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CME Courses

Conference Highlights: ACAAI 2016 moodlemobile://link=https://lms.physiciansweekly.com/course/view.php?id=38 Open the other app
MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics.

MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics.

Expert opinion on therapeutic targets 21(7) 671-683 doi 10.1080/14728222.2017.1336227 Abstract INTRODUCTION Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with chemokine-like functions that increasingly is being studied in different aspects of cardiovascular disease. MIF was first identified as a proinflammatory and pro-survival mediator within the immune system, and a second structurally related MIF family member, D-dopachrome tautomerase (a.k.a. MIF-2), was reported recently. Both MIF family members are released by myocardium and modulate the manifestations of cardiovascular disease, specifically in myocardial ischemia. Areas covered: A scientific overview is provided for the involvement of MIF family cytokines in the inflammatory pathogenesis of atherosclerosis, myocardial infarction, and ischemia-reperfusion injury. We summarize findings of experimental, human genetic and clinical studies, and suggest therapeutic opportunities for modulating the activity of MIF family proteins that potentially may be applied in a MIF allele specific manner. Expert opinion: Knowledge of MIF, MIF-2 and their receptor pathways are under active investigation in different types of cardiovascular diseases, and novel therapeutic opportunities are being identified. Clinical translation may be accelerated by accruing experience with MIF-directed therapies currently in human testing in cancer and...
Understanding sleep-wake mechanisms and drug discovery.

Understanding sleep-wake mechanisms and drug discovery.

Expert opinion on drug discovery 2017 05 2212(7) 643-657 doi 10.1080/17460441.2017.1329818 Abstract INTRODUCTION Although not discernible at first glance, sleep is a highly active and regulated brain state. Although we spend practically one third of our lifetimes in this stage, its importance is often taken for granted. Sleep loss can lead to disease, error and economic loss. Our understanding of how sleep is achieved has greatly advanced in recent years, and with that, the management of sleep disorders has improved. There is still room for improvement and recently many new compounds have reached clinical trials with a few being approved for commercial use. Areas covered: In this review, the authors make the case of sleep disorders as a matter of public health. The mechanisms of sleep transition are discussed emphasizing the wake and sleep promoting interaction of different brain regions. Finally, advances in pharmacotherapy are examined in the context of chronic insomnia and narcolepsy. Expert opinion: The orexinergic system is an example of a breakthrough in sleep medicine that has catalyzed drug development. Nevertheless, sleep is a topic still with many unanswered questions. That being said, the melanin-concentrating hormone system is becoming increasingly relevant and we speculate it will be the next target of sleep...
Is mercury exposure causing diabetes, metabolic syndrome and insulin resistance? A systematic review of the literature.

Is mercury exposure causing diabetes, metabolic syndrome and insulin resistance? A systematic review of the literature.

Environmental research 2017 05 05156() 747-760 pii S0013-9351(17)30325-0 Abstract INTRODUCTION Several populations are exposed to mercury (Hg) via their environment, occupation or diet. It is hypothesized that Hg exposure can lead to the development of diabetes mellitus (DM). Metabolic syndrome (MS) is also a possible outcome as its symptoms are closely linked to those of DM. METHOD We conducted a systematic review of the literature by screening Web of Science, MEDLINE, SciFinder and Embase and we included original studies pertaining to the relationship of total Hg exposure (elemental, inorganic or organic) to DM, MS or insulin resistance. The studies were selected based on the PICOS (patients, intervention, comparator, outcomes and study design) criteria and their quality assessed using a nine-point scale. Study characteristics and results were extracted and presented in structured tables. We also extracted covariates entered as confounding factors to evaluate possible biases in selected studies. Finally, a weight of evidence approach was used to assess the causality of the relationship. RESULTS A total of 34 studies were included in the present review. Epidemiological data assessment suggests a possible association between total Hg concentrations in different biological matrices and incidence of DM or MS, but the relationship is not consistent. In vivo and in vitro studies support the biological plausibility of the relation between Hg exposure and DM or MS. Five out of nine of Bradford Hill’s criteria were fulfilled: strength, temporality, plausibility, coherence and analogy. CONCLUSION Increased total Hg exposure may augment the risk of DM and MS, but the lack of consistency of the epidemiological evidence prevents inference of a causal relationship. Additional prospective cohort studies...
New perspectives for chronic pain treatment: a patent review (2010-2016).

New perspectives for chronic pain treatment: a patent review (2010-2016).

