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Vittorio Vellani,1 Silvia Franchi,2 Massimiliano Prandini,1 Sarah Moretti,2 Mara Castelli,2 Chiara Giacomoni,3 Paola Sacerdote21Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; 2Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; 3Department of Economics and Technology, University of the Republic of San Marino, Republic of San MarinoAbstract: Celecoxib, diclofenac, ibuprofen, and nimesulide are nonsteroidal anti-inflammatory drugs (NSAIDs) very commonly used for the treatment of moderate to mild pain, together with paracetamol (acetaminophen), a very widely used analgesic with a lesser anti-inflammatory effect. In the study reported here, we tested the efficacy of celecoxib, diclofenac, and ibuprofen on preprotachykinin mRNA synthesis, substance P (SP) release, prostaglandin E2 (PGE2) release, and protein kinase C epsilon (PKCε) translocation in rat cultured sensory neurons from dorsal root ganglia (DRGs). The efficacy of these NSAIDs was compared with the efficacy of paracetamol and nimesulide in in vitro models of hyperalgesia (investigated previously). While nimesulide and paracetamol, as in previous experiments, decreased the percentage of cultured DRG neurons showing translocation of PKCε caused by 100 nM thrombin or 1 µM bradykinin in a dose-dependent manner, the other NSAIDs tested did not have a significant effect. The amount of SP released by peptidergic neurons and the expression level of preprotachykinin mRNA were assessed in basal conditions and after 70 minutes or 36 hours of stimulation with an inflammatory soup (IS) containing potassium chloride, thrombin, bradykinin, and endothelin-1. The release of SP at 70 minutes was inhibited only by nimesulide, while celecoxib and diclofenac were effective at 36 hours. The mRNA basal level of the SP precursor preprotachykinin expressed in DRG neurons was reduced only by nimesulide, while the increased levels expressed during treatment with the IS were significantly reduced by all drugs tested, with the exception of ibuprofen. All drugs were able to decrease basal and IS-stimulated PGE2 release. Our study demonstrates novel mechanisms of action of commonly used NSAIDS.Keywords: PKCε, nociceptors, analgesia, nimesulide, celecoxib, diclofenac, ibuprofen, dorsal root ganglia

Vittorio Vellani1, Silvia Franchi2, Massimiliano Prandini1, Sarah Moretti2, Giorgia Pavesi1, Chiara Giacomoni3, Paola Sacerdote21Dipartimento di Scienze Biomediche, Università di Modena e Reggio Emilia, Modena, Italy; 2Dipartimento di Farmacologia Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Italy; 3Dipartimento di Economia e Tecnologia, Università degli Studi della Repubblica di San Marino, Montegiardino, Repubblica di San MarinoAbstract: In this paper we describe new actions of nimesulide and paracetamol in cultured peripheral neurons isolated from rat dorsal root ganglia (DRG). Both drugs were able to decrease in a dose-dependent fashion the number of cultured DRG neurons showing translocation of protein kinase C epsilon (PKCε) caused by exposure to 1 µM bradykinin or 100 nM thrombin. In addition, the level of substance P (SP) released by DRG neurons and the level of preprotachykinin mRNA expression were measured in basal conditions and after 70 minutes or 36 hours of stimulation with nerve growth factor (NGF) or with an inflammatory soup containing bradykinin, thrombin, endothelin-1, and KCl. Nimesulide (10 µM) significantly decreased the mRNA levels of the SP precursor preprotachykinin in basal and in stimulated conditions, and decreased the amount of SP released in the medium during stimulation of neurons with NGF or with the inflammatory soup. The effects of paracetamol (10 µM) on such response was lower. Nimesulide completely inhibited the release of prostaglandin E2 (PGE2) from DRG neurons, either basal or induced by NGF and by inflammatory soup, while paracetamol decreased PGE2 release only partially. Our data demonstrate, for the first time, a direct effect of two drugs largely used as analgesics on DRG neurons. The present results suggest that PKCε might be a target for the effect of nimesulide and paracetamol, while inhibition of SP synthesis and release is clearly more relevant for nimesulide than for paracetamol mechanism of action.Keywords: nociceptors, analgesia, hyperalgesia, dorsal root ganglia, PKCε

