Control Of Outflow Research Articles

Regeneration of degenerated urinary sphincter muscles: improved stem cell-based therapies and novel imaging technologies.

Stress urinary incontinence (SUI) is a largely ousted but significant medical, social, and economic problem. Surveys suggest that nowadays approximately 10% of the male and 15% of the female population suffer from urinary incontinence at some stage in their lifetime. In women, two major etiologies contribute to SUI: degeneration of the urethral sphincter muscle controlling the closing mechanism of the bladder outflow and changes in lower pelvic organ position associated with degeneration of connective tissue or with mechanical stress, including obesity and load and tissue injury during pregnancy and delivery. In males, the reduction of the sphincter muscle function is sometimes due to surgical interventions as a consequence of prostate cancer treatment, benign prostate hyperplasia, or of neuropathical origin. Accordingly, for women and men different therapies were developed. In some cases, SUI can be treated by physical exercise, electrophysiological stimulation, and pharmacological interventions. If this fails to improve the situation, surgical interventions are required. In standard procedures, endoprostheses for mechanical support of the weakened tissue or mechanical valves for a bladder outflow control are implanted. In 20% of cases treated, repeat procedures are required as implants yield all sorts of side effects in time. Based on preclinical studies, the application of an advanced therapy medicinal product (ATMP) such as implantation of autologous cells may be a curative and long-lasting therapy for SUI. Cellular therapy could also be an option for men suffering from incontinence caused by injury of the nerves controlling the muscular sphincter system. Here we briefly report on human progenitor cells, especially on mesenchymal stromal cells (MSCs), their expansion and differentiation to smooth muscle or striated muscle cells in vitro, labeling of cells for in vivo imaging, concepts of improved, precise, yet gentle application of cells in muscle tissue, and monitoring of injected cells in situ.

GABA in Paraventricular Nucleus Regulates Adipose Afferent Reflex in Rats.

BackgroundChemical stimulation of white adipose tissue (WAT) induces adipose afferent reflex (AAR), and thereby causes a general sympathetic activation. Paraventricular nucleus (PVN) is important in control of sympathetic outflow. This study was designed to investigate the role of γ-aminobutyric acid (GABA) in PVN in regulating the AAR.Methodology/Principal FindingsExperiments were carried out in anesthetized rats. Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were continuously recorded. AAR was evaluated by the RSNA and MAP responses to electrical stimulation of the right epididymal WAT (eWAT) afferent nerve. Electrical stimulation of eWAT afferent nerve increase RSNA. Bilateral microinjection of the GABAA receptor agonist isoguvacine or the GABAB receptor agonist baclofen attenuated the AAR. The effect of isoguvacine on the AAR was greater than that of baclofen. The GABAA receptor antagonist gabazine enhanced the AAR, while the GABAB receptor antagonist CGP-35348 had no significant effect on the AAR. Bilateral PVN microinjection of vigabatrin, a selective GABA-transaminase inhibitor, to increase endogenous GABA levels in the PVN abolished the AAR. The inhibitory effect of vigabatrin on the AAR was attenuated by the pretreatment with gabazine or CGP-35348. Pretreatment with combined gabazine and CGP-35348 abolished the effects of vigabatrin.ConclusionsActivation of GABAA or GABAB receptors in the PVN inhibits the AAR. Blockade of GABAA receptors in the PVN enhances the AAR. Endogenous GABA in the PVN plays an important role in regulating the AAR.

Transcatheter and percutaneous procedures for huge pelvic arteriovenous malformations causing high-output heart failure

We present the case of a 63-year-old woman presenting with a huge pelvic and retroperitoneal high flow arteriovenous malformation (AVM) causing high-output heart failure, who was treated with combined therapies, including transarterial embolization with n-butyl cyanoacrylate–iodized oil mixture (NBCA–lip) and coils for the right ovarian, both internal iliac, 3rd and 4th lumber arteries, venous sclerotherapy using coils and ethanolamine oleate (EO) for the right ovarian and both internal iliac veins with balloon-occluded retrograde transvenous obliteration technique, and direct percutaneous sclerotherapy using the NBCA–lip and EO for the large nidus of AVM under outflow control using occlusion balloon catheters.<Learning objective: Huge arteriovenous fistulae or malformation (AVF/M) are potentially life threatening due to the potential for spontaneous hemorrhaging and high-output heart failure and are notoriously difficult to diagnose and treat. To improve the high-output heart failure, intensive and invasive combined treatments for huge AVF/M are needed including transarterial and transvenous embolization and sclerotherapy and percutaneous nidus sclerotherapy.>

Laparoscopic Right Posterior Sectionectomy for Malignant Lesions: An Anatomic Approach.