Expert opinion on therapeutic patents 2017 03 0327(7) 787-796 doi 10.1080/13543776.2017.1297425 Abstract INTRODUCTION Chronic pain is a major problem of public health worldwide and is responsible for the increase in health costs. The therapeutic options available in the market for the treatment of chronic pain are often rather ineffective due to; the high number of adverse reactions, tolerance and dependence, reducing the quality of life, pharmacotherapy adherence and functional capacity. Hence, several studies have been conducted in the search for new treatment alternatives for chronic pain syndromes. Areas covered: This review brings together the therapeutic patents published over the past six years reporting the discovery of new drugs for the treatment of chronic pain, based on the perspective that these compounds are candidates for the management of chronic pain conditions. Expert opinion: Over the past 6 years, several pharmaceutical companies, as well as universities and researchers, have synthesized a series of compounds, which have been shown to be effective in controlling chronic pain in preclinical studies. These findings nurture the hope of discovering new therapeutic options for chronic pain. However, such studies are in early stages and there is a long and hard path to be followed until these compounds can become chemical entities available to the...
Selexipag, a selective prostacyclin receptor agonist in pulmonary arterial hypertension: a pharmacology review.

Selexipag, a selective prostacyclin receptor agonist in pulmonary arterial hypertension: a pharmacology review.

Expert review of clinical pharmacology 2017 05 1910(7) 753-762 doi 10.1080/17512433.2017.1322900 Abstract INTRODUCTION Pulmonary hypertension is defined by a mean pulmonary artery pressure ≥25 mm Hg at rest. Management of pulmonary arterial hypertension (PAH) includes specific drug therapy with calcium channel blockers in vasoreactive patients, or drugs approved for PAH in non-reactive patients that target the endothelin, nitric-oxide and prostacyclin pathways. Areas covered: The review covers receptor selectivity, pharmacokinetics, pharmacodynamics and adverse effects (AEs) of intravenous (IV) epoprostenol (synthetic prostacyclin); the prostacyclin analogs iloprost, beraprost, and treprostinil administered by IV, subcutaneous, inhaled or oral routes; and the oral selective prostacyclin receptor agonist selexipag. Expert commentary: Development of a selective prostacyclin receptor agonist has aimed at identifying compounds with improved pharmacological properties. The high selectivity of selexipag, and its active metabolite ACT-333679, for the prostacyclin receptor, in conjunction with pharmacokinetic properties that reduce peak-trough fluctuations and the up-titration regimen used at the start of treatment, are collectively considered to minimize AEs associated with prostacyclin use. In a large phase 3 study, selexipag-associated AEs were consistent with those observed with drugs that target the prostacyclin pathway, and mainly mild to moderate in severity. The dosing flexibility afforded by oral selexipag may facilitate achieving the maximum therapeutic effect with acceptable tolerability in patients with...
An Approach to Assess the Burden of Work-Related Injury, Disease, and Distress.

An Approach to Assess the Burden of Work-Related Injury, Disease, and Distress.

American journal of public health 2017 05 18107(7) 1051-1057 doi 10.2105/AJPH.2017.303765 Abstract The true burden (morbidity, mortality, disability, cost, pain, distress) of occupational and work-related diseases and injuries is unknown, and what is reported as burden is significantly underestimated. This underestimation affects the way decision-makers view investments in research and worker protection, which in turn has a substantial impact on national welfare and public health. To better describe the societal and individual burdens of occupational and work-related diseases and injuries, we propose an approach to gauge what is known about burden and where new assessments may be made. This approach consists of 4 elements to consider in burden assessments: (1) utilizing multiple domains, including the individual worker, the worker’s family, the community in which the workplace is located, the employer, and society as a whole; (2) taking a broader view of the work-relatedness of disease and injury; (3) assessing the impact of the entire working-life continuum; and (4) applying the comprehensive concept of "well-being" as an indicator in addressing contemporary changes in the nature of work, the workplace, and the workforce. Further research on burden and enhanced surveillance is needed to develop these...
Children with Cough and Fever: Up-to-date Imaging Evaluation and Management.

Children with Cough and Fever: Up-to-date Imaging Evaluation and Management.

Radiologic clinics of North America 2017 04 0655(4) 645-655 pii S0033-8389(17)30016-7 Abstract Cough and fever in infants and children are frequent but nonspecific symptoms. Several usual differential diagnoses are under consideration and imaging is often necessary to help arrive at an accurate diagnosis and ensure proper management. A broad spectrum of underlying disorders may be present. Radiologists must remain cognizant of the potential for immune dysfunction and underlying structural abnormalities. A clear understanding of up-to-date imaging evaluation recommendations and characteristic imaging features can assist radiologists and clinicians in arriving at the most accurate diagnosis in a timely manner and help ensure proper management and necessary follow-up imaging...
Sphingosine 1-phosphate signaling in bone remodeling: multifaceted roles and therapeutic potential.

