Frequency of carrier screening and preventive orientation among first degree relatives of Thalassaemia patients.

OBJECTIVE: To get preliminary data regarding the prevention of thalassaemia major in future generations. METHODS: This Knowledge Attitude Practices study was conducted at Pakistan Institute of Medical Sciences, Islamabad, Pakistan, from January to June 2016, using non-probability purposive sampling. Parents of children undergoing transfusion were interviewed. Questionnaires were used to collect demographics and data about awareness, attitude and frequency of screening among the first degree relatives of a thalassaemia major patient. SPSS 20 was used for data analysis. RESULTS: Of the 270 respondents 240(88.9%) had utilised screening services for their asymptomatic children and had a positive attitude towards prevention, but 30(11.1%) families did not screen asymptomatic children for thalassaemia minor. Besides, 49(18.1%) families had more than one thalassaemia major child in their nuclear family, while, 3(1.1%) were unwilling to let their children undergo tests. Nine (3.3%) respondents said they will not ask a prospective daughter/son-in-law to get tested for thalassaemia minor, while 194(71.9%) respondents had had cousin marriages. CONCLUSIONS: There were significant gaps in awareness among affected families.

Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis.

Fibrosis is a hallmark of chronic kidney disease, for which there is currently no effective cure. The hormone relaxin is emerging as an effective antifibrotic therapy; however, its mechanism of action is poorly understood. Recent studies have shown that relaxin disrupts the profibrotic actions of transforming growth factor-ß1 (TGF-ß1) by its cognate receptor, relaxin family peptide receptor 1 (RXFP1), extracellular signal-regulated kinase phosphorylation, and a neuronal nitric oxide synthase-dependent pathway to abrogate Smad2 phosphorylation. Since angiotensin II also inhibits TGF-ß1 activity through its AT2 receptor (AT2R), we investigated the extent to which relaxin interacts with the AT2R. The effects of the AT2R antagonist, PD123319, on relaxin activity were examined in primary rat kidney myofibroblasts, and in kidney tissue from relaxin-treated male wild-type and AT2R-knockout mice subjected to unilateral ureteric obstruction. Relaxin's antifibrotic actions were significantly blocked by PD123319 in vitro and in vivo, or when relaxin was administered to AT2R-knockout mice. While heterodimer complexes were formed between RXFP1 and AT2Rs independent of ligand binding, relaxin did not directly bind to AT2Rs but signaled through RXFP1-AT2R heterodimers to induce its antifibrotic actions. These findings highlight a hitherto unrecognized interaction that may be targeted to control fibrosis progression.

Targeting the tumor microenvironment: Potential strategy for cancer therapeutics.

Cellular and stromal components including tumor cells, immune cells, mesenchymal cells, cancer-linked fibroblasts, and extracellular matrix, constituent tumor microenvironment (TME). TME plays a crucial role in reprogramming tumor initiation, uncontrolled proliferation, invasion and metastasis as well as response to therapeutic modalities. In recent years targeting the TME has developed as a potential strategy for treatment of cancer because of its life-threatening functions in restricting tumor development and modulating responses to standard-of-care medicines. Cold atmospheric plasma, oncolytic viral therapy, bacterial therapy, nano-vaccine, and repurposed pharmaceuticals with combination therapy, antiangiogenic drugs, and immunotherapies are among the most effective therapies directed by TME that have either been clinically authorized or are currently being studied. This article discusses above-mentioned therapies in light of targeting TME. We also cover problems related to the TME-targeted therapies, as well as future insights and practical uses in this rapidly growing field.

In the Loop: Extrastriatal Regulation of Spiny Projection Neurons by GPR52.

GPR52 is a Gαs-coupled orphan receptor identified as a putative target for the treatment of schizophrenia. The unique expression and signaling profile of GPR52 in key areas of dopamine and glutamate dysregulation suggests its activation may resolve both cortical and striatal dysfunction in the disorder. GPR52 mRNA is enriched in the striatum, almost exclusively on dopamine D2-expressing medium spiny neurons (MSNs), and to a lesser extent in the cortex, predominantly on D1-expressing pyramidal neurons. Synthetic, small molecule GPR52 agonists are effective in preclinical models of psychosis; however, the relative contribution of cortical and striatal GPR52 is unknown. Here we show that the GPR52 agonist, 3-BTBZ, inhibits phencyclidine-induced hyperlocomotor activity to a greater degree than amphetamine-induced motor effects, suggesting a mechanism beyond functional antagonism of striatal dopamine D2 receptor signaling. Using DARPP-32 phosphorylation and electrophysiological recordings in either striatopallidal or striatonigral MSNs, we were surprised to find no significant effect of 3-BTBZ in striatopallidal MSNs, but GPR52-mediated effects in striatonigral MSNs, where its mRNA is absent. 3-BTBZ increases phosphorylation of T75 on DARPP-32 in striatonigral MSNs, an effect that was dependent on cortical inputs. A similar role for GPR52 in regulating extrastriatal glutamatergic drive onto striatonigral MSNs was also evident in recordings of spontaneous excitatory postsynaptic currents and was shown to be dependent on the metabotropic glutamate (mGlu) receptor subtype 1. Our results demonstrate that GPR52-mediated regulation of striatal function depends heavily on extrastriatal inputs, which may further support its utility as a novel target for the treatment of schizophrenia.

Morgagni-Larrey Hernia: A Possible Cause of Recurrent Lower Respiratory Tract Infections.