All animals need to sense temperature to avoid hostile environments and to regulate their internal homeostasis. A particularly obvious example is that animals need to avoid damagingly hot stimuli. The mechanisms by which temperature is sensed have until recently been mysterious, but in the last couple of years, we have begun to understand how noxious thermal stimuli are detected by sensory neurons. Heat has been found to open a nonselective cation channel in primary sensory neurons, probably by a direct action. In a separate study, an ion channel gated by capsaicin, the active ingredient of chili peppers, was cloned from sensory neurons. This channel (vanilloid receptor subtype 1, VR1) is gated by heat in a manner similar to the native heat-activated channel, and our current best guess is that this channel is the molecular substrate for the detection of painful heat. Both the heat channel and VR1 are modulated in interesting ways. The response of the heat channel is potentiated by phosphorylation by protein kinase C, whereas VR1 is potentiated by externally applied protons. Protein kinase C is known to be activated by a variety of inflammatory mediators, including bradykinin, whereas extracellular acidification is characteristically produced by anoxia and inflammation. Both modulatory pathways are likely, therefore, to have important physiological correlates in terms of the enhanced pain (hyperalgesia) produced by tissue damage and inflammation. Future work should focus on establishing, in molecular terms, how a single ion channel can detect heat and how the detection threshold can be modulated by hyperalgesic stimuli.

Correction to: The EMBO Journal (2005) 24, 3026–3037. doi:10.1038/sj.emboj.7600784 [ABSTRACT FROM AUTHOR]

Abstract Protease-activated receptors (PAR1-4) are activated by proteases released by cell damage or blood clotting, and are known to be involved in promoting pain and hyperalgesia. Previous studies have shown that PAR2 receptors enhance activation of TRPV1 but the role of other PARs is less clear. In this paper we investigate the expression and function of the PAR1, 3 and 4 thrombin-activated receptors in sensory neurones. Immunocytochemistry and in situ hybridization show that PAR1 and PAR4 are expressed in 10 - 15% of neurons, distributed across all size classes. Thrombin or a specific PAR1 or PAR4 activating peptide (PAR1/4-AP) caused functional effects characteristic of activation of the PLCβ/PKC pathway: intracellular calcium release, sensitisation of TRPV1, and translocation of the epsilon isoform of PKC (PKCε) to the neuronal cell membrane. Sensitisation of TRPV1 was significantly reduced by PKC inhibitors. Neurons responding to thrombin or PAR1-AP were either small nociceptive neurones of the peptidergic subclass, or larger neurones which expressed markers for myelinated fibres. Sequential application of PAR1-AP and PAR4-AP showed that PAR4 is expressed in a subset of the PAR1-expressing neurons. Calcium responses to PAR2-AP were by contrast seen in a distinct population of small IB4+ nociceptive neurones. PAR3 appears to be non-functional in sensory neurones. In a skin-nerve preparation the release of the neuropeptide CGRP by heat was potentiated by PAR1-AP. Culture with nerve growth factor (NGF) increased the proportion of thrombin-responsive neurons in the IB4- population, while glial-derived neurotropic factor (GDNF) and neurturin upregulated the proportion of thrombin-responsive neurons in the IB4+ population. We conclude that PAR1 and PAR4 are functionally expressed in large myelinated fibre neurons, and are also expressed in small nociceptors of the peptidergic subclass, where they are able to potentiate TRPV1 activity.

Sessile benthic organisms can be affected by global changes and local pressures, such as metal pollution, that can lead to damages at different levels of biological organization. Effects of exposure to marine heatwaves (MHWs) alone and in combination with environmentally relevant concentration of copper (Cu) were evaluated in the reef-forming tubeworm Ficopomatus enigmaticus using a multi-biomarker approach. Biomarkers of cell membrane damage, enzymatic antioxidant defences, metabolic activity, neurotoxicity, and DNA integrity were analyzed. The exposure to Cu alone did not produce any significant effect. Exposure to MHWs alone produced effects only on metabolic activity (increase of glutathione S-transferase) and energy reserves (decrease in protein content). MHWs in combination with copper was the condition that most influenced the status of cell homeostasis of exposed F. enigmaticus. The combination of MHWs plus Cu exposure induced increase of protein carbonylation and glutathione S-transferase activity, decrease in protein/carbohydrate content and carboxylesterase activity. This study on a reef-forming organism highlighted the additive effect of a climate change-related stressor to metals pollution of marine and brackish waters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Misinformation can negatively impact people's lives in domains ranging from health to politics. An important research goal is to understand how misinformation spreads in order to curb it. Here, we test whether and how a single repetition of misinformation fuels its spread. Over two experiments (N = 260) participants indicated which statements they would like to share with other participants on social media. Half of the statements were repeated and half were new. The results reveal that participants were more likely to share statements they had previously been exposed to. Importantly, the relationship between repetition and sharing was mediated by perceived accuracy. That is, repetition of misinformation biased people's judgment of accuracy and as a result fuelled the spread of misinformation. The effect was observed in the domain of health (Exp 1) and general knowledge (Exp 2), suggesting it is not tied to a specific domain., (Copyright © 2023. Published by Elsevier B.V.)

