Surgery

Diabetes and stress stimulate hippocampal 5-HT synthesis, metabolism and release. The present study was carried out to find the effects of insulin, Aegle marmelose alone and in combination with pyridoxine on the hippocampal 5-HT, 5-HT 2A receptor subtype, gene expression studies on 5-HT 2A , 5-HTT, INSR, immunohistochemical studies and elevated plus maze in streptozotocin induced diabetic rats. 5-HT content showed a significant decrease (p < 0.001) and a significant increase (p < 0.001) in 5-HIAA in hippocampus of diabetic rats compared to control. 5-HT receptor binding parameters B max and K d showed a significant decrease (p < 0.001) whereas 5-HT 2A receptor binding parameters B max showed a significant decrease (p < 0.001) with a significant increase (p < 0.05) in K d in hippocampus of diabetic rats compared to control. Gene expression studies of 5-HT 2A, 5-HTT and INSR in hippocampus showed a significant down regulation (p < 0.001) in diabetic rats compared to control. Pyridoxine treated in combination with insulin and A. marmelose to diabetic rats reversed the 5-HT content, B max , K d of 5-HT, 5-HT 2A and gene expression of 5-HT 2A , 5-HTT and INSR in hippocampus to near control. The gene expression of 5-HT 2A and 5-HTT were confirmed by immunohistochemical studies. Behavioural studies using elevated plus maze showed that serotonin through its transporter significantly increased (p < 0.001) anxiety-related traits in diabetic rats which were corrected by combination therapy. Our results suggest that pyridoxine treated in combination with insulin and A. marmelose has a role in the regulation of insulin synthesis and release, normalising diabetic related stress and anxiety through hippocampal serotonergic function. This has clinical significance in the management of diabetes.

In the present study, the effects of Bacopa monnieri and its active component, bacoside A, on motor deficit and alterations of GABA receptor functional regulation in the cerebellum of epileptic rats were investigated. Scatchard analysis of [ 3 H]GABA and [ 3 H]bicuculline in the cerebellum of epileptic rats revealed a significant decrease in B max compared with control. Real-time polymerase chain reaction amplification of GABA A receptor subunits-GABA A1 , GABA A5, and GABA Ad -was downregulated (P < 0.001) in the cerebellum of epileptic rats compared with control rats. Epileptic rats exhibit deficits in radial arm and Ymaze performance. Treatment with B. monnieri and bacoside A reversed these changes to near-control levels. Our results suggest that changes in GABAergic activity, motor learning, and memory deficit are induced by the occurrence of repetitive seizures. Treatment with B. monnieri and bacoside A prevents the occurrence of seizures thereby reducing the impairment of GABAergic activity, motor learning, and memory deficit.

Membrane depolarization of smooth muscle cells (myocytes) in the small arteries that regulate regional organ blood flow leads to vasoconstriction. Membrane depolarization also activates large-conductance calcium (Ca(2+))-activated potassium (BK) channels, which limits Ca(2+) channel activity that promotes vasoconstriction, thus leading to vasodilation. We showed that in human and rat arterial myocytes, membrane depolarization rapidly increased the cell surface abundance of auxiliary BK β1 subunits but not that of the pore-forming BKα channels. Membrane depolarization stimulated voltage-dependent Ca(2+) channels, leading to Ca(2+) influx and the activation of Rho kinase (ROCK) 1 and 2. ROCK1/2-mediated activation of Rab11A promoted the delivery of β1 subunits to the plasma membrane by Rab11A-positive recycling endosomes. These additional β1 subunits associated with BKα channels already at the plasma membrane, leading to an increase in apparent Ca(2+) sensitivity and activation of the...

Systemic blood pressure is determined, in part, by arterial smooth muscle cells (myocytes). Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, but it is unclear if these proteins control physiological blood pressure and contribute to hypertension in vivo. We generated the first inducible, smooth muscle-specific knockout mice for a TRP channel, namely for PKD2 (TRPP1), to investigate arterial myocyte and blood pressure regulation by this protein. Using this model, we show that intravascular pressure and α1-adrenoceptors activate PKD2 channels in arterial myocytes of different systemic organs. PKD2 channel activation in arterial myocytes leads to an inward Na+ current, membrane depolarization and vasoconstriction. Inducible, smooth muscle cell-specific PKD2 knockout lowers both physiological blood pressure and hypertension and prevents pathological arterial remodeling during hypertension. Thus, arterial myocyte PKD2 controls systemic...

