Diverse pharmacology of prostacyclin mimetics: Implications for pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a progressive vascular remodelling disease where patients ultimately die from heart failure. Increased production of vasoconstrictors (endothelin-1 and thromboxane A2) accompanied by loss of prostacyclin, nitric oxide (NO), bone morphogenetic protein receptor type 2 (BMPR2) and TASK-1 combine to cause endothelial apoptosis, smooth muscle hyperactivity and thickening of the blood vessel wall. Prostacyclin remains the most efficacious treatment for PAH, and several prostacyclin analogues are approved for use via different administration routes. They act as vasodilators but potently inhibit platelet aggregation, cell proliferation and inflammation. The pharmacology of each prostacyclin (IP) receptor agonist is distinct, with other targets contributing to their therapeutic and side-effect profile, including prostanoid EP1, EP3, EP2 and DP1 receptors, alongside peroxisome proliferator-activated receptors (PPARs), to which prostacyclin and some analogues directly bind. To improve selectivity, selexipag, a non-prostanoid was developed, whose only significant biological target is the IP receptor, but is a partial agonist in cyclic AMP assays and has no anti-aggregatory properties in vivo. Prostanoid receptor expression profiles in the normal and diseased lung demonstrate loss of the IP receptor and upregulation of EP2 and EP3 receptors in PAH, affecting the action of prostacyclin mimetics in different ways. We discuss how prostacyclins might rescue BMPR2 and TASK-1 dysfunction and the importance of EP2 receptors as negative modulators of vascular tone, proliferation and fibrosis. Alongside DP1 and EP4 receptors, they have specific roles in veins and airways. Whether drugs selective for the IP receptor confer a superior or reduced therapeutic benefit remains an important clinical question as do the role of platelets in PAH

Health Economic Studies of Colorectal Cancer and the Contribution of a National Administrative Data Repository: a Systematic Review

Introduction: Several forces are contributing to an increase in the number of people living with and surviving colorectal cancer (CRC). However, due to the lack of available data, little is known about the implications of these forces. In recent years, the use of administrative records to inform research has been increasing. The aim of this paper is to investigate the potential contribution that administrative data could have on the health economic research of CRC. Methods: To achieve this aim, we conducted a systematic review of the health economic CRC literature published in the United Kingdom and Europe within the last decade (2009–2019). Results: Thirty-seven relevant studies were identified and divided into economic evaluations, cost of illness studies and cost consequence analyses. Conclusions: The use of administrative data, including cancer registry, screening and hospital records, within the health economic research of CRC is commonplace. However, we found that this data often come from regional databases, which reduces the generalisability of results. Further, administrative data appear less able to contribute towards understanding the wider and indirect costs associated with the disease. We explore several ways in which various sources of administrative data could enhance future research in this area

Nongenomic actions of progesterone and 17β-estradiol on the chloride conductance of skeletal muscle.

Myotonia congenita, caused by mutations in ClC-1, tends to be more severe in men and is often exacerbated by pregnancy. We performed whole-cell patch clamp of mouse muscle chloride currents in the absence/presence of 100 μM progesterone or 17β-estradiol. 100 μM progesterone rapidly and reversibly shifted the ClC-1 activation curve of mouse skeletal muscle (V50 changed from -52.6 ± 9.3 to +35.5 ± 6.7; P < 0.01) and markedly reduced chloride currents at depolarized potentials. 17β-estradiol at the same concentration had a similar but smaller effect (V50 change from -57.2 ± 7.6 to -40.5 ± 9.8; P < 0.05). 1 μM progesterone produced no significant effect. Although the data support the existence of a nongenomic mechanism in mammalian skeletal muscle through which sex hormones at high concentration can rapidly modulate ClC-1, the influence of hormones on muscle excitability in vivo remains an open question. Copyright © 2013 Wiley Periodicals, Inc

Searching for help online: An analysis of peer-to-peer posts on a male-only infertility forum.

Men’s experiences of infertility help seeking are under-researched and thus less widely understood than women’s experiences, with men’s needs for support often missing from reproductive research knowledge. This article presents a thematic analysis of peer-to-peer posts within the context of a UK men-only online infertility forum. The key themes demonstrate that men value male support from those with experience, and that masculinity influences help-seeking requests and men’s accounts more broadly. We highlight the value of such online communities in offering support to men in need while recognising the importance of further research across other online settings in order to inform practice around supporting men in the reproductive realm

Utility of Whole Blood Thiamine Pyrophosphate Evaluation in TPK1-Related Diseases