The olfactory bulb (OB) is one of two regions of the mammalian brain which undergo continuous neuronal replacement during adulthood. A significant fraction of the cells added in adulthood to the bulbar circuitry is constituted by dopaminergic (DA) neurons. We took advantage of a peculiar property of dopaminergic neurons in transgenic mice expressing eGFP under the tyrosine hydroxylase (TH) promoter: while DA neurons located in the glomerular layer (GL) display full electrophysiological maturation, eGFP+ cells in the mitral layer (ML) show characteristics of immature cells. In addition, they also display a lower fluorescence intensity, possibly reflecting different degrees of maturation. To investigate whether this difference in maturation might be confirmed at the gene expression level, we used a fluorescence-activated cell sorting technique on enzymatically dissociated cells of the OB. The cells were divided into two groups based on their level of fluorescence, possibly corresponding to immature ML cells and fully mature DA neurons from the GL. Semiquantitative real-time PCR was performed to detect the level of expression of genes linked to the degree of maturation of DA neurons. We showed that indeed the cells expressing low eGFP fluorescence are immature neurons. Our method can be further used to explore the differences between these two groups of DA neurons.

Unidentified pathogenetic mechanisms and genetic and clinical heterogeneity represent critical factors hindering the development of treatments for inherited retinal dystrophies. Frameshift mutations in Cacna2d4 , which codes for an accessory subunit of voltage-gated calcium channels (VGCC), cause cone-rod dystrophy RCD4 in patients, but the underlying mechanisms remain unknown. To define its pathogenetic mechanisms, we investigated the impact of a Cacna2d4 frameshift mutation on the electrophysiological profile and calcium handling of mouse rod photoreceptors by patch-clamp recordings and calcium imaging, respectively. In mutant (MUT) rods, the dysregulation of calcium handling extends beyond the reduction in calcium entry through VGCC and surprisingly involves internal calcium stores' depletion and upregulation of calcium entry via non-selective cationic channels (CSC). The similar dependence of CSC on basal calcium levels in WT and MUT rods suggests that the primary defect in MUT rods lies in defective calcium stores. Calcium stores' depletion, leading to upregulated calcium and sodium influx via CSC, represents a novel and, so far, unsuspected consequence of the Cacna2d4 mutation. Blocking CSC may provide a novel strategy to counteract the well-known pathogenetic mechanisms involved in rod demise, such as the reticulum stress response and calcium and sodium overload due to store depletion.

Individual differences in behaviour, traits and mental-health are partially heritable. Traditionally, studies have focused on quantifying the heritability of high-order characteristics, such as happiness or education attainment. Here, we quantify the degree of heritability of lower-level mental processes that likely contribute to complex traits and behaviour. In particular, we quantify the degree of heritability of cognitive and affective factors that contribute to the generation of beliefs about risk, which drive behavior in domains ranging from finance to health. Monozygotic and dizygotic twin pairs completed a belief formation task. We first show that beliefs about risk are associated with vividness of imagination, affective evaluation and learning abilities. We then demonstrate that the genetic contribution to individual differences in these processes range between 13.5 and 39%, with affect evaluation showing a particular robust heritability component. These results provide clues to which mental factors may be driving the heritability component of beliefs formation, which in turn contribute to the heritability of complex traits., (© 2022. The Author(s).)

Seeking information when anxious may help reduce the aversive feeling of uncertainty and guide decision-making. If information is negative or confusing, however, this may increase anxiety further. Information gathered under anxiety can thus be beneficial and/or damaging. Here, we examine whether anxiety leads to a general increase in information-seeking, or rather to changes in the type of information and/or situations in which it is sought. In two controlled laboratory studies, we show that both trait anxiety and induced anxiety lead to a selective alteration in information-seeking. In particular, anxiety did not enhance the general tendency to seek information, nor did it alter the valence of the information gathered. Rather, anxiety amplified the tendency to seek information more in response to large changes in the environment. This was true even when the cause of the anxiety was not directly related to the information sought. As anxious individuals have been shown to have problems learning in changing environments, greater information-seeking in such environments may be an adaptive compensatory mechanism., (© 2022. The Author(s).)

