CAC was compared. Among the patients with HIV, 37% had detectable CAC compared to 28% of controls (p = 0.19); 16% of the patients with HIV had CAC >100 compared to 5% of controls (p = 0.03). With either detectable or undetectable CAC, HIV-infected subjects had higher IMT compared to controls (1.02 ± 0.34 vs 0.78 ± 0.12 mm, p <0.0001), even after adjustment for traditional risk factors. Among those with undetectable CAC, 34% of patients with HIV had markedly increased IMT (≥1 mm) compared to no controls (p <0.0001). HIV-related factors were associated with IMT but not with CAC. In conclusion, patients with HIV and controls had similar rates of detectable CAC, while absolute CAC scores were modestly higher in the HIV group. Conversely, carotid IMT detected advanced subclinical atherosclerosis in patients with HIV even in the absence of CAC. Thus, with HIV, IMT is associated with disease-related factors and may be a more sensitive indicator of subclinical atherosclerosis than CAC.     

Wild-type tumor repressor protein 53 (Trp53) promotes ovarian cancer cell survival

Loss of Pten in the Kras(G12D);Amhr2-Cre mutant mice leads to the transformation of ovarian surface epithelial (OSE) cells and rapid development of low-grade, invasive serous adenocarcinomas. Tumors occur with 100% penetrance and express elevated levels of wild-type tumor repressor protein 53 (TRP53). To test the functions of TRP53 in the Pten;Kras (Trp53+) mice, we disrupted the Trp53 gene yielding Pten;Kras(Trp53-) mice. By comparing morphology and gene expression profiles in the Trp53+ and Trp53- OSE cells from these mice, we document that wild-type TRP53 acts as a major promoter of OSE cell survival and differentiation: cells lacking Trp53 are transformed yet are less adherent, migratory, and invasive and exhibit a gene expression profile more like normal OSE cells. These results provide a new paradigm: wild-type TRP53 does not preferentially induce apoptotic or senescent related genes in the Pten;Kras(Trp53+) cancer cells but rather increases genes regulating DNA repair, cell cycle progression, and proliferation and decreases putative tumor suppressor genes. However, if TRP53 activity is forced higher by exposure to nutlin-3a (a mouse double minute-2 antagonist), TRP53 suppresses DNA repair genes and induces the expression of genes that control cell cycle arrest and apoptosis. Thus, in the Pten;Kras(Trp53+) mutant mouse OSE cells and likely in human TP53+ low-grade ovarian cancer cells, wild-type TRP53 controls global molecular changes that are dependent on its activation status. These results suggest that activation of TP53 may provide a promising new therapy for managing low-grade ovarian cancer and other cancers in humans in which wild-type TP53 is expressed.     

Continuous Monitoring of Glucose in Subcutaneous Tissue Using Microfabricated Differential Affinity Sensors

Objective

We describe miniaturized differential glucose sensors based on affinity binding between glucose and a synthetic polymer. The sensors possess excellent resistance to environmental disturbances and can potentially allow wireless measurements of glucose concentrations within interstitial fluid in subcutaneous tissue for long-term, stable continuous glucose monitoring (CGM).

Methods

The sensors are constructed using microelectromechanical systems (MEMS) technology and exploit poly(N-hydroxy-ethyl acrylamide-ran-3-acrylamidophenylboronic acid) (PHEAA-ran-PAAPBA), a glucose-binding polymer with excellent specificity, reversibility, and stability. Two sensing approaches have been investigated, which respectively, use a pair of magnetically actuated diaphragms and perforated electrodes to differentially measure the glucose-binding-induced changes in the viscosity and permittivity of the PHEAA-ran-PAAPBA solution with respect to a reference, glucose-unresponsive polymer solution.