s Presented 1. Pretty Mary Abraham, Korah P Kuruvilla, CS Paulose. Altered 5HT2a receptor gene expression in the brain stem of diabetic rats: supplementation of pyridoxine and aegle marmelose leaf extract. International Conference on Advances in neuroscience & XXXVI Annual Meeting of Indian academy of neuroscience. Department of Biotechnology, Cochin University of Science and Technology (December 2008). 2. Korah P Kuruvilla, Jes Paul, Nandhu M S and C S Paulose. Up Regulation of Dopamine D1 Receptor in Cerebellum and Brain Stem in Unilateral Rotenone Lesioned Parkinson’s Rat Model: Effect of Serotonin, Dopamine and Norepinephrine. 78th Annual Meeting of the Society of Biological Chemists, (India), Pune. (October 2009). 3. Nandhu. M. S, Jes Paul, Korah P Kuruvilla and C S Paulose. Dopamine D1 Receptor Up Regulation In Cerebellum and Brain Stem In Unilateral 6-Hydroxy Dopamine Rat Model: Antagonism By Serotonin And Gamma Amino Butyric Acid. Conference of Association of Clinical Bioche...

Hirschsprung disease (HSCR) is a common cause of intestinal obstruction in the newborn. Hirschsprungassociated enterocolitis (HAEC) is a significant and life-threatening complication of HSCR, affecting up to 60% of patients. Animal models of endothelin receptor B (EdnrB) mutation reliably model human HSCR and HAEC. We previously demonstrated intestinal dysbiosis and a gut-specific deficiency of B-lymphocyte-produced secretory IgA (sIgA), the primary effector molecule of mucosal immunity, in mice with homozygous neural crest cell-conditional deletion of EdnrB (EdnrB NCC2/2). To determine mechanisms for sIgA deficiency, we examined intrinsic and extrinsic aspects of B-lymphocyte development and function. Expression of the endothelin axis components [endothelin-1 (ET-1), endothelin-3 (ET-3), endothelin receptor A (EdnrA), EdnrB] were determined over a developmental time course. B-lymphocyte survival and Ig production were assayed in vitro. Polymeric Ig receptor (pIgR)-mediated IgA transport into the intestinal lumen was interrogated. We found endothelin axis component (EdnrA, EdnrB, ET-1, ET-3) expression in developing extramedullary hematopoietic organs and that some splenic B lymphocytes express EdnrB. Splenic B lymphocytes from EdnrB NCC2/2 mice showed no intrinsic defect in survival vs. wild-type (WT) B lymphocytes. In vitro stimulation of splenic B lymphocytes demonstrated decreased IgA, IgG, and IgM production in EdnrB NCC2/2 vs. WT mice. Additionally, small intestinal pIgR was decreased ∼50% in EdnrB NCC2/2 mice. These results suggest an intrinsic B-lymphocyte defect in antibody production as well as an extrinsic defect in IgA transport in the EdnrB NCC2/2 model of HAEC. Our results are consistent with human HAEC observations of decreased luminal sIgA and mouse models of other inflammatory bowel diseases, in which decreased pIgR is seen in concert with a dysregulated microbiota. Finally, our results suggest targeting the dysbiotic microbiome and pIgRmediated sIgA transport as potential therapeutic approaches in prevention and treatment of HAEC.-Medrano, G.,

Systemic blood pressure is determined, in part, by arterial smooth muscle cells (myocytes). Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, but it is unclear if these proteins control physiological blood pressure and contribute to hypertension in vivo. We generated the first inducible, smooth muscle-specific knockout for a TRP channel, namely for PKD2 (TRPP1), to investigate arterial myocyte and blood pressure regulation by this protein. Using this model, we show that intravascular pressure and α 1-receptors activate PKD2 channels in arterial myocytes of different systemic organs. PKD2 channel activation in arterial myocytes leads to an inward Na + current, membrane depolarization and vasoconstriction. Inducible, smooth muscle cell-specific PKD2 knockout lowers both physiological blood pressure and hypertension and prevents pathological arterial remodeling during hypertension. In summary, we show for the first time that arterial myocyte PKD2 channels control systemic blood pressure and targeting reduces high blood pressure. .