Good indications for laparoscopic hepatectomy are still considered to be tumors located over anterolateral segments of the liver. Tumors located over the right posterior section are considered to be difficult for laparoscopic resection. In this case series, we present our experience on laparoscopic right posterior sectionectomy. All patient data were prospectively collected. Data on patient demographics, tumor characteristics, operative data, and postoperative outcome were collected and analyzed. During the period of May 2010-May 2014, we performed 13 laparoscopic right posterior sectionectomies. The diagnoses were hepatocellular carcinoma in 11 patients, of which 2 were cases of colorectal liver metastasis. Median operative time was 381 minutes, and median blood loss was 1500 mL. Significant bleeding occurred in the first 5 patients. The median size of the tumor resected was 3.7 cm, and the median resection margin was 8.7 mm. Four of the 13 patients (30.8%) were cirrhotic on histological examination. There was no postoperative mortality. Median hospital stay was 7 days. Laparoscopic right posterior sectionectomy is technically demanding. A proper inflow and outflow control is mandatory for proper anatomical resection. This surgical principle should not be compromised in the era of laparoscopic hepatectomy.

Cardiovascular Autonomic Dysfunction in Chronic Kidney Disease: a Comprehensive Review

Cardiovascular autonomic dysfunction is a major complication of chronic kidney disease (CKD), likely contributing to the high incidence of cardiovascular mortality in this patient population. In addition to adrenergic overdrive in affected individuals, clinical and experimental evidence now strongly indicates the presence of impaired reflex control of both sympathetic and parasympathetic outflow to the heart and vasculature. Although the principal underlying mechanisms are not completely understood, potential involvements of altered baroreceptor, cardiopulmonary, and chemoreceptor reflex function, along with factors including but not limited to increased renin-angiotensin-aldosterone system activity, activation of the renal afferents and cardiovascular structural remodeling have been suggested. This review therefore analyzes potential mechanisms underpinning autonomic imbalance in CKD, covers results accumulated thus far on cardiovascular autonomic function studies in clinical and experimental renal failure, discusses the role of current interventional and therapeutic strategies in ameliorating autonomic deficits associated with chronic renal dysfunction, and identifies gaps in our knowledge of neural mechanisms driving cardiovascular disease in CKD.

(In)activity-related neuroplasticity in brainstem control of sympathetic outflow: unraveling underlying molecular, cellular, and anatomical mechanisms.

More people die as a result of physical inactivity than any other preventable risk factor including smoking, high cholesterol, and obesity. Cardiovascular disease, the number one cause of death in the United States, tops the list of inactivity-related diseases. Nevertheless, the vast majority of Americans continue to make lifestyle choices that are creating a rapidly growing burden of epidemic size and impact on the United States healthcare system. It is imperative that we improve our understanding of the mechanisms by which physical inactivity increases the incidence of cardiovascular disease and how exercise can prevent or rescue the inactivity phenotype. The current review summarizes research on changes in the brain that contribute to inactivity-related cardiovascular disease. Specifically, we focus on changes in the rostral ventrolateral medulla (RVLM), a critical brain region for basal and reflex control of sympathetic activity. The RVLM is implicated in elevated sympathetic outflow associated with several cardiovascular diseases including hypertension and heart failure. We hypothesize that changes in the RVLM contribute to chronic cardiovascular disease related to physical inactivity. Data obtained from our translational rodent models of chronic, voluntary exercise and inactivity suggest that functional, anatomical, and molecular neuroplasticity enhances glutamatergic neurotransmission in the RVLM of sedentary animals. Collectively, the evidence presented here suggests that changes in the RVLM resulting from sedentary conditions are deleterious and contribute to cardiovascular diseases that have an increased prevalence in sedentary individuals. The mechanisms by which these changes occur over time and their impact are important areas for future study.

