Antisense-induced downregulation of major circadian genes modulates the expression of histone deacetylase-2 (HDAC-2) and CREB-binding protein (CBP) in the medial shell region of nucleus accumbens of mice exposed to chronic excessive alcohol consumption.

Circadian genes in the medial accumbal shell (mNAcSh) region regulate binge alcohol consumption. Here, we investigated if antisense-induced knockdown of major circadian genes (Per1, Per2, and NPAS2) in the mNAcSh of mice exposed to intermittent access two-bottle choice (IA2BC) paradigm modulates the expression of histone deacetylase-2 (HDAC-2) and CREB-binding protein (CBP), key epigenetic modifiers associated with withdrawal-associated behaviors such as anxiety. Adult male C57BL/6J mice (N = 28), surgically implanted with bilateral guide cannulas above the mNAcSh, were chronically (4 weeks) exposed to alcohol (20% v/v) or saccharin (0.03%) via IA2BC paradigm. In the fourth week, a mixture of antisense (AS-ODNs; N = 14/group) or nonsense (NS-ODNs; N = 14/group) oligodeoxynucleotides against circadian genes were bilaterally infused into the mNAcSh. Subsequently, alcohol/saccharin consumption and preference were measured followed by euthanization of animals and verification of microinjection sites by visual inspection and the expression of HDAC-2 and CBP by using RT-PCR along with the verification of antisense-induced downregulation of circadian genes in the mNAcSh. As compared with NS-ODNs, AS-ODNs infusion significantly attenuated the alcohol-induced increase in HDAC-2 and reduction in CBP expression in the mNAcSh along with a significant reduction in alcohol consumption and preference. No significant effect was observed on either saccharin consumption or preference. Our results suggest that circadian genes in the mNAcSh may have a causal to play in mediating epigenetic changes observed after chronic alcohol consumption.

Activation of dopamine D2 receptors in the medial shell region of the nucleus accumbens increases Per1 expression to enhance alcohol consumption.

Circadian genes, including Per1, in the medial shell region of nucleus accumbens (mNAcSh), regulate binge alcohol consumption. However, the upstream mechanism regulating circadian genes-induced alcohol consumption is not known. Since activation of dopamine D2 receptors (D2R) increases Per1 gene expression, we hypothesised that local infusion of quinpirole, a D2R agonist, by increasing Per1 gene expression in the mNAcSh, will increase binge alcohol consumption in mice. We performed two experiments on male C57BL/6J mice, instrumented with bilateral guide cannulas above the mNAcSh, and exposed to a 4-day drinking-in-dark (DID) paradigm. The first experiment determined the effects of bilateral infusion of quinpirole (100 ng/300 nl/site) or DMSO (Vehicle group) in the mNAcSh on Per1 gene expression and alcohol consumption. The second experiment determined the effect of antisense-induced downregulation of Per1 in the mNAcSh on the quinpirole-induced increase in alcohol consumption. Control experiments were performed by exposing the animals to sucrose (10% w/v). After the experiment, animals were euthanised, brains removed and processed for localisation of injection sites and analysis of Per1 gene expression in the mNAcSh. As compared with the DMSO, local bilateral infusion of quinpirole significantly increased the expression of Per1 in the mNAcSh along with an increase in the amount of alcohol consumed in mice exposed to DID paradigm. In addition, local antisense-induced downregulation of Per1 significantly attenuated the effects of intro-accumbal infusion of quinpirole on alcohol consumption. Our results suggest that Per1 in the mNAcSh mediates D2R activation-induced increase in alcohol consumption.

Mitral valve paravalvular leaks: Comprehensive review of literature.

BACKGROUND: Mitral paravalvular leaks (mPVL) are a recognized complication for patients with mitral valve prostheses. Although clinically insignificant for many patients, it may pose life-threatening haemolysis and regurgitation-induced heart failure, and so clinicians should have a high index of suspicion in the presence of new symptoms. AIMS: This review discusses the pathogenesis, clinical features, diagnosis, imaging and treatment of mPVLs. METHODS: A comprehensive literature search was performed using PubMed, EMBASE, Cochrane database, Google Scholar and Ovid. Search terms used included "mitral valve paravalvular leak," "transthoracic echocardiography," "2D transoesophageal echocardiography," "3D transoesophageal echocardiography," "cardiac computed tomography," (CT) "cardiac magnetic resonance imaging," "intracardiac echocardiography," "cinefluoroscopy," "fluoroscopy," and "percutaneous closure." RESULTS: All patients with mPVLs should undergo regular full evaluation, including patient history, physical examination, laboratory work-up, imaging, and referral, if necessary. Echocardiography is fundamental to the diagnosis, and is augmented with cardiac magnetic resonance imaging, cardiac computerized tomography and fluoroscopy for further characterization and procedural planning amongst the structural heart team. CONCLUSION: The prevalence of mPVL is expected to increase proportionally to the growing number of surgical and transcatheter valve replacements conducted in the ageing population. Multimodal imaging is instrumental in guiding diagnostic and therapeutic strategies when managing mPVLs. Advances in imaging and capabilities of transcather devices will prompt growing uptake of percutaneous treatment over conventional, higher-risk surgery for mPVL management.

