The i148m Pnpla3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls

BACKGROUND: Reduced adiponectin is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), and the I148M Patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism predisposes to NAFLD and liver damage progression in NASH and chronic hepatitis C (CHC) by still undefined mechanisms, possibly involving regulation of adipose tissue function. Aim of this study was to evaluate whether the I148M PNPLA3 polymorphism influences serum adiponectin in liver diseases and healthy controls. METHODS: To this end, we considered 144 consecutive Italian patients with NAFLD, 261 with CHC, 35 severely obese subjects, and 257 healthy controls with very low probability of steatosis, all with complete clinical and genetic characterization, including adiponectin (ADIPOQ) genotype. PNPLA3 rs738409 (I148M) and ADIPOQ genotypes were evaluated by Taqman assays, serum adiponectin by ELISA. Adiponectin mRNA levels were evaluated by quantitative real-time PCR in the visceral adipose tissue (VAT) of 35 obese subjects undergoing bariatric surgery. RESULTS: Adiponectin levels were independently associated with the risk of NAFLD and with the histological severity of the disease. Adiponectin levels decreased with the number of 148\u2009M PNPLA3 alleles at risk of NASH both in patients with NAFLD (p\u2009=\u20090.03), and in healthy subjects (p\u2009=\u20090.04). At multivariate analysis, PNPLA3 148\u2009M alleles were associated with low adiponectin levels (<6\u2009mg/ml, median value) independently of NAFLD diagnosis, age, gender, BMI, and ADIPOQ genotype (OR 1.67, 95% c.i. 1.07-2.1 for each 148\u2009M allele). The p.148\u2009M PNPLA3 variant was associated with decreased adiponectin mRNA levels in the VAT of obese patients (p\u2009<\u20090.05) even in the absence of NASH. In contrast, in CHC, characterized by adiponectin resistance, low adiponectin was associated with male gender and steatosis, but not with PNPLA3 and ADIPOQ genotypes and viral features. CONCLUSIONS: The I148M PNPLA3 variant is associated with adiponectin levels in patients with NAFLD and in healthy subjects, but in the presence of adiponectin resistance not in CHC patients. The I148M PNPLA3 genotype may represent a genetic determinant of serum adiponectin levels. Modulation of serum adiponectin might be involved in mediating the susceptibility to steatosis, NASH, and hepatocellular carcinoma in carriers of the 148\u2009M PNPLA3 variant without CHC, with potential therapeutic implications

Development and implementation of a prescription opioid registry across diverse health systems

Objective: Develop and implement a prescription opioid registry in 10 diverse health systems across the US and describe trends in prescribed opioids between 2012 and 2018. Materials and Methods: Using electronic health record and claims data, we identified patients who had an outpatient fill for any prescription opioid, and/or an opioid use disorder diagnosis, between January 1, 2012 and December 31, 2018. The registry contains distributed files of prescription opioids, benzodiazepines and other select medications, opioid antagonists, clinical diagnoses, procedures, health services utilization, and health plan membership. Rates of outpatient opioid fills over the study period, standardized to health system demographic distributions, are described by age, gender, and race/ethnicity among members without cancer. Results: The registry includes 6 249 710 patients and over 40 million outpatient opioid fills. For the combined registry population, opioid fills declined from a high of 0.718 per member-year in 2013 to 0.478 in 2018, and morphine milligram equivalents (MMEs) per fill declined from 985 MMEs per fill in 2012 to 758 MMEs in 2018. MMEs per member declined from 692 MMEs per member in 2012 to 362 MMEs per member in 2018. Conclusion: This study established a population-based opioid registry across 10 diverse health systems that can be used to address questions related to opioid use. Initial analyses showed large reductions in overall opioid use per member among the combined health systems. The registry will be used in future studies to answer a broad range of other critical public health issues relating to prescription opioid use

Efficacy and Tolerability of Pharmacotherapies to Aid Smoking Cessation in Adolescents