Norepinephrine (NE) Increases Production of Superoxide (O2• ‐) in Cultured Peripheral Blood Mononuclear Cells (PBMCs) and Splenocytes Isolated from Rats

Physiological/pathophysiological states with increased sympathetic nerve activity (SNA) are associated with oxidative stress. It is known that increased O2• ‐ in specific brain regions results in increased efferent SNA. Recently we found that NE increased intracellular O2• ‐ production (Dihydroethidium, DHE) and mRNA for NADPH oxidase (NOX‐2) subunits in cultured PBMCs from humans suggesting elevated SNA may increase systemic O2• ‐ production. Current experiments tested whether the rat is a good experimental model of humans to further study the interaction between sympathoexcitation and PBMC‐derived O2• ‐. Primary PBMCs and splenocytes were isolated from male rats and incubated at 37°C for 36 hr with either vehicle (Veh), 50 pcg/ml, 50 ng/ml, or 50 µg/ml NE. Similar to human PBMCs, relative to Veh, NE increased intracellular O2• ‐ production in rat PBMCs (50 µg/ml NE = 11± 5 fold; P&lt; 0.05) and tended to increase mRNA for NOX‐2 subunits (50 ng/ml NE: gp 91phox = 1.8 ± 0.4; p22phox = 1.6± 0.5). NE also increased O2• ‐ in rat splenocytes (50 µg/ml NE = 11± 6 fold; P&lt; 0.05). Thus, results in rat PBMCs and splenocytes are similar to human PBMCs, and are consistent with a positive feedback system whereby increased NE promotes increased O2• ‐ in circulating PBMCs which in turn could activate CNS sites to promote further increases in SNA. Using the rat as a model, future experiments will evaluate a potential role of circulating PBMCs on activation of brain regions involved in the control of sympathetic outflow. R01 HL091164

Solar illumination control of ionospheric outflow above polar cap arcs

AbstractWe measure the flux density, composition, and energy of outflowing ions above the polar cap, accelerated by quasi‐static electric fields parallel to the magnetic field and associated with polar cap arcs, using Cluster. Mapping the spacecraft position to its ionospheric foot point, we analyze the dependence of these parameters on the solar zenith angle (SZA). We find a clear transition at SZA between ∼94° and ∼107°, with the O+ flux higher above the sunlit ionosphere. This dependence on the illumination of the local ionosphere indicates that significant O+ upflow occurs locally above the polar ionosphere. The same is found for H+, but to a lesser extent. This effect can result in a seasonal variation of the total ion upflow from the polar ionosphere. Furthermore, we show that low‐magnitude field‐aligned potential drops are preferentially observed above the sunlit ionosphere, suggesting a feedback effect of ionospheric conductivity.

Chronic intermittent hypoxia orchestrates cardiorespiratory cacophony--adapting melody to malady.

Chronic intermittent hypoxia orchestrates cardiorespiratory cacophony--adapting melody to malady.

Bleeding control during laparoscopic liver resection: a review of literature.

Despite the established advantages of laparoscopy, bleeding control during laparoscopic liver resection (LLR) is a liver-specific improvement. The 2nd International Consensus Conference on Laparoscopic Liver Resection was held in October 2014 at Morioka, Japan. One of the most capital questions was: What is essential in bleeding control during LLR? In order to correctly address this question, we conducted a comprehensive review of the literature. Essential points based on personal experience of the expert panel are also discussed. A total of 54 publications were identified. Based on this analysis, the working group built these recommendations: (1) a pneumoperitoneum of 10-14 mmHg should be used as it allows a good control of the bleeding without significant modifications of hemodynamics; (2) a low central venous pressure (<5 mmHg) should be used; (3) laparoscopy facilitates inflow and outflow control; and (4) surgeons should be experienced with the use of all surgical devices for liver transection and should master laparoscopic suture before starting LLR. Precoagulation with radiofrequency can be useful, particularly in cases of atypical resection. These recommendations are mostly based on experts' opinions and on B or C quality of evidence grade studies. More prospective data are required to confirm these results.

Ultrasonographic evaluation of cerebral arterial and venous haemodynamics in multiple sclerosis: a case-control study.

