Ncx3-Induced Mitochondrial Dysfunction in Midbrain Leads to Neuroinflammation in Striatum of A53t-α-Synuclein Transgenic Old Mice.

The exact mechanism underlying selective dopaminergic neurodegeneration is not completely understood. The complex interplay among toxic alpha-synuclein aggregates, oxidative stress, altered intracellular Ca2+-homeostasis, mitochondrial dysfunction and disruption of mitochondrial integrity is considered among the pathogenic mechanisms leading to dopaminergic neuronal loss. We herein investigated the molecular mechanisms leading to mitochondrial dysfunction and its relationship with activation of the neuroinflammatory process occurring in Parkinson's disease. To address these issues, experiments were performed in vitro and in vivo in mice carrying the human mutation of α-synuclein A53T under the prion murine promoter. In these models, the expression and activity of NCX isoforms, a family of important transporters regulating ionic homeostasis in mammalian cells working in a bidirectional way, were evaluated in neurons and glial cells. Mitochondrial function was monitored with confocal microscopy and fluorescent dyes to measure mitochondrial calcium content and mitochondrial membrane potential. Parallel experiments were performed in 4 and 16-month-old A53T-α-synuclein Tg mice to correlate the functional data obtained in vitro with mitochondrial dysfunction and neuroinflammation through biochemical analysis. The results obtained demonstrated: 1. in A53T mice mitochondrial dysfunction occurs early in midbrain and later in striatum; 2. mitochondrial dysfunction occurring in the midbrain is mediated by the impairment of NCX3 protein expression in neurons and astrocytes; 3. mitochondrial dysfunction occurring early in midbrain triggers neuroinflammation later into the striatum, thus contributing to PD progression during mice aging.

The role of computed tomography for the prediction of esophageal variceal bleeding: Current status and future perspectives.

Esophageal variceal bleeding (EVB) is one of the most common and severe complications related to portal hypertension (PH). Despite marked advances in its management during the last three decades, EVB is still associated with significant morbidity and mortality. The risk of first EVB is related to the severity of both PH and liver disease, and to the size and endoscopic appearance of esophageal varices. Indeed, hepatic venous pressure gradient (HVPG) and esophagogastroduodenoscopy (EGD) are currently recognized as the "gold standard" and the diagnostic reference standard for the prediction of EVB, respectively. However, HVPG is an invasive, expensive, and technically complex procedure, not widely available in clinical practice, whereas EGD is mainly limited by its invasive nature. In this scenario, computed tomography (CT) has been recently proposed as a promising modality for the non-invasive prediction of EVB. Although CT is only a diagnostic modality, thus being not capable of supplanting EGD or HVPG in providing therapeutic and physiological data, it could potentially assist liver disease scores, HVPG, and EGD in a more effective prediction of EVB. However, to date, evidence concerning the role of CT in this setting is still lacking. Our review aimed to summarize and discuss the current evidence concerning the role of CT in predicting the risk of EVB.

The effectiveness of current acute variceal bleed treatments in unselected cirrhotic patients: refining short-term prognosis and risk factors.

OBJECTIVES: The mortality from esophageal variceal hemorrhage in liver cirrhosis patients remains approximately 15-20%. Predictors of short-term outcomes, such as the hepatic venous pressure gradient, are often unavailable in the acute setting. Clinical variables seem to have a similar predictive performance, but some variables including active bleeding during endoscopy have not been reevaluated after the utilization of endoscopic banding as endoscopic procedure. In addition, patients with severe liver failure are often excluded from clinical trials. The aim of this study was to prospectively reevaluate the risk factors affecting a 5-day failure after acute variceal bleeding in unselected cirrhotic patients, managed with the current standard treatment using vasoactive drugs, band ligation, and antibiotics. METHODS: One hundred and eighty five patients with liver cirrhosis and variceal bleeding admitted from January 2010 to July 2011 were evaluated. RESULTS: Hepatocellular carcinoma was present in 28.1% of cases and portal vein thrombosis (PVT) was present in 17.3% of cases. Band ligation was feasible in 92.4% of cases. Five-day failure occurred in 16.8% of cases; 12 patients (6.5%) experienced failure to control bleeding or early rebleeding, and 66.7% of patients died within 5 days. The overall 5-day mortality rate was 14.6%. By multivariate analysis, we determined that Child-Pugh class C, a white blood cell count over 10 × 10(9)/l, and the presence of PVT were the only independent predictors of the 5-day failure. CONCLUSIONS: The prognosis of a consistent group of liver cirrhosis patients with variceal bleeding remains poor. The current treatment is highly effective in controlling variceal bleeding, but mortality is related mainly to the severity of liver failure.