The ability to experience, use and eventually control anger is crucial to maintain well-being and build healthy relationships. Despite its relevance, the neural mechanisms behind individual differences in experiencing and controlling anger are poorly understood. To elucidate these points, we employed an unsupervised machine learning approach based on independent component analysis to test the hypothesis that specific functional and structural networks are associated with individual differences in trait anger and anger control. Structural and functional resting state images of 71 subjects as well as their scores from the State-Trait Anger Expression Inventory entered the analyses. At a structural level, the concentration of grey matter in a network including ventromedial temporal areas, posterior cingulate, fusiform gyrus and cerebellum was associated with trait anger. The higher the concentration, the higher the proneness to experience anger in daily life due to the greater tendency to orient attention towards aversive events and interpret them with higher hostility. At a functional level, the activity of the default mode network (DMN) was associated with anger control. The higher the DMN temporal frequency, the stronger the exerted control over anger, thus extending previous evidence on the role of the DMN in regulating cognitive and emotional functions in the domain of anger. Taken together, these results show, for the first time, two specialized brain networks for encoding individual differences in trait anger and anger control., (© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Humans are motivated to seek information from their environment. How the brain motivates this behavior is unknown. One speculation is that the brain employs neuromodulatory systems implicated in primary reward-seeking, in particular dopamine, to instruct information-seeking. However, there has been no causal test for the role of dopamine in information-seeking. Here, we show that administration of a drug that enhances dopamine function (dihydroxy-L-phenylalanine; L-DOPA) reduces the impact of valence on information-seeking. Specifically, while participants under Placebo sought more information about potential gains than losses, under L-DOPA this difference was not observed. The results provide new insight into the neurobiology of information-seeking and generates the prediction that abnormal dopaminergic function (such as in Parkinson's disease) will result in valence-dependent changes to information-seeking., Competing Interests: VV, Ld, AG, TS No competing interests declared, (© 2020, Vellani et al.)

The amphibian Bv8 and the mammalian prokineticin 1 (PROK1) and 2 (PROK2) are new chemokine-like protein ligands acting on two G protein-coupled receptors, prokineticin receptor 1 (PKR1) and 2 (PKR2), participating to the mediation of diverse physiological and pathological processes. Prokineticins (PKs), specifically activating the prokineticin receptors (PKRs) located in several areas of the central and peripheral nervous system associated with pain, play a fundamental role in nociception. In this paper, to improve the understanding of the prokineticin system in the neurobiology of pain, we investigated the role of PKR2 in pain perception using pkr2 gene-deficient mice. We observed that, compared to wildtype, pkr2-null mice were more resistant to nociceptive sensitization to temperatures ranging from 46 to 48 °C, to capsaicin and to protons, highlighting a positive interaction between PKR2 and the non-selective cation channels TRPV1. Moreover, PKR2 knock-out mice showed reduced nociceptive response to cold temperature (4 °C) and to mustard oil-induced inflammatory hyperalgesia, suggesting a functional interaction between PKR2 and transient receptor potential ankyrin 1 ion (TRPA1) channels. This notion was supported by experiments in dorsal root ganglia (DRG) cultures from pkr1 and-pkr2-null mice, demonstrating that the percentage of Bv8-responsive DRG neurons which were also responsive to mustard oil was much higher in PKR1-/- than in PKR2-/- mice. Taken together, these findings suggest a functional interaction between PKR2 and TRP channels in the development of hyperalgesia. Drugs able to directly or indirectly block these targets and/or their interactions may represent potential analgesics., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: CR4056 is a first-in-class imidazoline-2 (I 2 ) receptor ligand characterized by potent analgesic activity in different experimental animal models of pain. In a recent phase II clinical trial, CR4056 effectively reduced pain in patients with knee osteoarthritis. In the present study, we investigated the effects of CR4056 on PKCε translocation in vitro and on PKCε activation in vivo in dorsal root ganglia (DRG) neurons., Experimental Approach: Effects of CR4056 on bradykinin-induced PKCε translocation were studied in rat sensory neurons by immunocytochemistry. PKCε activation was investigated by immunohistochemistry analysis of DRG from complete Freund's adjuvant-treated animals developing local hyperalgesia. The analgesic activity of CR4056 was tested on the same animals., Key Results: CR4056 inhibited PKCε translocation with very rapid and long-lasting activity. CR4056 decreased hyperalgesia and phospho-PKCε immunoreactivity in the DRG neurons innervating the inflamed paw. The effect of CR4056 on PKCε translocation was blocked by pertussis toxin, implying that the intracellular pathways involved G i proteins. The inhibition of PKCε translocation by CR4056 was independent of the α 2 -adrenoeceptor and, surprisingly, was also independent of idazoxan-sensitive I 2 binding sites. The I 2 agonist 2BFI had no effect alone but potentiated the activity of low concentrations of CR4056., Conclusions and Implications: Our results demonstrate that CR4056 shares the ability to inhibit PKCε translocation with other analgesics. Whether the inhibition of PKCε involves binding to specific subtype(s) of I 2 receptors should be further investigated. If so, this would be a new mode of action of a highly specific I 2 receptor ligand., (© 2019 The British Pharmacological Society.)