ObjectiveAlthough recent studies excluded an association between Chronic Cerebrospinal Venous Insufficiency and Multiple Sclerosis (MS), controversial results account for some cerebrovascular haemodynamic impairment suggesting a dysfunction of cerebral autoregulation mechanisms. The aim of this cross-sectional, case-control study is to evaluate cerebral arterial inflow and venous outflow by means of a non-invasive ultrasound procedure in Relapsing Remitting (RR), Primary Progressive (PP) Multiple Sclerosis and age and sex-matched controls subjects.Material and MethodsAll subjects underwent a complete extra-intracranial arterial and venous ultrasound assessment with a color-coded duplex sonography scanner and a transcranial doppler equipment, in both supine and sitting position by means of a tilting chair. Basal arterial and venous morphology and flow velocities, postural changes in mean flow velocities (MFV) of middle cerebral arteries (MCA), differences between cerebral venous outflow (CVF) in clinostatism and in the seated position (ΔCVF) and non-invasive cerebral perfusion pressure (CPP) were evaluated.Results85 RR-MS, 83 PP-MS and 82 healthy controls were included. ΔCVF was negative in 45/85 (52.9%) RR-MS, 63/83 (75.9%) PP-MS (p = 0.01) and 11/82 (13.4%) controls (p<0.001), while MFVs on both MCAs in sitting position were significantly reduced in RR-MS and PP-MS patients than in control, particularly in EDSS≥5 subgroup (respectively, 42/50, 84% vs. 66/131, 50.3%, p<0.01 and 48.3±2 cm/s vs. 54.6±3 cm/s, p = 0.01). No significant differences in CPP were observed within and between groups.ConclusionsThe quantitative evaluation of cerebral blood flow (CBF) and CVF and their postural dependency may be related to a dysfunction of autonomic nervous system that seems to characterize more disabled MS patients. It's not clear whether the altered postural control of arterial inflow and venous outflow is a specific MS condition or simply an “epiphenomenon” of neurodegenerative events.

Management of Type II Endoleak after Endovascular Repair of Arteriocaval Fistula Complicating Aortoiliac Aneurysm: Case Report and Literature Review

Endovascular treatment for arteriocaval fistula (ACF) has become the preferred alternative to open repair. However, endoleaks sometimes occur and maintain the ACF. A 64-year-old man presented with persistent fistula after placement of a bifurcated stent-graft for ACF complicating an aortoiliac aneurysm that was maintained by endoleaks from the inferior mesenteric and lumbar arteries. Transarterial embolization of the aneurysm sac and inferior mesenteric artery successfully resolved the problem without any complications observed over 16 months of follow-up. A literature review and discussion of the management options for this entity are presented. A combination of inflow and outflow control is important to obtain better long-term outcomes.

Central mechanisms for exercise training-induced reduction in sympatho-excitation in chronic heart failure.

The control of sympathetic outflow in the chronic heart failure (CHF) state is markedly abnormal. Patients with heart failure present with increased plasma norepinephrine and increased sympathetic nerve activity. The mechanism for this sympatho-excitation is multiple and varied. Both depression in negative feedback sensory control mechanisms and augmentation of excitatory reflexes contribute to this sympatho-excitation. These include the arterial baroreflex, cardiac reflexes, arterial chemoreflexes and cardiac sympathetic afferent reflexes. In addition, abnormalities in central signaling in autonomic pathways have been implicated in the sympatho-excitatory process in CHF. These mechanisms include increases in central Angiotensin II and the Type 1 receptor, increased in reactive oxygen stress, upregulation in glutamate signaling and NR1 (N-methyl-D-aspartate subtype 1) receptors and others. Exercise training in the CHF state has been shown to reduce sympathetic outflow and result in increased survival and reduced cardiac events. Exercise training has been shown to reduce central Angiotensin II signaling including the Type 1 receptor and reduce oxidative stress by lowering the expression of many of the subunits of NADPH oxidase. In addition, there are profound effects on the central generation of nitric oxide and nitric oxide synthase in sympatho-regulatory areas of the brain. Recent studies have pointed to the balance between Angiotensin Converting Enzyme (ACE) and ACE2, translating into Angiotensin II and Angiotensin 1-7 as important regulators of sympathetic outflow. These enzymes appear to be normalized following exercise training in CHF. Understanding the precise molecular mechanisms by which exercise training is sympatho-inhibitory will uncover new targets for therapy.

The adrenergic system in cardiovascular pathophysiology: a translational science point of view.