Sphingosine 1-phosphate signaling in bone remodeling: multifaceted roles and therapeutic potential.

Expert opinion on therapeutic targets 2017 06 0721(7) 725-737 doi 10.1080/14728222.2017.1332180 Abstract INTRODUCTION Sphingolipids belong to a complex class of lipid molecules that are crucially involved in the regulation of important biological processes including proliferation, migration and apoptosis. Given the significant progress made in understanding the sphingolipid pathobiology of several diseases, sphingolipid-related checkpoints emerge as attractive targets. Recent data indicate the multifaceted contribution of the sphingolipid machinery to osteoclast – osteoblast crosstalk, representing one of the pivotal interactions underlying bone homeostasis. Imbalances in the interplay of osteoblasts and osteoclasts might lead to bone-related diseases such as osteoporosis, rheumatoid arthritis, and bone metastases. Areas covered: We summarize and analyze the progress made in bone research in the context of the current knowledge of sphingolipid-related mechanisms regulating bone remodeling. Particular emphasis was given to bioactive sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs). Moreover, the mechanisms of how dysregulations of this machinery cause bone diseases, are covered. Expert opinion: In the context of bone diseases, pharmacological interference with sphingolipid machinery may lead to novel directions in therapeutic strategies. Implementation of knowledge derived from in vivo animal models and in vitro studies using pharmacological agents to manipulate the S1P/S1PRs axes suggests S1PR2 and S1PR3 as potential drug targets, particularly in conjunction with technology for local drug...
Cyanotic Congenital Heart Disease: Essential Primer for the Practicing Radiologist.

Cyanotic Congenital Heart Disease: Essential Primer for the Practicing Radiologist.

Radiologic clinics of North America 2017 04 0655(4) 693-716 pii S0033-8389(17)30018-0 Abstract The cyanotic congenital heart diseases are a rare and heterogeneous group of disorders, often requiring urgent neonatal management. Although echocardiography is the mainstay for imaging, continued technological advances have expanded the role for computed tomography and magnetic resonance imaging, helping to limit invasive cardiac catheterization. In this article, the authors review the broad spectrum of cyanotic congenital heart disease, focusing on the utility of advanced noninvasive imaging modalities while highlighting key clinical features and management...
Impact of the 2016 Ecuador Earthquake on Zika Virus Cases.

Impact of the 2016 Ecuador Earthquake on Zika Virus Cases.

American journal of public health 2017 05 18107(7) 1137-1142 doi 10.2105/AJPH.2017.303769 Abstract OBJECTIVES To evaluate the impact of the April 2016 7.8-magnitude earthquake in Ecuador on the incidence of Zika virus (ZIKV) cases. METHODS We used the national public health surveillance system for reportable transmissible conditions and included suspected and laboratory-confirmed ZIKV cases. We compared the number of cases before and after the earthquake in areas closer to and farther from the epicenter. RESULTS From January to July 2016, 2234 patients suspected of having ZIKV infection were reported in both affected and control areas. A total of 1110 patients had a reverse transcription-polymerase chain reaction assay, and 159 were positive for ZIKV. The cumulative incidence of ZIKV in the affected area was 11.1 per 100 000 after the earthquake. The odds ratio of having ZIKV infection in those living in the affected area was 8.0 (95% CI = 4.4, 14.6;...
S100-alarmins: potential therapeutic targets for arthritis.

S100-alarmins: potential therapeutic targets for arthritis.

Expert opinion on therapeutic targets 2017 05 2521(7) 739-751 doi 10.1080/14728222.2017.1330411 Abstract INTRODUCTION In arthritis, inflammatory processes are triggered by numerous factors that are released from joint tissues, promoting joint destruction and pathological progression. During inflammation, a novel family of pro-inflammatory molecules called alarmins is released, amplifying inflammation and joint damage. Areas covered: With regard to the role of the alarmins S100A8 and S100A9 in the pathogenesis of arthritis, recent advances and the future prospects in terms of therapeutic implications are considered. Expert opinion: There is still an urgent need for novel treatment strategies addressing the local mechanisms of joint inflammation and tissue destruction, offering promising therapeutic alternatives. S100A8 and S100A9, which are the most up-regulated alarmins during arthritis, are endogenous triggers of inflammation, defining these proteins as promising targets for local suppression of arthritis. In murine models, the blockade of S100A8/S100A9 ameliorates inflammatory processes, including arthritis, and there are several lines of evidence that S100-alarmins may already be targeted in therapeutic approaches in...
Influenza detection and prediction algorithms: comparative accuracy trial in Östergötland county, Sweden, 2008-2012.