Systemic blood pressure is determined, in part, by arterial smooth muscle cells (myocytes). Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, but it is unclear if these proteins control physiological blood pressure and contribute to hypertension in vivo. We generated the first inducible, smooth muscle-specific knockout for a TRP channel, namely for PKD2 (TRPP1), to investigate arterial myocyte and blood pressure regulation by this protein. Using this model, we show that intravascular pressure and α 1-receptors activate PKD2 channels in arterial myocytes of different systemic organs. PKD2 channel activation in arterial myocytes leads to an inward Na + current, membrane depolarization and vasoconstriction. Inducible, smooth muscle cell-specific PKD2 knockout lowers both physiological blood pressure and hypertension and prevents pathological arterial remodeling during hypertension. In summary, we show for the first time that arterial myocyte PKD2 channels control systemic blood pressure and targeting reduces high blood pressure. .

Parkinson's disease (PD) is due to widespread degeneration in the central and peripheral nervous systems. The hallmark pathology remains in the dopaminergic striatal insufficiency and degeneration of dopaminergic neurons in the substantia nigra. Objectives: The present study analysed the effect of serotonin (5-HT), dopamine, and norepinephrine as treatment on rotenone induced hemi-Parkinson's disease in rats and its role in the regulation of dopamine receptor subtypes in the corpus striatum of the experimental rats. Methods: Unilateral stereotaxic single-dose infusions of rotenone were administered to the substantia nigra of adult male Wistar rats. Neurotransmitters serotonin (5-HT), dopamine, and norepinephrine treatments were given to rotenone induced hemi-Parkinson's rats. Dopamine receptor and its subtypes (D 1 and D 2) binding assay were carried out. Gene expression studies of dopamine D 1 and D 2 were carried out using real-time PCR. Results: Scatchard analysis of dopamine and dopamine D 2 receptor showed a significant increase (P,0.001) and dopamine D 1 receptor showed a significant decrease (P,0.001) in the B max in corpus striatum of the PD rats compared to control. These altered parameters were reversed to near control in the serotonin-and norepinephrine-treated PD rats and no change was observed in dopamine-treated PD rats. Real-time PCR results confirmed the receptor data. Conclusion: Our results showed that serotonin and norepinephrine functionally reversed in dopamine receptors in rotenone-induced hemi-Parkinson's rat. This has clinical significance in the therapeutic management of PD.

The purpose of this study was to review the long-term outcome of patients with Ebstein anomaly who underwent complete repair as neonates and young infants. Methods: Between March 1994 and May 2010, 32 patients (23 neonates and 9 young infants) underwent surgery for Ebstein anomaly. Mean weight was 3.9 AE 2.0 kg (range, 1.9-8.6 kg). The Great Ormond Street Echocardiography score was greater than 1.5 in 22 of the 23 neonates and greater than 1.0 in all infants. All associated cardiac defects were repaired including pulmonary atresia in 15 and ventricular septal defect in 4. Primary outcome measures included (1) early and late survival, (2) freedom from reoperation, (3) durability of tricuspid valve repair, and (4) functional status. Results: Early survival was 78.1% (25/32). There was 1 late death. Fifteen-year survival estimate was 74% AE 8%. For patients with pulmonary atresia, early and late survival was 60% AE 12% (9/15) versus 94.1% (16/17) (P<.05), respectively; for those without pulmonary atresia, early and late survival was 60% AE 12% versus 85% AE 10 (P ¼ .06), respectively. The mean follow-up was 5.9 AE 4.5 years (0.1-16 years). A biventricular repair was achieved in 90.6% (29/32) patients. Median preoperative tricuspid regurgitation was 4/4 and at late follow-up, 1/ 4. Freedom from reoperation at 15 years was 74% AE 10% for patients undergoing biventricular repair. All survivors are in New York Heart Association class I or II. Conclusions: Biventricular repair of Ebstein anomaly in symptomatic neonates is feasible with good early and late survival, especially in those without pulmonary atresia. Tricuspid valve repair is durable, and functional status is excellent.