Background: Carotid sinus syndrome accounts for one third of patients who presents with unexplained syncope. Prevalence of carotid sinus hypersensitivity (CSH) in Indians has not been studied till now., Objectives: To assess the prevalence and associations of CSH in symptomatic patients above 50 years and to study its prognostic significance pertaining to sudden cardiac death, syncope, recurrent pre syncope and falls on 1 year follow up., Methods: Patients above 50 years who presented with unexplained syncope, recurrent syncope or falls were considered cases and those without these symptoms were considered as controls. All the patients underwent carotid sinus massage and their responses noted. All symptomatic patients were followed up and observed for events like sudden cardiac death, syncope, recurrent pre syncope and falls during 1 year follow up. Patients with recurrent syncope and predominant cardioinhibitory syncope were advised permanent pacemaker implantation., Results: A total of 252 patients were screened, 130 patients constituted cases and 49 patients constituted controls. CSH was demonstrable in 32% (n = 42) of cases as compared to 8% (n = 4) in controls (p < 0.001). Cardioinhibitory response was the predominant response (88%, n = 38) followed by mixed response (12%, n = 4). CSH was associated with advancing age, male gender (93%, n = 39, p < 0.001) and history of smoking (63%, n = 27, p = 0.009). Composite outcomes of sudden cardiac death, syncope, recurrent pre syncope and falls were significantly higher in patients with symptomatic CSH than in those without it (45%, n = 16 vs. 6.8%, n = 6; p < 0.001)., Conclusions: In conclusion, the prevalence of CSH in patients above 50 yrs with unexplained syncope was high in our population. Patients with CSH and baseline symptoms developed recurrent syncope during follow up. Carotid sinus massage should be a part of routine examination protocol for unexplained syncope., (Copyright © 2019 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Gabapentin is a well-established anticonvulsant drug which is also effective for the treatment of neuropathic pain. Although the exact mechanism leading to relief of allodynia and hyperalgesia caused by neuropathy is not known, the blocking effect of gabapentin on voltage-dependent calcium channels has been proposed to be involved. In order to further evaluate its analgesic mechanisms, we tested the efficacy of gabapentin on protein kinase C epsilon (PKC ε ) translocation in cultured peripheral neurons isolated from rat dorsal root ganglia (DRGs). We found that gabapentin significantly reduced PKC ε translocation induced by the pronociceptive peptides bradykinin and prokineticin 2, involved in both inflammatory and chronic pain. We recently showed that paracetamol (acetaminophen), a very commonly used analgesic drug, also produces inhibition of PKC ε . We tested the effect of the combined use of paracetamol and gabapentin, and we found that the inhibition of translocation adds up. Our study provides a novel mechanism of action for gabapentin in sensory neurons and suggests a mechanism of action for the combined use of paracetamol and gabapentin, which has recently been shown to be effective, with a cumulative behavior, in the control of postoperative pain in human patients., Competing Interests: The authors report no competing interests in this work.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat migraine, but the mechanisms of their effects in this pathology are not fully elucidated. The trigeminal ganglia and calcitonin gene-related peptide (CGRP) have been implicated in the pathophysiology of migraine. The release of CGRP and prostaglandin E 2 (PGE 2 ) from freshly isolated rat trigeminal ganglia was evaluated after oral administration of nimesulide, etoricoxib, and ketoprofen, NSAIDs with different pharmacological features. Thirty minutes after oral administration, nimesulide, 10 mg/Kg, decreased the GCRP release induced by an inflammatory soup, while the other NSAIDs were ineffective at this point in time. Two hours after oral nimesulide (5 and 10 mg/Kg) and ketoprofen (10 mg/Kg), but not of etoricoxib, a significant decrease in the CGRP release was observed. All drugs reduced PGE 2 , although with some differences in timing and doses, and the action on CGRP does not seem to be related to PGE 2 inhibition. The reduction of CGRP release from rat trigeminal ganglia after nimesulide and ketoprofen may help to explain the mechanism of action of NSAIDs in migraine. Since at 30 minutes only nimesulide was effective in reducing CGRP release, these results suggest that this NSAID may exert a particularly rapid effect in patients with migraine.