Heart failure (HF) is one of the leading causes for mortality and morbidity worldwide. Despite advantages in the management and treatment of this syndrome, nowadays, it is estimated that 50% of HF patients die within 5 years from diagnosis (McMurray et al., 2012). Thus, a better understanding of the molecular mechanisms underlying structural, functional, neuro-hormonal, and metabolic alterations of the failing heart is necessary for the identification of new therapeutic targets and strategies. The adrenergic system is crucial for cardiac function, and even more critical in diseased states characterized by elevated sympathetic nervous system (SNS) hyperactivity (Lymperopoulos et al., 2013). SNS hyperactivity is a salient characteristic of chronic HF and causes cardiac up-regulation of G protein-coupled receptor kinase 2 (GRK2), which in turn induces beta-adrenergic receptor dysregulation in the heart (Rengo et al., 2009, 2012). The present Research Topic aims to present some of the more relevant and recent acquisitions on the molecular abnormalities of the adrenergic system occurring in HF. Dr. Lymperopoulos has reported the molecular mechanisms of regulation of SNS in HF patho-physiology, discussing their therapeutic implications for the failing heart (Lymperopoulos, 2013). The importance of SNS hyperactivity as a main therapeutic target in HF, represents the rationale for the use of beta-blockers, as discussed by Drs. Barrese and Taglialatela. These authors also reported the molecular bases explaining the differences in response to beta-blocker therapy among HF patients (Barrese and Taglialatela, 2013). Dr. Ferrara and collaborators showed the molecular similarities between physiological aging and HF. Both these conditions are characterized by SNS hyperactivity and cardiac beta-adrenergic receptor signaling dysfunction, and this may help to explain why HF is more frequent and its manifestation more severe in the elderly patients (Ferrara et al., 2014). The interconnections between adrenergic system and cardiac metabolism, oxidative stress and nitric oxide signaling have also been discussed in this Research Topic. It is known from several years that the adrenergic system has a profound effect on the regulation of cardiac metabolism. In this regard, Ciccarelli et al. reported the most updated discoveries in the molecular mechanisms involved in the interactions between adrenergic system hyperactivity and metabolic abnormalities, such as insulin resistance and altered glucose metabolism (Ciccarelli et al., 2013). The effects of beta-adrenoceptors on Reactive Oxygen Species generation are described by Corbi et al.; these authors reported also a fascinating hypothesis of the involvement of sirtuins on beta-adrenergic receptors signaling with a potential role in HF pathophysiology (Corbi et al., 2013). Dr. Conti and collaborators reported the mechanisms of the crosstalk between nitric oxide and beta-adrenergic receptor system, in particular in the control of endothelial function and vascular tone (Conti et al., 2013). Evidences accumulated over the past 20 years support the pathogenic key role of cardiac GRK2 levels/activity in determining HF-related beta-adrenergic receptor dysfunction and cardiac inotropic reserve reduction. All these data indicate GRK2 inhibition, via gene therapy, as a new HF therapeutic approach that has been shown to be compatible and, in some models, also synergistic to beta-blockers. Cannavo et al. provide a contemporary update of this field by describing the therapeutic potentialities of this approach and its beneficial effects not only on beta-adrenergic receptor signaling, but also on cardiac metabolism, apoptosis, and mitochondrial dysfunction (Cannavo et al., 2013). De Lucia and collaborators extended the therapeutic potentialities of GRK2 inhibition to the adrenal glands and to the control of HF-related SNS outflow (de Lucia et al., 2014). Since its first demonstration by Lymperopoulos et al. (2007), GRK2 appeared to be critical in the regulation of adrenal alfa2 adrenergic receptor function, extending also to other organs the therapeutic benefits of GRK2 inhibition in HF. Finally, Dr. Leosco in his review explained the molecular mechanisms involved in the beneficial effects of exercise training in curbing SNS hyperactivity and beta-adrenergic receptor dysfunction observed in HF. A crucial role seems to be played by the ability of physical activity to reduce GRK2 levels both in the heart and in the adrenal medulla, with relevant effects on cardiovascular function (Leosco et al., 2013). The overall Research Topic indicates that the great advances achieved in the last decades in understanding the molecular alterations involved in the pathophysiology of HF are opening new opportunities for the treatment of this syndrome and, potentially, their future application to the clinical practice might result to further improvements of patient care. Moreover, the interesting new findings, discussed herein, will hopefully stimulate further research on these arguments.

Surgical strategy for isolated caudate lobectomy: experience with 16 cases.