Ebstein's anomaly is a congenital heart disease that results from failure of delamination of the tricuspid valve with resulting apical displacement of the septal and posterior leaflets of the tricuspid valve. Age at presentation can vary greatly but neonatal presentation is associated with extraordinary high mortality rates. Comprehensive multispecialty care is required starting at the time of fetal diagnosis. Fetal echocardiography is vital in monitoring progression of the disease in utero. Fetal echocardiogram can evaluate for complications such as arrhythmias, pericardial effusion, or fetal hydrops. Post-natal evaluation should include evaluation of functional pulmonary atresia or circular shunt. Despite advances in surgical technique for Ebstein's anomaly, mortality for it remains high with early surgical intervention. Aggressive medical management should be used to support patients with Ebstein's anomaly during the neonatal period. Surgical procedures for neonatal Ebstein's vary widely from systemic to pulmonary shunts with or without tricuspid valve closure to tricuspid valve repair.

We describe the case of 7-day-old neonate with pulmonary atresia, intact ventricular septum, and severe tricuspid valve (TV) dysplasia who underwent a Starnes right ventricular exclusion procedure (RVEP). The patient had severe tricuspid stenosis and regurgitation and right ventricular dysfunction after perforation and balloon dilation of the pulmonary valve.

Background-Liver cirrhosis is recognized with long-term follow-up of patients after the Fontan procedure. The effect of liver cirrhosis on the use of heart transplant (HT) and on post-HT outcomes is unknown. Methods-We reviewed Fontan patients evaluated for HT from 2004 to 2012 with hepatic computed tomography (CT) imaging, classified as normal, non-cirrhotic changes, or cirrhosis. The primary outcome was 1-year all-cause mortality, and the secondary outcome was differences in serial post-HT liver evaluation. Results-CT imaging in 32 Fontan patients evaluated for HT revealed 20 (63%) with evidence of liver disease, including 13 (41%) with cirrhosis. Twenty underwent HT, including 5 noncirrhotic and 7 cirrhosis patients. Characteristics at listing between normal or non-cirrhotic (n = 13) and cirrhosis (n = 7) groups were similar, except cirrhosis patients were older (median 17.6 vs 9.6 years, p = 0.002) and further from Fontan (median 180 vs 50 months, p < 0.05). Serial liver evaluation was similar, including aspartate aminotransferase, alanine aminotransferase, bilirubin, albumin, and tacrolimus dose at 1, 3, 6, 9, and 12 months. Overall patient survival was 80% at 1 year, with no difference between cirrhosis and non-cirrhosis patients (86% vs 77%, p = 0.681). Liver biopsies were performed in 7 patients before HT, and all specimens showed architectural changes with bridging fibrosis. Conclusions-Most patients evaluated for HT had abnormal liver findings by CT, with cirrhosis in 41%. One-year mortality and serial liver evaluation were similar between groups after HT.

Alveolar capillary dysplasia is a frequently fatal congenital pulmonary disease during infancy. 1 Lung transplantation (LT) is the only means of survival. We report the case of an infant with alveolar capillary dysplasia who subsequently had development of severe hemodynamic compromise as a result of refractory pulmonary hypertension (PH) and was successfully bridged to LT with a paracorporeal lung assist device (PLAD) in a unique configuration.

Objective: To evaluate paracorporeal lung assist devices to treat neonates and children with decompensated respiratory failure as a bridge to recovery or lung transplantation. Methods: One neonate (23 days old) and 3 young children (aged 2, 9, and 23 months) presented with primary lung disease with pulmonary hypertension, including alveolar capillary dysplasia in 2 and right pulmonary hypoplasia and primary pulmonary hypertension in 1. The patients were listed for lung transplantation but decompensated and required extracorporeal membrane oxygenation (ECMO). The patients were transitioned from ECMO to a pumpless paracorporeal lung assist device (Maquet Quadrox-iD oxygenator in 3, Novalung in 1) with inflow from the pulmonary artery and return to the left atrium. Results: The patients were weaned from ECMO and supported by the device for 44 AE 29 days (range, 5-74). Three patients were extubated while supported by the device (after 9, 15, and 72 days). One patient was bridged to lung transplant (9 months old, with alveolar capillary dysplasia, supported 5 days). One patient was bridged to recovery with maximal medical therapy (23 months old, with primary pulmonary hypertension, supported 23 days). Two patients died while awaiting a suitable lung donor after a support time of 54 and 72 days. Conclusions: Pediatric patients bridged from ECMO to lung transplantation have poor results. An alternative method for longer term respiratory support was necessary as a bridge for these patients. The use of a paracorporeal lung assist device successfully supported 4 patients to recovery, lung transplantation, or past the average wait time for pediatric donor lungs (27 days). This therapy has the potential to bridge children with decompensated respiratory failure to lung transplantation.