TPK1 mutations are a rare, but potentially treatable, cause of thiamine deficiency. Diagnosis is challenging given the phenotypic overlap that exists with other metabolic and neurological disorders. We report a case of TPK1-related disease presenting with Leigh-like syndrome and review the diagnostic utility of thiamine pyrophosphate (TPP) blood measurement. The proband, a 35-year-old male, presented at four months of age with recurrent episodes of post-infectious encephalopathy. He subsequently developed epilepsy, learning difficulties, sensorineural hearing loss, spasticity, and dysphagia. There was a positive family history for Leigh syndrome in an older brother. Plasma lactate was elevated (3.51 mmol/L) and brain MRI showed bilateral basal ganglia hyperintensities, indicative of Leigh syndrome. Histochemical and spectrophotometric analysis of mitochondrial respiratory chain complexes I, II+III, and IV was normal. Genetic analysis of muscle mitochondrial DNA was negative. Whole exome sequencing of the proband confirmed compound heterozygous variants in TPK1: c. 426G>C (p. Leu142Phe) and c. 258+1G>A (p.?). Blood TPP levels were reduced, providing functional evidence for the deleterious effects of the variants. We highlight the clinical and bioinformatics challenges to diagnosing rare genetic disorders and the continued utility of biochemical analyses, despite major advances in DNA sequencing technology, when investigating novel, potentially disease-causing, genetic variants. Blood TPP measurement represents a fast and cost-effective diagnostic tool in TPK1-related diseases

Carney-Complex: Multiple resections of recurrent cardiac myxoma

We report a case of a female patient who was operated at the third relapse of an atrial myxoma caused by Carney complex. The difficult operation was performed without any complications despite extensive adhesions caused by the previous operations. The further inpatient course went without complications and the patient was discharged to the consecutive treatment on the 9th postoperative day. The echocardiographic finding postoperative showed no abnormalities

Cardiorespiratory comorbidity and postoperative complications following esophagectomy: a European multicenter cohort study

BACKGROUND: The impact of cardiorespiratory comorbidity on operative outcomes after esophagectomy remains controversial. This study investigated the effect of cardiorespiratory comorbidity on postoperative complications for patients treated for esophageal or gastroesophageal junction cancer. PATIENTS AND METHODS: A European multicenter cohort study from five high-volume esophageal cancer centers including patients treated between 2010 and 2017 was conducted. The effect of cardiorespiratory comorbidity and respiratory function upon postoperative outcomes was assessed. RESULTS: In total 1590 patients from five centers were included; 274 (17.2%) had respiratory comorbidity, and 468 (29.4%) had cardiac comorbidity. Respiratory comorbidity was associated with increased risk of overall postoperative complications, anastomotic leak, pulmonary complications, pneumonia, increased Clavien-Dindo score, and critical care and hospital length of stay. After neoadjuvant chemoradiotherapy, respiratory comorbidity was associated with increased risk of anastomotic leak [odds ratio (OR) 1.83, 95% confidence interval (CI) 1.11-3.04], pneumonia (OR 1.65, 95% CI 1.10-2.47), and any pulmonary complication (OR 1.52, 95% CI 1.04-2.22), an effect which was not observed following neoadjuvant chemotherapy or surgery alone. Cardiac comorbidity was associated with increased risk of cardiovascular and pulmonary complications, respiratory failure, and Clavien-Dindo score ≥ IIIa. Among all patients, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio > 70% was associated with reduced risk of overall postoperative complications, cardiovascular complications, atrial fibrillation, pulmonary complications, and pneumonia. CONCLUSIONS: The results of this study suggest that cardiorespiratory comorbidity and impaired pulmonary function are associated with increased risk of postoperative complications after esophagectomy performed in high-volume European centers. Given the observed interaction with neoadjuvant approach, these data indicate a potentially modifiable index of perioperative risk

Emoting infertility online: A qualitative analysis of men's forum posts

Relatively little research on infertility focuses exclusively or significantly on men’s experiences, particularly in relation to emotional aspects. Evidence that does exist around male infertility suggests that it is a distressing experience for men, due to stigma, threats to masculinity and the perceived need to suppress emotions, and that men and women experience infertility differently. Using thematic analysis, this article examines the online emoting of men in relation to infertility via forum posts from a men-only infertility discussion board. It was noted that men ‘talked’ to each other about the emotional burdens of infertility, personal coping strategies and relationships with others. Three major themes were identified following in-depth analysis: ‘the emotional rollercoaster’, ‘the tyranny of infertility’ and ‘infertility paranoia’. This article then offers insights into how men experience infertility emotionally, negotiate the emotional challenges involved (especially pertaining to diagnosis, treatment outcomes and their intimate relationships) and how they share (and find value in doing so) with other men the lived experience of infertility

Arctic cut-off high drives the poleward shift of a new Greenland melting record

Large-scale atmospheric circulation controls the mass and energy balance of the Greenland ice sheet through its impact on radiative budget, runoff and accumulation. Here, using reanalysis data and the outputs of a regional climate model, we show that the persistence of an exceptional atmospheric ridge, centred over the Arctic Ocean, was responsible for a poleward shift of runoff, albedo and surface temperature records over the Greenland during the summer of 2015. New records of monthly mean zonal winds at 500 hPa and of the maximum latitude of ridge peaks of the 5,700±50 m isohypse over the Arctic were associated with the formation and persistency of a cutoff high. The unprecedented (1948–2015) and sustained atmospheric conditions promoted enhanced runoff, increased the surface temperatures and decreased the albedo in northern Greenland, while inhibiting melting in the south, where new melting records were set over the past decade