Introduction. Surgical resection is the most effective treatment for neoplasm in the caudate lobe. Isolated caudate lobectomy is still a challenge for hepatobiliary surgeons. No widely accepted surgical strategy for the procedure has been developed yet. Objective. To get a better understanding of isolated caudate lobectomy and to optimize the procedure. Materials and Methods. 16 cases of isolated caudate lobectomy were reviewed to summarize the surgical experience. Results. All the 16 cases of isolated caudate lobectomy were carried out successfully, among which left side approach was adopted in two cases (12.5%), right side approach in three cases (18.75%), and both sides approach in 11 cases (68.75%). No severe complications occurred. Conclusion. The majority of neoplasms confined to the caudate lobe can be resected safely by left and right side approach with proper anatomic surgical procedure, usually in the sequence of mobilization, outflow control, inflow control, and division of the hepatic parenchyma. Fully mobilizing the caudate lobe from the inferior vena cava (IVC) is of great importance. Division of the retrohepatic ligament and the venous ligament facilitated the procedure.

From control by capital to control of capital: Iceland's boom and bust, and the IMF's unorthodox rescue package

ABSTRACTFor decades past the IMF has been a byword for economic orthodoxy, which included disapproval of policy limits on cross-border capital flows. But in 2012 it announced a new “institutional view” giving more scope for capital flow management and in effect restricting the rights of capital owners. The Fund's program in Iceland after the October 2008 crash helped to pave the way; it was the first time the Fund had endorsed capital controls in a developed country. The essay describes Iceland's boom and bust, and how the government and IMF tried to manage the crisis. With IMF support, the government implemented capital outflow controls, initially as an emergency response and then as a longer-term stabilization measure. The control regime evolved in a complicated “game”, sometimes referred to in public debate as “the battle of Iceland”, between the central bank implementing a professionally-led capital account liberalization strategy versus political parties seeking to turn the controls to their advantage. From this political economy perspective we explain why the “temporary” capital controls remain in place more than five years on. At the end we draw some broad lessons from the Iceland case for the financial booms and busts to come.

Inhibition of endoplasmic reticulum function in PVN by thapsigargin increases neuronal excitability and sympathetic nerve activity (1125.4)

Control of sympathetic outflow by paraventricular nucleus (PVN) is partially mediated through a monosynaptic axon projecting to the rostral ventrolateral medulla (PVN‐RVLM). Here we investigated the role of thapsigargin (TG), the endoplasmic reticulum (ER) Ca2+ ATPase inhibitor, in regulating the excitability of PVN‐RVLM neurons under brain slice preparation. In current‐clamp recordings, graded current injections evoked graded increases in spike frequency. Maximum discharge was evoked by +200 pA injections and averaged 22 ± 2 Hz (n=7) and was significantly greater (P &lt; 0.05) in the presence of TG (0.5 µM) (31 ± 3 Hz, n=9). The effect of ER Ca2+ store depletion in regulating renal SNA (RSNA) and mean arterial pressure (MAP) was assessed by bilateral PVN microinjection of TG in anesthetized rats. PVN injection of TG (0.15, 0.3 0.75 and 1.5 nmol/100nl) increased RSNA and MAP in a dose‐dependent manner. Maximum increases in RSNA and MAP elicited by PVN TG (0.75 nmol/100nl; n=3) were 105 ± 31% and 18 ± 11 mmHg respectively. Pre‐treatment with CyPPA (5 nmol/100 nl), a small conductance, Ca2+ activated K (SK) channel activator (n=3), attenuated the PVN TG evoked sympathoexcitatory and pressor responses (7 ± 7% for RSNA and 4 ± 7 mmHg for MAP). PVN CyPPA did not significantly alter baseline RSNA and MAP. Our data indicate that inhibition of ER function with TG enhances in vitro excitability of PVN‐RVLM neurons and increases in vivo RSNA and MAP. The effect of TG on the excitability of PVN neurons and SNA through ER Ca2+ store depletion may involve reduced SK channel activity.Grant Funding Source: Supported by AHA10SDG2640130

The trabecular meshwork in normal eyes and in exfoliation glaucoma.