Influenza detection and prediction algorithms: comparative accuracy trial in Östergötland county, Sweden, 2008-2012.

Epidemiology and infection 2017 05 17145(10) 2166-2175 doi 10.1017/S0950268817001005 Abstract Methods for the detection of influenza epidemics and prediction of their progress have seldom been comparatively evaluated using prospective designs. This study aimed to perform a prospective comparative trial of algorithms for the detection and prediction of increased local influenza activity. Data on clinical influenza diagnoses recorded by physicians and syndromic data from a telenursing service were used. Five detection and three prediction algorithms previously evaluated in public health settings were calibrated and then evaluated over 3 years. When applied on diagnostic data, only detection using the Serfling regression method and prediction using the non-adaptive log-linear regression method showed acceptable performances during winter influenza seasons. For the syndromic data, none of the detection algorithms displayed a satisfactory performance, while non-adaptive log-linear regression was the best performing prediction method. We conclude that evidence was found for that available algorithms for influenza detection and prediction display satisfactory performance when applied on local diagnostic data during winter influenza seasons. When applied on local syndromic data, the evaluated algorithms did not display consistent performance. Further evaluations and research on combination of methods of these types in public health information infrastructures for ‘nowcasting’ (integrated detection and prediction) of influenza activity are...
Outbreak of diarrhoea among participants of a triathlon and a duathlon on 12 July 2015 in Utrecht, the Netherlands.

Outbreak of diarrhoea among participants of a triathlon and a duathlon on 12 July 2015 in Utrecht, the Netherlands.

Epidemiology and infection 2017 05 17145(10) 2176-2184 doi 10.1017/S0950268817001017 Abstract On 12 July 2015, a triathlon competition with 900 participants took place in Utrecht, the Netherlands. An outbreak investigation was initiated after 56 participants reported health complaints. An online questionnaire was sent to 700 participants. Stool specimens from six participants and four water specimens were collected from the swimming location. A total of 239 participants completed the questionnaire (response rate: 34%), 73 (31%) of them met the case definition for acute gastrointestinal illness (AGI). A total of 67% of the respondents were male and the median age was 38 years. Almost half (42%) of swimmers reported health complaints. Consumption of energy drinks and ingesting ⩾3 mouthfuls of canal water were identified as risk factors for AGI among swimmers only (adjusted relative risks (aRR) 1·6; 95% confidence intervals (CI) 1·0-2·5 and aRR 2·6; 95% CI 1·5-4·8). The collected water specimens tested positive for norovirus genogroup I and rotavirus and stool specimens tested positive for norovirus genogroup II. Our findings indicate that the outbreak could have been caused by exposure to norovirus during swimming. Swimmers should get information about the health risks for making an informed choice about participating. For future events, the organisers decided to change the swimming location from a canal to a recreational...
Use of a Digital Health Application for Influenza Surveillance in China.

Use of a Digital Health Application for Influenza Surveillance in China.

American journal of public health 2017 05 18107(7) 1130-1136 doi 10.2105/AJPH.2017.303767 Abstract OBJECTIVES To examine whether a commercial digital health application could support influenza surveillance in China. METHODS We retrieved data from the Thermia online and mobile educational tool, which allows parents to monitor their children’s fever and infectious febrile illnesses including influenza. We modeled monthly aggregated influenza-like illness case counts from Thermia users over time and compared them against influenza monthly case counts obtained from the National Health and Family Planning Commission of the People’s Republic of China by using time series regression analysis. We retrieved 44 999 observations from January 2014 through July 2016 from Thermia China. RESULTS Thermia appeared to predict influenza outbreaks 1 month earlier than the National Health and Family Planning Commission influenza surveillance system (P = .046). Being younger, not having up-to-date immunizations, and having an underlying health condition were associated with participant-reported influenza-like illness. CONCLUSIONS Digital health applications could supplement traditional influenza surveillance systems in China by providing access to consumers’ symptom reporting. Growing popularity and use of commercial digital health applications in China potentially affords opportunities to support disease detection and monitoring and rapid treatment...
Protocatechuic acid inhibits hepatitis B virus replication by activating ERK1/2 pathway and down-regulating HNF4α and HNF1α in vitro.

Protocatechuic acid inhibits hepatitis B virus replication by activating ERK1/2 pathway and down-regulating HNF4α and HNF1α in vitro.