Hypoxic hepatitis occurring in cirrhosis after variceal bleeding: still a lethal disease.

BACKGROUND: Hypoxic hepatitis (HH) occurring after gastrointestinal bleeding in cirrhotic patients has been scarcely studied and is reported as a rare occurrence carrying a severe prognosis. The management of bleeding from esophageal varices (BEV) and similarly the prognosis has improved in the last decades. GOALS: To evaluate retrospectively the incidence, clinical features, risk factors, and outcome of HH occurring in cirrhotic patients with BEV treated with the current standard therapy. Cirrhotics with BEV consecutively admitted from 2004 to 2008 were considered. Standard therapy consisted of intensive care support, somatostatin, antibiotics, and band ligation. HH was diagnosed if an elevation of alanine aminotransferase >10-fold from basal occurred. RESULTS: Among 349 patients admitted for BEV, 24 (6.8%) had HH. Most patients were over 60 years old and had advanced liver disease; 41.7% had hepatocellular carcinoma, and 29.2% had portal vein thrombosis (PVT). Hypovolemic shock occurred in 16 (66.7%) patients, and failure to control initial bleeding in 12 (50%) patients. The 6-week mortality rate was 83.3% in HH compared with 24.6% in non-HH patients. Causes of death were massive bleeding in 4, hepatic encephalopathy in 7, and renal failure in 9. Binary logistic regression analysis showed that failure to control initial bleeding, diabetes, and PVT were factors independently associated with the development of HH. CONCLUSIONS: HH occurring in cirrhosis with gastrointestinal bleeding still carries an ominous prognosis. The severity of hemorrhage as expressed by failure to control bleeding contributes heavily to HH; in addition, the presence of PVT and diabetes further compromising the hepatic circulatory reserve may favor hypoxic damage.

Role of multidetector computed tomography angiography in non-variceal upper gastrointestinal bleeding: A comprehensive review.

Non-variceal upper gastrointestinal bleeding (NVUGIB) is a common gastroenterological emergency associated with significant morbidity and mortality. Upper gastrointestinal endoscopy is currently recommended as the gold standard modality for both diagnosis and treatment, with computed tomography traditionally playing a limited role in the diagnosis of acute NVUGIB. Following the introduction of multidetector computed tomography (MDCT), this modality is emerging as a promising tool in the diagnosis of NVUGIB. However, to date, evidence concerning the role of MDCT in the NVUGIB diagnosis is still lacking. The aim of our study was to review the current evidence concerning the role of MDCT in the diagnosis of acute NVUGIB.

Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis.

BACKGROUND: Treatment of portal vein thrombosis (PVT) in patients with liver cirrhosis is not well established. AIM: We intended to assess the safety and efficacy of low molecular weight heparin (LMWH) to treat PVT in cirrhotic patients. STUDY: All 39 patients diagnosed with non-neoplastic PVT and cirrhosis from June 2005 to December 2006 were evaluated for anticoagulation therapy (AT). PVT was occludent in 15.4%, partial in 64.1%, and portal cavernoma presented in 20.5%. Twenty-eight patients received 200 U/kg/d of enoxaparin for at least 6 months. In 39.3% of patients PVT was an occasional finding, in 10.7% presented with acute abdominal pain, in 50% with bleeding from gastroesophageal varices. In this last group LMWH was started after endoscopic eradication of varices by band ligation. RESULTS: Complete recanalization of portal vein occurred in 33.3%, partial recanalization in 50% and no response in 16.7% of patients. Further 12 patients who continued AT obtained complete recanalization at a median time of 11 months (range 7 to 17 mo). Overall, a complete response was obtained in 75% of patients. No significant side effects, particularly bleeding complications, were observed during the treatment. CONCLUSIONS: LMWH demonstrated safe and effective in the treatment of PVT in patients with liver cirrhosis.

Mitochondrial Homeostasis and Signaling in Parkinson's Disease.

The loss of dopaminergic (DA) neurons in the substantia nigra leads to a progressive, long-term decline of movement and other non-motor deficits. The symptoms of Parkinson's disease (PD) often appear later in the course of the disease, when most of the functional dopaminergic neurons have been lost. The late onset of the disease, the severity of the illness, and its impact on the global health system demand earlier diagnosis and better targeted therapy. PD etiology and pathogenesis are largely unknown. There are mutations in genes that have been linked to PD and, from these complex phenotypes, mitochondrial dysfunction emerged as central in the pathogenesis and evolution of PD. In fact, several PD-associated genes negatively impact on mitochondria physiology, supporting the notion that dysregulation of mitochondrial signaling and homeostasis is pathogenically relevant. Derangement of mitochondrial homeostatic controls can lead to oxidative stress and neuronal cell death. Restoring deranged signaling cascades to and from mitochondria in PD neurons may then represent a viable opportunity to reset energy metabolism and delay the death of dopaminergic neurons. Here, we will highlight the relevance of dysfunctional mitochondrial homeostasis and signaling in PD, the molecular mechanisms involved, and potential therapeutic approaches to restore mitochondrial activities in damaged neurons.