Antisense-induced knockdown of cAMP response element-binding protein downregulates Per1 gene expression in the shell region of nucleus accumbens resulting in reduced alcohol consumption in mice.

INTRODUCTION: We recently showed that circadian genes expressed in the shell region of nucleus accumbens (NAcSh) play a key role in alcohol consumption, though, the molecular mechanism of those effects is unclear. Because CREB-binding protein (CBP) promotes Per1 gene expression, we hypothesized that alcohol consumption would increase CBP expression in the NAcSh and antisense-induced knockdown of CBP would reduce Per1 expression and result in a reduction in alcohol consumption. METHODS: To test our hypothesis, we performed two experiments. The Drinking-in-the-dark (DID) paradigm was used to evaluate alcohol consumption in male C57BL/6J mice. In Experiment 1 we examined the effects of alcohol consumption on CBP gene expression in the NAcSh. Control animals were exposed to, sucrose [10% (w/v) taste and calorie] and water (consummatory behavior). In Experiment 2 examined the effects of CBP gene silencing on the expression of the Per1 gene in the NAcSh and alcohol consumption in mice exposed to alcohol using the DID paradigm. CBP gene silencing was achieved by local infusion of two doses of either CBP antisense oligodeoxynucleotides (AS-ODNs; Antisense group) or nonsense ODNs (NS-ODNs; Nonsense group) bilaterally microinjected into the NAcSh within 24 h before alcohol consumption on Day 4 of the DID paradigm. The microinfusion sites were verified by cresyl violet staining. RESULTS: Compared to sucrose, alcohol consumption, under the DID paradigm, significantly increased the expression of CBP in the NAcSh. Compared to Controls, bilateral infusion of CBP AS-ODNs significantly reduced the expression of Per1 in the NAcSh and alcohol consumption without affecting the amount of sucrose consumed. CONCLUSIONS: Our results suggest that CBP is an upstream regulator of Per1 expression in the NAcSh and may act via Per1 to modulate alcohol consumption.

Sudden cardiac death in children with congenital heart disease: a critical review of the literature.

Sudden cardiac death is an uncommon but yet catastrophic event, which can occur in neonates and young children. Although extensive research has been carried out assessing the underlying causes, there still remains a degree of uncertainty around this area. Congenital heart disease (CHD) is one known cause of sudden cardiac death in children, the aetiology of which embraces virally induced mechanisms, genetic susceptibility, drug-induced, and maternal factors. Screening tools and investigations including electrocardiograms and echocardiograms alongside a concise history taking and physical examination can be used to identify the potential cardiovascular risk factors of sudden death. This review has comprehensively studied the causes and risk factors for sudden cardiac death in children with CHD and provides a collation and summary of the evidence available so far underpinning the complex link between the two. Moreover, current screening and prevention methods are discussed in detail in order to increase awareness and understanding of how we can improve patient outcomes.

Cytoprotective and Anti-secretory Effects of Azadiradione Isolated from the Seeds of Azadirachta indica (neem) on Gastric Ulcers in Rat Models.

Azadirachta indica is well known medicinal plant mentioned in ancient herbal texts. It has been extensively used in Ayurvedic, Unani and Homoeopathic medicine and has become a luminary of modern medicine. As part of our drug discovery program we isolated azadiradione from the ethanolic extract of seeds of A. indica and evaluated for in-vivo antiulcer activity in cold restraint induced gastric ulcer model, aspirin induced gastric ulcer model, alcohol induced gastric ulcers model and pyloric ligation induced ulcer model. Azadiradione exhibited potent antiulcer activity through the inhibition of H+ K+-ATPase (proton pump) activity via its cytoprotective effect and also via its antisecretory effect. This combined effect has valuable potential in the future treatment of peptic ulceration.

Viral Hepatitis in Pregnancy--A study of its Effect on Maternal and Foetal Outcome.