Abstract Adolescent smoking remains a public health problem. Despite concerns regarding adolescent nicotine dependence, few well-designed smoking cessation studies have been conducted with teen smokers. This is particularly true regarding pharmacological treatments for nicotine dependence. Currently, pharmacological aids are not recommended for treating adolescent nicotine dependence, as efficacy has not been shown in this population. This review includes studies that have examined the efficacy of pharmacotherapy for smoking abstinence and/or reduction in cigarette consumption among adolescent smokers who want to quit smoking, lab-based adolescent studies that have examined the effectiveness of these medications in reducing cravings and/or withdrawal symptoms, and/or studies that have assessed the tolerability of medications for smoking cessation in adolescent smokers. This review provides information on the pharmacologic action of each medication, the efficacy of each medication for adolescent smoking cessation, the tolerability of each medication based on reported adverse events, and compliance with the medication protocols. Thirteen relevant articles were identified and included in the review. Nicotine patch, nicotine gum, nicotine nasal spray, bupropion, and varenicline have been studied in adolescent smokers. The adverse events reported in the studies on pharmacology for adolescent smoking suggest that the side effect profiles for nicotine replacement therapy, bupropion, and varenicline are similar to those reported in adult studies. There is some evidence of efficacy of nicotine patch and bupropion at end of treatment (efficacy of varenicline has not been assessed), but none of the medications included in this review were efficacious in promoting long-term smoking cessation among adolescent smokers. It is noted that many of the study protocols did not follow the recommended dose or length of pharmacotherapy for adults, rendering it difficult to determine the true efficacy of medication for adolescent smoking cessation. Future efficacy studies are warranted before recommending pharmacotherapy for adolescent smoking cessation. Adolescent Smoking and Pharmacotherapy Adolescent smoking remains a high priority public health concern. The U.S. Department of Health and Human Services has retained the goal of reducing adolescent smoking rates in the Healthy People 2020 initiative. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Considering that over 80% of adult smokers begin smoking prior to age of 18, Relatively few well-designed smoking cessation studies have been conducted with teen smokers. This is particularly true regarding pharmacological treatments for nicotine dependence. To date, nicotine replacement, bupropion (Zyban), and varenicline have been approved as therapies for adult smokers and the recommended treatment for adult nicotine dependence is a combination of psychotherapy and pharmacotherapy. Methods Study Identification and Inclusion Searches were conducted through the PubMed and PsycINFO online databases (through May 2011) and were limited to &quot;English Language&quot; and &quot;Human.&quot; The following keywords were used in the initial search &quot;smoking cessation&quot;, &quot;adolescent OR teen&quot; and then limited by the separate use of the following terms: &quot;bupropion&quot;, &quot;Zyban&quot;, &quot;nicotine replacement therapy&quot;, &quot;varenicline&quot;, &quot;Chantix&quot;, &quot;nicotine patch&quot;, &quot;nicotine gum&quot;, &quot;nicotine nasal spray&quot;, and &quot;pharmacotherapy.&quot; Only studies that targeted adolescent smokers for recruitment and enrollment were included. In addition, studies referenced in relevant review articles, metaanalyses, and all selected articles were examined. The searches yielded 14 relevant studies that included pharmacotherapy for adolescent nicotine dependence. One study was excluded from the review because the focus was on reduction of smoking among adolescents that did not want to quit and did not include data on adverse events. Nicotine replacement therapy This review focuses on nicotine replacement therapy (NRT) that has been evaluated for smoking cessation among adolescent smokers (nicotine patch, gum, and spray); however, there are other nicotine replacement products approved for smoking cessation, including a nicotine inhaler, a nicotine lozenge and, in some countries outside of the United States, a nicotine sublingual tablet. Nicotine replacement therapy (NRT) replaces the nicotine delivered while smoking to reduce craving and withdrawal symptoms and is available in different forms and dosages depending on the number of cigarettes smoked. Open-label studies- The earliest study to use NRT with adolescent smokers was conducted by Smith and colleagues in 1996. No adverse events were associated with discontinuation of patch therapy. Hurt et al. conducted a larger open-label study (n = 101) that coupled six weeks of 15 mg/ 16-hour NP therapy with an optional brief individual counseling session at the first clinic visit. Randomized clinical trials (RCT)- The first randomized, double-blind, placebocontrolled study of NRT was conducted by Hanson et al. in 2003. [16] Initial dose and titration schedules were based on the teens&apos; level of cigarette consumption. Participants (n = 