Aim: Mitral stenosis (MS) is found to produce left ventricular (LV) dysfunction in some studies. We sought to study the left ventricular function in patients with rheumatic MS undergoing balloon mitral valvotomy (BMV). Ours is the first study to analyze effect of BMV on mitral annular plane systolic excursion (MAPSE), and to quantify prevalence of longitudinal left ventricular dysfunction in rheumatic MS., Methods: In this prospective cohort study, we included 43 patients with severe rheumatic mitral stenosis undergoing BMV. They were compared to twenty controls whose distribution of age and gender were similar to that of patients. The parameters compared were LV ejection fraction (EF) by modified Simpson's method, mitral annular systolic velocity (MASV), MAPSE, mitral annular early diastolic velocity (E'), and myocardial performance index (MPI). These parameters were reassessed immediately following BMV and after 3 months of procedure., Results: MASV, MAPSE, E', and EF were significantly lower and MPI was higher in mitral stenosis group compared to controls. Impaired longitudinal LV function was present in 77% of study group. MAPSE and EF did not show significant change after BMV while MPI, MASV, and E' improved significantly. MASV and E' showed improvement immediately after BMV, while MPI decreased only at 3 months follow-up., Conclusions: There were significantly lower mitral annular motion parameters including MAPSE in patients with rheumatic mitral stenosis. Those with atrial fibrillation had higher MPI. Immediately after BMV, there was improvement in LV long axis function with a gradual improvement in global LV function. There was no significant change of MAPSE after BMV., (Copyright © 2015 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Background: Beta-blockers are frequently used in patients with mitral stenosis to control the heart rate and alleviate exercise-related symptoms. The objective of our study was to examine whether ivabradine was superior to atenolol for achieving higher exercise capacity in patients with moderate mitral stenosis in sinus rhythm. We also evaluated their effects on left ventricular myocardial performance index (MPI)., Methods and Results: Eighty-two patients with moderate mitral stenosis in sinus rhythm were randomized to receive ivabradine (n=42) 5mg twice daily or atenolol (n=40) 50mg daily for 6 weeks. Transthoracic echocardiography and treadmill test were performed at baseline and after completion of 6 weeks of treatment. Mean total exercise duration in seconds markedly improved in both study groups at 6 weeks (298.57±99.05s vs. 349.12±103.53s; p=0.0001 in ivabradine group, 290.90±92.42s vs. 339.90±99.84s; p=0.0001 in atenolol group). On head-to-head comparison, there was no significant change in improvement of exercise time between ivabradine and atenolol group (p=0.847). Left ventricular MPI did not show any significant change from baseline and at 6 weeks in both drug groups (49.8%±8% vs. 48.3%±7% in ivabradine group, 52.9%±10% vs. 50.9%±10% in atenolol groups; p=0.602)., Conclusion: Ivabradine or atenolol can be used for heart rate control in patients with moderate mitral stenosis in sinus rhythm. Ivabradine is not superior to atenolol for controlling heart rate or exercise capacity. Left ventricular MPI was unaffected by either of the drugs., (Copyright © 2015 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Background: Obese patients with established coronary artery disease have reduced mortality compared to normal or low body mass index (BMI) patients. The reason for the relation is not yet clearly understood. We sought to evaluate the association of BMI and waist circumference (WC) at the time of presentation in patients with myocardial infarction (MI) with one-year adverse cardiac events., Methods: In this prospective cohort study, we included consecutive patients with acute MI admitted to a tertiary care hospital during a period of one year. Upon admission, BMI and WC were measured. Patients were followed-up for a period of one year and the primary composite outcome of death or non-fatal MI was correlated with BMI and WC categories., Results: There were 703 patients (males 559 (79.5%)). Combined non-fatal MI and death at one year was 128 (18.2%). Incidence of primary outcome was 25.0% in low BMI group, 19.9% in normal BMI group, 13.1% in overweight group, 13.4% in class I obese, and 11.1% in class II obese groups. In univariate analysis, the inverse correlation was significant (p value=0.007). In one-year follow-up period, 12.8% in high and 20.8% in normal WC groups had primary outcome (p value=0.01). Both BMI and WC lost their predictive value in multivariate analysis., Conclusions: Low BMI and normal WC were associated with a worse short-term outcome in patients with acute MI. Neither BMI nor WC independently predicted cardiac events or death after acute MI., (Copyright © 2016. Published by Elsevier B.V.)

A previously asymptomatic 53-year-old male presented 5 days after an acute anterior wall myocardial infarction, who was fibrinolytic naïve, with worsening dyspnea. Transthoracic echocardiographic evaluation revealed rupture of the interventricular septum and pseudoaneurysm of the left ventricle, confirmed by angiography. Coronary angiogram revealed multivessel disease. The patient underwent successful closure of ventricular septal rupture with repair of pseudoaneurysm and saphenous vein grafts to posterior descending branch of right coronary artery and obtuse marginal branch of left circumflex artery. Double ventricular ruptures following acute myocardial infarction are very rare with a reported incidence of 0.3% from various series in the revascularization era. They are also associated with exceedingly high mortality rates reaching up to 50%, even when intervened emergently., (Copyright © 2015 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Pulmonary arteriovenous malformations (AVM) are very rare and carry the risk of cerebral thrombo-embolism, brain abscess or pulmonary hemorrhage. The Amplatzer vascular plug II (AVP II) is a new device, used for embolization of the pulmonary AVMs. We report a case of pulmonary AVM successfully managed by using AVP II in a patient with hereditary hemorrhagic telangiectasia (HHT)., (Copyright © 2015. Published by Elsevier B.V.)