BACKGROUND AND AIMS: The outcome of Hepatitis during pregnancy has been observed to be widely different by various authors, ranging from the benign to fatal. A poor outcome has increasingly been observed in pregnant women suffering from Hepatitis in Central India. Hence, this study was undertaken to study the incidence, causative organisms and chief prognostic factors affecting the outcome of viral hepatitis in pregnant women. METHODS: Sixty-eight pregnant women reporting to the hospital with jaundice were enrolled as cases and their Haematological, Biochemical and Viral profiles were studied. Sixteen non- pregnant women were enrolled as controls and a similar workup was done. A comparison was done between the two groups We also divided the cases into two groups--survivors and non- survivors and tried to find out the factors predicting mortality. The unpaired student t test and chi square test were used to find out whether the differences were statistically significant. RESULTS: Viral Hepatitis in pregnancy caused a very high maternal mortality (19.1%) and foetal wastage (42.6%). Hepatitis E virus was the commonest causative organism (77.9%) responsible for viral hepatitis during pregnancy. It also caused the highest maternal mortality due to fulminant hepatic failure. Maternal mortality was significantly higher in those women presenting with features of encephalopathy, SIRS, high bilirubin levels and prolonged prothrombin time. Vertical transmission was noted in Hepatitis B and E. CONCLUSIONS: Hepatitis E is the chief causative organism causing fulminant hepatic failure in pregnant women in Central India. It lead to very high rates of maternal mortality and foetal wastage.

Saroglitazar Enhances Memory Functions and Adult Neurogenesis via Up-Regulation of Wnt/ß Catenin Signaling in the Rat Model of Dementia.

Peroxisome proliferator-activated receptors (PPARs) have emerged as a promising target for the treatment of various neurodegenerative disorders. Studies have shown that both PPAR α & γ individually modulate various pathophysiological events like neuroinflammation and insulin resistance, which are known to variedly affect neurogenesis. Our study aimed to evaluate the effect of saroglitazar (SGZR), a dual PPAR agonist, on adult neurogenesis and spatial learning and memory, in intracerebroventricular streptozotocin (ICV STZ)-induced dementia in rats. We have found that SGZR at the dose of 4 mg/kg per oral showed significant improvement in learning and memory compared to ICV STZ-treated rats. A substantial increase in neurogenesis was observed in the subventricular zone (SVZ) and the dentate gyrus (DG), as indicated by an increase in the number of 5-bromo-2'-deoxyuridine (BrdU)+ cells, BrdU+ nestin+ cells, and doublecortin (DCX)+cells. Treatment with SGZR also decreased the active form of glycogen synthase kinase 3ß (GSK3ß) and hence enhanced the nuclear translocation of the ß-catenin. Enhanced expression of Wnt transcription factors and target genes indicates that the up-regulation of Wnt signaling might be involved in the observed increase in neurogenesis. Hence, it can be concluded that the SGZR enhances memory functions and adult neurogenesis via the upregulation of Wnt ß-catenin signaling in ICV STZ-treated rats.

Irradiated fuel salt data library for a molten salt reactor produced with Serpent2 and SOURCES 4C codes.

This paper describes the creation and description of a nuclear fuel isotopics dataset for irradiated fuel salt from a Molten Salt Reactor (MSR). The dataset has been created using simulations carried out using the Monte-Carlo particle transport code, Serpent 2.1.32 (released February 24, 2021) and the calculation code SOURCES 4C (released October 09, 2002) for computing properties of irradiated molten fuel salt. The dataset comprises isotopic mass densities of 1362 isotopes (including fission products and major and minor actinides) and their corresponding contributions to decay heat, gamma activity, and spontaneous fission rates computed by Serpent 2.1.32 as well as overall neutron emission rates from spontaneous fission and (ɑ, n) reactions computed by SOURCES 4C. These quantities are computed for a model MSR core utilizing a full-core 3D model of the Seaborg Compact Molten Salt Reactor (CMSR). The dataset spans a wide range of values of burnup (BU), initial enrichment (IE) and cooling time (CT) over which the above-mentioned quantities are reported. The structure of the dataset includes isotopic mass densities (in g/cm3), followed by isotope-wise contributions to decay heat (denoted by suffix '_DH' and reported in Watts), gamma photon emission rates (denoted by suffix '_GS' and reported photons per second), and spontaneous fission rates (denoted by suffix '_SF' and reported in fissions per second). In addition to these columns, the data also includes total neutron emission rates from 1) spontaneous fission (denoted by 'SF' and reported in neutrons per second per cm3), and 2) (ɑ, n) reactions (denoted by 'AN' and reported in neutrons per second per cm3). In total, the dataset has 310,575 rows of different combinations of fuel burnup, initial enrichment, and cooling time (BIC) values spanning the realistic possible range of these parameters. The dataset is made available for public use in a comma-separated value file that can be easily read using one of the numerous popular data analysis tools such as NumPy or Pandas.