100) received 10 weeks of NP therapy and cognitive-behavioral therapy and a contingency management procedure. There were no significant differences between groups in biologically verified, 7-day point prevalence abstinence at end of treatment (Week 10) (28.0% NP vs. 24.0% placebo), 30-day point prevalence abstinence (20.0% NP vs. 18.0% placebo), or continuous abstinence from the quit date. Compared to the placebo patch group, the active NP group experienced a significantly lower craving score and overall withdrawal symptom score. Participants in the placebo patch group reported more headaches than those in the active NP group (75.6% vs. 56.3%, respectively). None reported dropping out as a result of an adverse event and no significant differences in dropout rates or medication compliance were observed across the treatment groups. A community-based, double-blind pilot RCT was conducted by Roddy and colleagues with 98 regular smokers (defined as &gt; 1 cigarette per day or &lt; 1 cigarette per day but reported past or anticipated withdrawal). Moolchan and colleagues Finally, Rubinstein et al. conducted a pilot randomized trial of nicotine nasal spray (NNS) in 40 adolescent smokers. Summary of efficacy See Safety/tolerability None of the studies reported any severe or life-threatening side effects. The adverse events reported by adolescents for NRT were similar to those reported by adult smokers. Of the NRT studies, only three reported discontinuation of study medication during treatment due to an adverse event. Special considerations for use in adolescent smokers Controversy remains over the use of NRT in adolescents. Studies with animals indicate that nicotine can elicit neuronal damage and long-term changes in synaptic function, suggesting that there could be long-term adverse consequences of nicotine exposure in adolescence. Bupropion Bupropion was initially marketed as an atypical antidepressant and was approved in 1997, under the name Zyban, as the first non-nicotine medication to aid in smoking cessation for adults. Bupropion inhibits the reuptake of dopamine and norepinephrine in the central nervous system Randomized clinical trials (RCT)-Four RCTs have assessed the efficacy of bupropion for smoking cessation with adolescents. In the only study to examine bupropion SR in combination with NP therapy, Killen and colleagues randomized adolescent smokers (n = 211) to receive eight weeks of NP therapy and nine weeks of either 150 mg/day bupropion SR or placebo pills. Finally, Gray and colleagues examined the efficacy of 300 mg/day bupropion SR and contingency management (CM). Summary of efficacy See None of the studies with 300 mg/day bupropion SR were longer than six weeks in duration. The full dose was well tolerated by adolescent smokers and resulted in higher end of treatment abstinence than 150 mg/day bupropion SR in the only adolescent multi-dose study. However, similar to the few multi-dose studies in adults, the higher dose did not produce a better outcome at follow-up. Paediatr Drugs. Author manuscript; available in PMC 2012 April 4. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Given that none of the studies that have examined the use of bupropion SR for adolescent nicotine dependence followed the dosage recommendations for adult smokers, a future study that adheres to these guidelines is warranted. Safety/tolerability The most common adverse events reported by adolescent smokers were similar to those reported by their adult counterparts Although bupropion SR was generally well tolerated by adolescent smokers, hospitalizations occurred on three occasions. One was due to the intentional ingestion of Jimson weed in combination with bupropion SR, resulting in an anticholinergic crisis. Compliance rates Three of the five studies provided compliance data, but the methods used to assess compliance varied across the three studies. Special considerations for use in adolescent smokers Zyban contains the same active ingredient as the antidepressant medications Wellbutrin, Wellbutrin SR, and Wellbutrin XL. In 2004, the FDA directed manufacturers to add a &quot;black box&quot; to the health professional label of all antidepressants warning that antidepressants increased the risk compared to placebo of suicidal thinking and suicidal behavior in NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript children, adolescents, and young adults in short-term studies of major depressive disorder and other psychiatric disorders. In the RCTs with bupropion SR for smoking cessation in adolescent smokers, two adverse events were deemed to be intentional suicide attempts. Varenicline In 2006, the United States FDA approved varenicline as a prescription-only pharmacological aid for adult smoking cessation. It is also an approved smoking cessation aid in some countries outside of the U.S. Varenicline is a selective nicotinic acetylcholine receptor partial antagonist that binds to the α 4 β 2 receptor subtype, thereby reducing the reinforcing effects of nicotine. Due to its mixed agonist-antagonist properties, varenicline is effective at relieving craving and withdrawal during abstinence and blocking the reinforcing effects of smoking. Literature on varenicline in adolescent smokers One RCT examined the pharmacokinetics, safety and tolerability of varenicline in adolescent smokers