Photoreceptors of nocturnal geckoes are scotopic, with rod-shaped outer segments, and sensitivities to light similar to the one of retinal rods from other species of lower vertebrates. However, these cells are not rods, but they originated from cones of ancestral diurnal geckoes with pure-cone retinas, after being forced to adapt to a nocturnal behavior. Several interesting adaptations of these rod-like cones have been studied to date; molecular biology and functional studies confirmed that several proteins of the phototransductive cascade display structural and functional properties that indicate their origin from cones rather than from rods. In this paper, we investigate, with whole cell voltage clamp in the photoreceptor detached outer segment preparation, the voltage rectification properties of cGMP-gated channels in three species, Gekko gecko, Tarentola mauritanica, and Hemidactylus frenatus. We show that the current-voltage properties in the physiological voltage range are reminiscent of the ones of cGMP-gated channels from cones rather than from rods of other cold-blooded vertebrates. The origin and the relevance of the mechanisms investigated are discussed.

Background: Presence of right ventricular (RV) infarction imposes a higher risk of adverse events in inferior wall myocardial infarction (IWMI). In this study, we attempted to correlate various indices of RV function assessed by echocardiography with presence of a proximal right coronary artery (RCA) stenosis in patients with first episode of acute IWMI., Methods: In a prospective study, patients with first episode of acute IWMI underwent echocardiographic assessment within 24 h of symptom onset and indices of RV function viz. RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), myocardial performance index (MPI) and tissue Doppler velocities from RV free wall were measured. Patients who underwent coronary angiogram (CAG) within one month and they were classified into group 1 and group 2 based on the presence or absence, respectively, of a significant proximal RCA stenosis., Results: There were 90 patients with first episode of IWMI of which 67 patients underwent CAG. There was significant difference between group 1 (n = 26) and group 2 (n = 41) in TAPSE (13.5 ± 1.3 vs 21.3 ± 1.7, p < 0.001), MPI by tissue Doppler (0.87 ± 0.1 vs 0.55 ± 0.2, p < 0.001) and in tissue Doppler systolic velocity from RV free wall (S' 9.8 ± 1.1 vs 15.0 ± 1.5, p < 0.001). There was a good interobserver correlation for TAPSE, MPI by TDI, and S' velocity. TAPSE ≤ 16 (sensitivity 93%, specificity 100%), MPI-TDI ≥ 0.69 (sensitivity 94.7%, specificity 93.5%), S ≤ 12.3 (sensitivity 90.3%, specificity 94.3%) were useful in predicting presence of proximal RCA stenosis., Conclusion: RV function indices like TAPSE, MPI-TDI and S' velocity are useful in predicting proximal RCA stenosis in first episode of acute IWMI., (Copyright © 2013 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Objective: Dysfunction of the coronary microcirculation is considered as one of the factors responsible for symptoms and abnormal stress tests in patients with angina and normal coronaries (syndrome X). We sought to evaluate the usefulness of coronary sinus filling time (CSFT) to assess coronary microcirculation in this group of patients., Methods: We compared the CSFT of patients having definite angina or atypical angina with positive treadmill electrocardiography test (angina group), with that of patients undergoing coronary angiogram (CAG) prior to balloon mitral valvuloplasty (control group). During CAG, coronary sinus was visualized in appropriate views and CSFT in seconds was derived from frame count. Thrombolysis In Myocardial Infarction (TIMI) flow grade, corrected TIMI (cTIMI) frame count, TIMI Myocardial Perfusion grade (TMP) were assessed., Results: There were 41 patients in angina group and 16 in control group. Among the angina group 68.8% were females as against 81.8% in the control group. 87.8% (n = 36) had typical angina. Mean CSFT was 4.25 ± 0.72 s and 3.46 ± 0.99 s in the angina group and control group respectively (p = 0.001). No significant differences were found between the groups with respect to TMP (p = 0.68) & cTIMI frame count (p = 0.22)., Conclusion: CSFT is a simple method to assess the transit time through coronary microcirculation. CSFT was significantly delayed in patients with angina and normal coronaries. TMP and cTIMI frame count were not significantly different between groups., (Copyright © 2013 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Activation of endothelin receptors expressed in DRG neurons is functionally coupled to translocation of PKCε from cytoplasm to the plasma membrane. Using immunocytochemistry we show that in DRG cultured neurons PKCε translocation induced by endothelin-1 was prominently seen in a peptidergic subpopulation of cultured DRG neurons largely negative for isolectin B4 staining, indicating that in basal conditions functional expression of endothelin receptors does not occur in non-peptidergic, RET-expressing nociceptors. Translocation was blocked by the specific ETA-R antagonist BQ-123 while it was unaffected by the ETB-R antagonist BQ-788. No calcium response in response to endothelin-1 was observed in sensory neurons, while large and long-lasting responses were observed in the majority of non-neuronal cells present in DRG cultures, which are ensheathing Schwann cells and satellite cells, identified with the glial marker S-100. Calcium responses in non-neuronal cells were abolished by BQ-788. The fraction of peptidergic PKCε-translocated neurons was significantly increased by nerve growth factor, while in the presence of neurturin or glia-derived neurotropic factor (GDNF), an IB4-positive subpopulation of small- and medium-sized neurons showed PKCε translocation induced by endothelin-1 which could be blocked by BQ-123 but not by BQ-788. Our in vitro results show that the level of expression of functional endothelin receptors coupled to PKCε is different in peptidergic and non-peptidergic nociceptors and is modulated with different mechanisms in distinct neuronal subpopulations., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Protease-activated receptors (PAR1-4) are activated by proteases released by cell damage or blood clotting, and are known to be involved in promoting pain and hyperalgesia. Previous studies have shown that PAR2 receptors enhance activation of TRPV1 but the role of other PARs is less clear. In this paper we investigate the expression and function of the PAR1, 3 and 4 thrombin-activated receptors in sensory neurones. Immunocytochemistry and in situ hybridization show that PAR1 and PAR4 are expressed in 10 - 15% of neurons, distributed across all size classes. Thrombin or a specific PAR1 or PAR4 activating peptide (PAR1/4-AP) caused functional effects characteristic of activation of the PLCβ/PKC pathway: intracellular calcium release, sensitisation of TRPV1, and translocation of the epsilon isoform of PKC (PKCε) to the neuronal cell membrane. Sensitisation of TRPV1 was significantly reduced by PKC inhibitors. Neurons responding to thrombin or PAR1-AP were either small nociceptive neurones of the peptidergic subclass, or larger neurones which expressed markers for myelinated fibres. Sequential application of PAR1-AP and PAR4-AP showed that PAR4 is expressed in a subset of the PAR1-expressing neurons. Calcium responses to PAR2-AP were by contrast seen in a distinct population of small IB4+ nociceptive neurones. PAR3 appears to be non-functional in sensory neurones. In a skin-nerve preparation the release of the neuropeptide CGRP by heat was potentiated by PAR1-AP. Culture with nerve growth factor (NGF) increased the proportion of thrombin-responsive neurons in the IB4- population, while glial-derived neurotropic factor (GDNF) and neurturin upregulated the proportion of thrombin-responsive neurons in the IB4+ population. We conclude that PAR1 and PAR4 are functionally expressed in large myelinated fibre neurons, and are also expressed in small nociceptors of the peptidergic subclass, where they are able to potentiate TRPV1 activity.