Trabecular meshwork (TM) and ciliary muscle contraction and relaxation function together to provide control of outflow. The active role the TM plays in the regulation of intraocular pressure (IOP) is mediated by cytoskeletal and contractility mechanisms as well as signal/transduction factors that mediate its response to stressors. This complex system is altered with age and the glaucomas, and it can be difficult to differentiate between the various etiological effects/agents. Factors such as a compromised antioxidant defense system and altered extracellular matrix metabolism are known to contribute to impaired outflow and may be common to primary open-angle glaucoma, exfoliation syndrome, and exfoliation glaucoma (XFG). Genes differentially expressed in diseased ocular tissue or in cultured HTM cell models, and thus implicated in the disease process, include SOD2, ALDH1A1, MGST1, LOX, and LOXL1, elements of the transforming growth factor-β/bone morphogenetic protein/SMAD signaling pathways, connective tissue growth factor, matrix metalloproteinase-2, a tissue inhibitor of metalloproteinases also known as TIMP-2, and endothelin-1 (ET-1). In exfoliation syndrome and XFG fibrillar, proteinaceous extracellular material is produced in excess and accumulates in both outflow pathways but does not always lead to elevated IOP. Locally produced material may accumulate in the intertrabecular spaces, juxtacanalicular (JCT) meshwork, and the inner wall of Schlemm's canal as a result of a combination of both excessive synthesis and insufficient degradation. An increase in JCT plaque and decreased cellularity in the TM are thought to contribute to decreased outflow facility in glaucoma patients, but XFG patient specimens show reduced extracellular plaque material in the JCT, and the structural integrity of trabecular endothelial cells is mostly retained and cellularity remains unchanged. The distinctions between causes/effects of structural changes leading to reduced outflow/elevated IOP are important for developing effective, individualized treatment strategies.

Expert consensus on laparoscopic hepatectomy (2013 Version)

Laparoscopic hepatectomy has many advantages over open surgery, including minimization of local injury, reduced systemic reactions, and faster postoperative recovery. The aim of this "Consensus" is to provide guidance and reference to surgeons who perform, or are interested in performing laparoscopic liver surgeries. The National Hepatic Surgery Group of the Society of Surgery, a professional society of the Chinese Medical Association, gathered 60 expert hepatic surgeons in Wuhan, China in December 2012, and an "Expert Consensus on Laparoscopic Hepatectomy" was developed. The types of hepatectomy, indications and contraindications, preoperative preparation, anesthesia, patient position, insufflation pressure, port position, control of hepatic inflow and outflow, indications for conversion to open surgery, and surgical devices and equipment are reviewed. Techniques and procedures of various laparoscopic hepatectomies are also discussed.

Abstract 35: PI3K-mTOR Axis is a Critical Node for Hypothalamic Insulin Receptor Signaling and Sympathetic Activation Induced by Insulin

Insulin action in the hypothalamus produces sympathetic nerve activation with pathological implications in obesity and type 2 diabetes. However, the molecular events mediating the sympathetic effects evoked by hypothalamic action of insulin are poorly understood. Mammalian target of rapamycin (mTOR) which can be activated by the insulin receptor has emerged as an important regulator of sympathetic nerve activity (SNA). Phosphatidylinositol 3-kinase (PI3K) pathway is an important upstream regulator of mTOR signaling; and insulin stimulates PI3K in the hypothalamus. Thus, we postulate that the PI3K-mTOR axis is critical for insulin-induced sympathetic nerve activation. In hypothalamic GT1-7 neurons, we found that insulin (100 nM) activated mTOR signaling as indicated by the increase in phosphorylated levels of the downstream effectors, S6K (1.5-fold) and S6 (1.4-fold), measured by Western blot. In GT1-7 neurons, insulin also increased the phosphorylation levels of Akt (2.7-fold), a downstream effector of PI3K. Importantly, inhibition of PI3K (LY294202, 10 μM) abolished insulin-induced activation of S6K and S6. To study further the contribution of PI3K signaling to the insulin action, we used p110αD933/WT mice which carry a heterozygous mutation disrupting PI3K signaling. In wild type (WT) control mice, ICV administration of insulin (100 μU) significantly elevated the number of phospho-S6 positive cells in the hypothalamic arcuate nucleus (29±1, n=3, p&lt;0.05 vs. vehicle), assessed by immunohistochemistry. This response was significantly attenuated in p110αD933/WT mice (12±3, n=3, p&lt;0.05 vs. WT mice). Moreover, the increase in renal SNA, measured directly using multifiber recording, induced by ICV insulin (100 μU) was blunted (p&lt;0.05) in the p110αD933A/WT mice (-15±25%, n=6) as compared to littermate controls (327±115%, n=6). In WT mice, ICV pre-treatment with an mTOR inhibitor (rapamycin, 1 ng) also attenuated the renal SNA response induced by ICV insulin (-16±14%, n=6), mimicking the effect of PI3K inhibition. These results suggest that hypothalamic PI3K-mTOR axis is a critical node in the control of renal sympathetic outflow by insulin.