Prescription Opioid Use Patterns, Use Disorder Diagnoses, and Addiction Treatment Receipt after the 2014 Medicaid Expansion in Oregon

Background/Aims: Evidence suggests Medicaid beneficiaries in the USA are prescribed opioids more frequently than are people who are privately‐insured, but little is known about opioid prescribing patterns among Medicaid enrollees who gained coverage via the Affordable Care Act Medicaid expansions. This study compared the prevalence of receipt of opioid prescriptions and opioid‐use‐disorder (OUD), along with time from OUD diagnosis to medication‐assisted treatment (MAT) receipt between Oregon residents who had been continuously insured by Medicaid, were newly insured after Medicaid expansion in 2014, or returned to Medicaid coverage after expansion. Design: Cross‐sectional study using inverse‐propensity weights to adjust for differences among insurance groups. Setting: Oregon. Participants: 225,295 Oregon Medicaid adult beneficiaries insured 2014‐2015 and either: 1) newly enrolled, 2) returning in 2014 after a \u3e 12‐month gap, or 3) continuously insured between 2013 and 2015. We excluded patients in hospice care or with cancer diagnoses. Measurements: Any opioid dispensed, chronic (≥90‐day) and high dose (≥ 90 daily morphine milligram equivalence) opioid use, documented OUD diagnosis, and MAT receipt. Findings: Compared with the continuously insured, newly and returning insured enrollees were less likely to be dispensed opioids [newly: 42.3%, 95% confidence interval (95%CI) 42.0‐42.7%; returning: 49.3%, 95%CI 48.8‐49.7%; continuously: 52.5%, 95%CI 52.0‐53.0%], use opioids chronically (newly: 12.8%, 95%CI 12.4‐13.1%; returning: 11.9%, 95%CI 11.5‐12.3%, continuously: 15.8%, 95%CI 15.4‐16.2%), have OUD diagnoses (newly: 3.6%, 95%CI 3.4‐3.7%; returning: 3.9%, 95%CI 3.8‐4.1%, continuously: 4.7%, 95%CI 4.5‐4.9%), and receive MAT after OUD diagnosis [Hazard Ratio newly: 0.57, 95%CI 0.53‐0.61; Hazard Ratio returning: 0.60, 95%CI 0.56‐0.65 (REF: continuously)]. Conclusions: Residents of Oregon, USA who enrolled or re‐enrolled in Medicaid health insurance after expansion of coverage in 2014 as a result of the Affordable Care Act were less likely than those already covered to receive opioids, use them chronically, or receive medication‐assisted treatment for opioid use disorder

A Conceptual Framework for Choosing Target Species for Wildlife-Inclusive Urban Design

Recent research has highlighted the significance of cities for biodiversity, making them important places for conservation in their own right. Current conservation approaches in cities are mostly defensive. Thus, they focus on remnant pockets of natural areas or try to protect particular species that occur in the built environment. These approaches are vulnerable to further urban development and do not create habitats. An alternative strategy is to make wildlife an integral part of urban development and thereby create a new habitat in the built-up area. Here we address the challenge of choosing target species for such wildlife-inclusive urban design. The starting point of our conceptual framework is the regional species pool, which can be obtained from geo-referenced species data. The existing habitat types on and around the development site and dispersal barriers limit the species numbers to the local species potential. In the next step, the site&rsquo;s potential for each species is analyzed&mdash;how can it be upgraded to host species given the planned development and the life-cycle of the species? For the final choice of target species, traits related to the human&ndash;animal interaction are considered. We suggest that stakeholders will be involved in the final species selection. Our approach differs from existing practice, such as expert choice of priority species, by (1) representing an open process where many species are potential targets of conservation, (2) the involvement of stakeholders in a participatory way. Our approach can also be used at larger spatial scales such as quarters or entire cities

Adipokine actions on cartilage homeostasis

Epidemiological studies have shown an intriguing correlation between obesity and articular cartilage disease. An increase in mechanical forces across weight-bearing joints has long been considered the primary factor leading to joint degeneration. However, emerging data suggest that addition-al soluble factors such as the adipocyte-derived molecules "adipokines" may also play an important role in the onset and progression of weight-associated cartilage degradative process. Adipokines are pleiotropic secretory molecules mainly produced by white adipose tissue. Adipokines exert their actions through endocrine, paracrine, autocrine, or juxtacrine cross talk in a wide variety of physiological or pathophysiological processes. In particular, they are mainly involved in the regulation of food intake and energy metabolism, in both health and disease states, and in the in?ammatory response. Recent observations have shown that, among adipokines, leptin, adiponectin, resistin, visfatin, and apelin may also participate to the complex mechanisms that regulate skeleton biology, both at bone and cartilage level. Herein, we review the present knowledge about the role of these adipokines in cartilage function as well as in in?ammatory and degenerative joint diseases. Moreover, we describe some methodological approaches which can be utilized in the measurement of these adipokines in different biological matrices, like plasma and synovial fluid (SF), and may be helpful to better clarify the involvement of these molecules in cartilage disease