Results

In vivo characterization of the MEMS affinity sensors were performed by controlling blood glucose concentrations of laboratory mice by exogenous glucose and insulin administration. The sensors experienced an 8–30 min initialization period after implantation and then closely tracked commercial capillary glucose meter readings with time lags ranging from 0–15 min during rapid glucose concentration changes. Clarke error grid plots obtained from sensor calibration suggest that, for the viscometric and dielectric sensors, respectively, approximately 95% (in the hyperglycemic range) and 84% (ranging from hypoglycemic to hyperglycemic glucose concentrations) of measurement points were clinically accurate, while 5% and 16% of the points were clinically acceptable.

Conclusions

The miniaturized MEMS sensors explore differential measurements of affinity glucose recognition. In vivo testing demonstrated excellent accuracy and stability, suggesting that the devices hold the potential to enable long-term and reliable CGM in clinical applications.     

Mortality in Obstructive Sleep Apnea: Association with Impaired Wakefulness

Sleep fragmentation from obstructive sleep apnea (OSA) is correlated with a shortened sleep latency on the Maintenance of Wakefulness Test (MWT) and the Multiple Sleep Latency Test. Whether impairment of wakefulness is associated with increased mortality in OSA patients is unknown. We evaluated survival over an average timespan of 7.5 years from the date of diagnosis in a consecutive series of 322 OSA patients who had undergone nocturnal polysomnograpy and the MWT. Evaluable survival data were obtained in 142 patients. Twenty two had died. Deaths were predominantly due to cardiovascular disease. A comparison of the demographic and sleep study data between the alive and dead groups was significant for differences in MWT sleep latency and in age at time of diagnosis. The MWT mean sleep latency, when adjusted for age, was significantly shortened in the dead patients (28 ± 11 min vs. 21 ± 10 min, p < 0.005). Also, there was a significant decrease in survival in the patients whose MWT mean sleep latency was less than 20 min. These findings demonstrate an association between impairment of wakefulness and long-term mortality in OSA patients. This association was not evident for the other measures used to assess OSA severity.Supported by NIH grants NS30019, MH47680 to Dr. Mitler and Clinical Research Center grant AA08235 to the Scripps Research Institute.     

Insulin and IGF1 enhance IL‐17‐induced chemokine expression through a GSK3B‐dependent mechanism: a new target for melatonin's anti‐inflammatory action

Obesity is a chronic inflammation with increased serum levels of insulin, insulin‐like growth factor 1 (IGF1), and interleukin‐17 (IL‐17). The objective of this study was to test a hypothesis that insulin and IGF1 enhance IL‐17‐induced expression of inflammatory chemokines/cytokines through a glycogen synthase kinase 3β (GSK3B)‐dependent mechanism, which can be inhibited by melatonin. We found that insulin/IGF1 and lithium chloride enhanced IL‐17‐induced expression of C‐X‐C motif ligand 1 (Cxcl1) and C‐C motif ligand 20 (Ccl20) in the Gsk3b^+/+, but not in Gsk3b^?/? mouse embryonic fibroblast (MEF) cells. IL‐17 induced higher levels of Cxcl1 and Ccl20 in the Gsk3b^?/? MEF cells, compared with the Gsk3b^+/+ MEF cells. Insulin and IGF1 activated Akt to phosphorylate GSK3B at serine 9, thus inhibiting GSK3B activity. Melatonin inhibited Akt activation, thus decreasing P‐GSK3B at serine 9 (i.e., increasing GSK3B activity) and subsequently inhibiting expression of Cxcl1 and Ccl20 that was induced either by IL‐17 alone or by a combination of insulin and IL‐17. Melatonin's inhibitory effects were only observed in the Gsk3b^+/+, but in not Gsk3b^?/? MEF cells. Melatonin also inhibited expression of Cxcl1, Ccl20, and Il‐6 that was induced by a combination of insulin and IL‐17 in the mouse prostatic tissues. Further, nighttime human blood, which contained high physiologic levels of melatonin, decreased expression of Cxcl1, Ccl20, and Il‐6 in the PC3 human prostate cancer xenograft tumors. Our data support our hypothesis and suggest that melatonin may be used to dampen IL‐17‐mediated inflammation that is enhanced by the increased levels of insulin and IGF1 in obesity.