Life sciences 2017 05 12180() 68-74 pii S0024-3205(17)30237-0 Abstract AIMS Protocatechuic acid (PCA) is a phenolic compound found in many antiviral Chinese herbal medicines. HNF4α and HNF1α, the members of hepatocyte nuclear factor (HNF) family, play an important regulatory role in the gene transcription of hepatitis B virus (HBV). Previous studies found that PCA inhibited HBV antigen secretion and HBV DNA replication in HepG2.2.15 cells, but its anti-HBV mechanism has not been fully understood. We aim to illustrate the anti-HBV mechanism of PCA. MATERIALS AND METHODS MTT was used to estimate cytotoxicity. The content of HBsAg or HBeAg was detected using an enzyme-linked immunosorbent assay kit. HBV DNA in cell-free culture media was detected by PCR kit. HNF1α and HNF4α mRNA expression was detected by real-time PCR. HNF1α, HNF4α and ERK1/2 protein expression was detected by western blotting and HBV promoter activity was tested by luciferase reporter assay. KEY FINDINGS Our results demonstrated that PCA inhibited the gene transcription and protein translation of HNF1α and HNF4α in Huh7 and HepG2.2.15 cells, as well as the promoter activities of HBV X and preS1 in Huh7 cells transfected with the luciferase reporter plasmid of HBV promoter. Further study suggested that PCA induced the phosphorylation of extracellular-signal-related kinase (ERK) 1/2, and thereby inhibited HNF4α and HNF1α expression in HepG2.2.15 cells to exert its antiviral activity. SIGNIFICANCE To our knowledge, this study is the first to reveal the anti-HBV mechanism of PCA. Our results demonstrate that PCA inhibits HBV replication by activating ERK1/2 pathway and subsequently down-regulating HNF4α and HNF1α in HepG2.2.15...
Toxicokinetics of ibogaine and noribogaine in a patient with prolonged multiple cardiac arrhythmias after ingestion of internet purchased ibogaine.

Toxicokinetics of ibogaine and noribogaine in a patient with prolonged multiple cardiac arrhythmias after ingestion of internet purchased ibogaine.

Clinical toxicology (Philadelphia, Pa.) 2017 02 0955(6) 600-602 doi 10.1080/15563650.2017.1287372 Abstract BACKGROUND Ibogaine is an agent that has been evaluated as an unapproved anti-addictive agent for the management of drug dependence. Sudden cardiac death has been described to occur secondary to its use. We describe the clinical effects and toxicokinetics of ibogaine and noribogaine in a single patient. For this purpose, we developed a LC-MS/MS-method to measure ibogaine and noribogaine plasma-concentrations. We used two compartments with first order absorption. CASE DETAILS The maximum concentration of ibogaine was 1.45 mg/L. Our patient developed markedly prolonged QTc interval of 647ms maximum, several multiple cardiac arrhythmias (i.e., atrial tachycardia and ventricular tachycardia and Torsades des Pointes). QTc-prolongation remained present until 12 days after ingestion, several days after ibogaine plasma-levels were low, implicating clinically relevant noribogaine concentrations long after ibogaine had been cleared from the plasma. The ratio k12/k21 for noribogaine was 21.5 and 4.28 for ibogaine, implicating a lower distribution of noribogaine from the peripheral compartment into the central compartment compared to ibogaine. CONCLUSIONS We demonstrated a linear relationship between the concentration of the metabolite and long duration of action, rather than with parent ibogaine. Therefore, after (prolonged) ibogaine ingestion, clinicians should beware of long-term effects due to its...
Protective roles of bioactive peptides during ischemia-reperfusion injury: From bench to bedside.

Protective roles of bioactive peptides during ischemia-reperfusion injury: From bench to bedside.

Life sciences 2017 05 17180() 83-92 pii S0024-3205(17)30236-9 Abstract Ischemia-reperfusion (I/R) is a well-known pathological condition which may lead to disability and mortality. I/R injury remains an unresolved and complicated situation in a number of clinical conditions, such as cardiac arrest with successful reanimation, as well as ischemic events in brain and heart. Peptides have many attractive advantages which make them suitable candidate drugs in treating I/R injury, such as low toxicity and immunogenicity, good solubility property, distinct tissue distribution pattern, and favorable pharmacokinetic profile. An increasing number of studies indicate that peptides could protect against I/R injury in many different organs and tissues. Peptides also face several therapeutic challenges that limit their clinical application. In this review, we present the mechanisms of action of peptides in reducing I/R injury, as well as further discuss modification strategies to improve the functional properties of bioactive...
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