Morgagni-Larrey hernia is an exceedingly rare presentation of congenital diaphragmatic hernia. Despite its rarity, it is associated with significant risk of morbidity and mortality. Herein, we describe a unique case report of an elderly woman who presented with left-sided chest pain, dyspnea, and chronic history of recurrent respiratory tract infections. On the basis of her medical history, general physical examination and imaging studies, she was operated for a presumptive diagnosis of thymolipoma. However, the intra-operative findings revealed that it was an unusual variant of a diaphragmatic hernia and the hernia sac appeared through the retrosternal foramen of Morgagni. Hence we concluded that it was a Morgagni-Larrey hernia compressing the lungs and heart. Consequently, the hernia was reduced and the defect was repaired. During the postoperative period, the patient had an uneventful recovery. To conclude, the possibility of a Morgagni-Larrey hernia should be strongly considered while evaluating a patient with recurrent chest infections, dyspnea, and vague chest pain.

Dual or Mono Antiplatelet Therapy for the Prevention of Ischemic Stroke: A Literature Review.

Ischemic stroke is defined as a sudden loss of blood to the brain which results in deprivation of oxygen and other nutrients. It can be either a transient episode called as "transient ischemic attack" (TIA), or it could last longer than 24 hours giving rise to "infarction of tissues" in the central nervous system. Anti-platelet agents are widely used for the secondary prophylaxis of ischemic stroke, and amongst them, aspirin remains the drug of choice. In this literature review, we summarized the existing data regarding the ischemic type of strokes with particular attention to the use of antiplatelet agents for this purpose. The following review highlights the significance of the use of dual antiplatelet (aspirin and clopidogrel) regimen for the stroke prevention. The role of dual antiplatelet (aspirin and clopidogrel) in patients with a recent TIA (within 30 days) or severe stenosis (70%-99%) of a major intracranial artery, for 90 days, might be a beneficial approach.

The actions of relaxin on the human cardiovascular system.

The insulin-like peptide relaxin, originally identified as a hormone of pregnancy, is now known to exert a range of pleiotropic effects including vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory effects in both males and females. Relaxin produces these effects by binding to a cognate receptor RXFP1 and activating a variety of signalling pathways including cAMP, cGMP and MAPKs as well as by altering gene expression of TGF-ß, MMPs, angiogenic growth factors and endothelin receptors. The peptide has been shown to be effective in halting or reversing many of the adverse effects including fibrosis in animal models of cardiovascular disease including ischaemia/reperfusion injury, myocardial infarction, hypertensive heart disease and cardiomyopathy. Relaxin given to humans is safe and produces favourable haemodynamic changes. Serelaxin, the recombinant form of relaxin, is now in extended phase III clinical trials for the treatment of acute heart failure. Previous clinical studies indicated that a 48 h infusion of relaxin improved 180 day mortality, yet the mechanism underlying this effect is not clear. This article provides an overview of the cellular mechanism of effects of relaxin and summarizes its beneficial actions in animal models and in the clinic. We also hypothesize potential mechanisms for the clinical efficacy of relaxin, identify current knowledge gaps and suggest new ways in which relaxin could be useful therapeutically. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.

ML290 is a biased allosteric agonist at the relaxin receptor RXFP1.

Activation of the relaxin receptor RXFP1 has been associated with improved survival in acute heart failure. ML290 is a small molecule RXFP1 agonist with simple structure, long half-life and high stability. Here we demonstrate that ML290 is a biased agonist in human cells expressing RXFP1 with long-term beneficial actions on markers of fibrosis in human cardiac fibroblasts (HCFs). ML290 did not directly compete with orthosteric relaxin binding and did not affect binding kinetics, but did increase binding to RXFP1. In HEK-RXFP1 cells, ML290 stimulated cAMP accumulation and p38MAPK phosphorylation but not cGMP accumulation or ERK1/2 phosphorylation although prior addition of ML290 increased p-ERK1/2 responses to relaxin. In human primary vascular endothelial and smooth muscle cells that endogenously express RXFP1, ML290 increased both cAMP and cGMP accumulation but not p-ERK1/2. In HCFs, ML290 increased cGMP accumulation but did not affect p-ERK1/2 and given chronically activated MMP-2 expression and inhibited TGF-ß1-induced Smad2 and Smad3 phosphorylation. In vascular cells, ML290 was 10x more potent for cGMP accumulation and p-p38MAPK than for cAMP accumulation. ML290 caused strong coupling of RXFP1 to Gαs and GαoB but weak coupling to Gαi3. ML290 exhibited signalling bias at RXFP1 possessing a signalling profile indicative of vasodilator and anti-fibrotic properties.

Ligand-directed signalling at beta-adrenoceptors.

beta-Adrenoceptors (ARs) classically mediate responses to the endogenous ligands adrenaline and noradrenaline by coupling to Gsalpha and stimulating cAMP production; however, drugs designed as beta-AR agonists or antagonists can activate alternative cell signalling pathways, with the potential to influence clinical efficacy. Furthermore, drugs acting at beta-ARs have differential capacity for pathway activation, described as stimulus trafficking, biased agonism, functional selectivity or ligand-directed signalling. These terms refer to responses where drug A has higher efficacy than drug B for one signalling pathway, but a lower efficacy than drug B for a second pathway. The accepted explanation for such responses is that drugs A and B have the capacity to induce or stabilize distinct active conformations of the receptor that in turn display altered coupling efficiency to different effectors. This is consistent with biophysical studies showing that drugs can indeed promote distinct conformational states. Agonists acting at beta-ARs display ligand-directed signalling, but many drugs acting as cAMP antagonists are also able to activate signalling pathways central to cell survival and proliferation or cell death. The observed complexity of drug activity at beta-ARs, prototypical G protein-coupled receptors, necessitates rethinking of the approaches used for screening and characterization of novel therapeutic agents. Most studies of ligand-directed signalling employ recombinant cell systems with high receptor abundance. While such systems are valid for examining upstream signalling events, such as receptor conformational changes and G protein activation, they are less robust when comparing downstream signalling outputs as these are likely to be affected by complex pathway interactions.