Genomic insights into Mycobacterium simiae human colonization

Abstract Mycobacterium simiae (Karassova V, Weissfeiler J, Kraszanay E, Acta Microbiol Acad Sci Hung 12:275-82, 1965) is a slow-growing nontuberculous Mycobacterium species found in environmental niches, and recently evidenced as an opportunistic Human pathogen. We report here the genome of a clinical isolate of M. simiae (MsiGto) obtained from a patient in Guanajuato, Mexico. With a size of 6,684,413 bp, the genomic sequence of strain MsiGto is the largest of the three M. simiae genomes reported to date. Gene prediction revealed 6409 CDSs in total, including 6354 protein-coding genes and 52 RNA genes. Comparative genomic analysis identified shared features between strain MsiGto and the other two reported M. simiae genomes, as well as unique genes. Our data reveals that M. simiae MsiGto harbors virulence-related genes, such as arcD, ESAT-6, and those belonging to the antigen 85 complex and mce clusters, which may explain its successful transition to the human host. We expect the genome information of strain MsiGto will provide a better understanding of infective mechanisms and virulence of this emergent pathogen

Study of the Modulation of Cytokine Release by Natural Compounds with Pharmacological Properties Using Cell-Based Systems

Background: The screening of the pharmacological properties of natural compounds (i.e., anti-inflammatory effects) may take advantage of some specific cell-based systems. Parthenolide (PTN) and Copaifera langsdorfii (Copaiba) are natural compounds used to prevent and treat headache and migraine and in inflammatory diseases involving respiratory airways, genital-urinary apparatus and skin, respectively, but their effects at the cellular level are poorly understood. Methods: Mouse BV-2 microglia and human THP-1 monocyte cell lines were used. The nuclear translocation of nuclear factor (NF)-kB was evaluated by Western blotting analysis. The secretion of inflammatory cytokines (interleukin (IL)-1\u3b2, IL-6, tumor necrosis factor-\u3b1 (TNF\u3b1)) was evaluated by immunometric assays (ELISA). Results: Treatment of BV-2 cells with 1 \u3bcM PTN and of THP-1 cells with 10 \u3bcM Copaiba oleoresin (OR), containing diterpene acids, diterpenes and sesquiterpenes, strongly reduced the NF-kB translocation to the cell nucleus induced by 1 \u3bcg/mL lipopolysaccaride (LPS). In BV-2 cells, PTN reduced IL-6 secretion in a dosedependent manner (-29% at 200 nM, P < 0.001; -45% at 1 \u3bcM, P < 0.001; -98% at 5 \u3bcM, P < 0.001; ANOVA). Moreover, at 5 \u3bcm (highest concentration tested) PTN also reduced TNF-\u3b1 secretion (-54%, P < 0.001). Preincubation of LPS-stimulated THP-1 monocytes with OR (dose-range: 0.1-10 mM), reduced the release of all tested cytokines (IL-1\u3b2, IL-6, TNF-\u3b1). Conclusions: The results obtained provide strong evidence that both cell-based models are useful to validate the anti-inflammatory properties of PTN and OR at the cellular level and suggest that they are related to inhibition of cytokine secretion and NF-\u3baB nuclear translocation

Tanacetum parthenium nel controllo e nel trattamento dell&#8217;emicrania

Tanacetum parthenium For control and treatment of migraine Summary Feverfew (Tanacetum parthenium L.) is a herb traditionally used for the control of inflammatory and painful diseases. The sesquiterpene lactone parthenolide is the most represented species among the components of the plant, and the most active. In the preparations containing feverfew, parthenolide should be formulated at 0.2% concentration at least. Control and treatment of migraine are the most interesting clinical uses of feverfew. According to available studies, feverfew use is well tolerated and is an effective treatment in controlling migraine as well in treating acute migraine attacks. Among the proposed mechanisms of action, there are inhibition of synthesis and production of prostaglandins, antagonism of serotonin receptors, inhibition of histamine release and modulation of neuroinflammation. The determination of parthenolide in food supplements is carried out by high performance liquid chromatography with UV detection, while measurement of plasma level requires more sensitive analysis systems (HPLC-MS/MS, GC-MS/ MS). The use of feverfew and its extracts represents a promising advancement in the field of food supplements for the control and treatment of migraine. The establishment of a rigorous standardization of extraction processes, stabilization and conservation of plant complex and the choice of an optimal formulation are key requirements for the reproducibility of the effect of these products