N-arachidonoylethanolamine (anandamide, AEA), is a full agonist at both cannabinoid CB(1) receptors and "transient receptor potential vanilloid" type 1 (TRPV1) channels, and N-palmitoylethanolamine (PEA) potentiates these effects. In neurons of the rat dorsal root ganglia (DRG), TRPV1 is activated and/or sensitised by AEA as well as upon activation of protein kinases C (PKC) and A (PKA). We investigated here the effect on AEA levels of PKC and PKA activators in DRG neurons. AEA levels were significantly enhanced by both phorbol-miristoyl-acetate (PMA), a typical PKC activator, and forskolin (FSK), an adenylate cyclase stimulant, as well as by thrombin, which also activates PKC by stimulating protease-activated receptors (PARs). The levels of the other endocannabinoid and TRPV1-inactive compound, 2-arachidonoylglycerol (2-AG), were enhanced only by thrombin and to a lesser extent than AEA, whereas PEA was not affected by any of the treatments. Importantly, FSK- and PMA-induced elevation of AEA levels was not sensitive to intracellular Ca2+ chelation with BAPTA-acetoxymethyl (AM) ester. In human embryonic kidney (HEK-293) cells, which constitutively express PARs, thrombin, PMA and FSK elevated AEA levels, and the effects of the two former compounds were counteracted by the PKC inhibitor, RO318220, whereas the effect of FSK was reduced by the PKA inhibitor RpcAMPs. In conclusion, we report that AEA levels are stimulated by both PKC, either directly or after thrombin receptor activation, and PKA, possibly in a way independent from intracellular calcium. Since AEA activates TRPV1, these findings may suggest the existence of an amplificatory cascades on this receptor in sensory neurons.