Nuclear-encoded NCX3 and AKAP121: Two novel modulators of mitochondrial calcium efflux in normoxic and hypoxic neurons.

Mitochondria are highly dynamic organelles extremely important for cell survival. Their structure resembles that of prokaryotic cells since they are composed with two membranes, the inner (IMM) and the outer mitochondrial membrane (OMM) delimitating the intermembrane space (IMS) and the matrix which contains mitochondrial DNA (mtDNA). This structure is strictly related to mitochondrial function since they produce the most of the cellular ATP through the oxidative phosphorylation which generate the electrochemical gradient at the two sides of the inner mitochondrial membrane an essential requirement for mitochondrial function. Cells of highly metabolic demand like those composing muscle, liver and brain, are particularly dependent on mitochondria for their activities. Mitochondria undergo to continual changes in morphology since, they fuse and divide, branch and fragment, swell and extend. Importantly, they move throughout the cell to deliver ATP and other metabolites where they are mostly required. Along with the capability to control energy metabolism, mitochondria play a critical role in the regulation of many physiological processes such as programmed cell death, autophagy, redox signalling, and stem cells reprogramming. All these phenomena are regulated by Ca2+ ions within this organelle. This review will discuss the molecular mechanisms regulating mitochondrial calcium cycling in physiological and pathological conditions with particular regard to their impact on mitochondrial dynamics and function during ischemia. Particular emphasis will be devoted to the role played by NCX3 and AKAP121 as new molecular targets for mitochondrial function and dysfunction.

In-hospital mortality in non-variceal upper gastrointestinal bleeding Forrest 1 patients.

OBJECTIVE: Non-variceal upper gastrointestinal bleeding (NVUGIB) is recognized world-wide as a common cause of emergency hospitalization, and it often represents a life-threatening event. The purpose of this prospective study was to assess in-hospital mortality in NVUGIB Forrest 1 patients admitted to the emergency unit owing to active bleeding. MATERIAL AND METHODS: We enrolled all patients consecutively admitted to the emergency unit for NVUGIB, acutely bleeding at endoscopy (spurting or oozing). Demographic characteristics, clinical and biochemical parameters, endoscopic findings and treatments were evaluated. RESULTS: Of a total of 142 patients (98 M (69%), mean age+/-SD=66+/-14 years), spurting (16 (11.3%)) and oozing (126 (88.7%)) were identified. All patients received endoscopic treatment within 6 h of admission and were managed according to the guidelines. Seventeen (12%) patients suffered rebleeding, 4 patients (2.8%) required surgery to stop the bleeding, and 8 (5.6%) died during hospitalization (4 within 5 days and the remainder within 24 days of admission) - 3 as a consequence of bleeding (2.1%) and 5 of non-surgical complications (3.5%). Cox regression analysis showed that the lesions in more than one segment of the esophagogastroduodenal tract (p=0.008, hazard ratio (95% CI)=7.623 (1.680-34.600)) and the number of blood units transfused during the first 48 h of hospitalization (p=0.038, 2.075 (1.041-4.135)) were predictive of in-hospital death. CONCLUSIONS: In Forrest 1 patients given rapid endoscopic treatment, in-hospital mortality seems to be related to the contemporaneous presence of bleeding and non-bleeding lesions in more than one segment of the esophagogastroduodenal tract and the number of blood units transfused during the first 48 h of hospitalization.

A small linear peptide encompassing the NGF N-terminus partly mimics the biological activities of the entire neurotrophin in PC12 cells.

Ever since the discovery of its neurite growth promoting activity in sympathetic and sensory ganglia, nerve growth factor (NGF) became the prototype of the large family of neurotrophins. The use of primary cultures and clonal cell lines has revealed several distinct actions of NGF and other neurotrophins. Among several models of NGF activity, the clonal cell line PC12 is the most widely employed. Thus, in the presence of NGF, through the activation of the transmembrane protein TrkA, these cells undergo a progressive mitotic arrest and start to grow electrically excitable neuritis. A vast number of studies opened intriguing aspects of NGF mechanisms of action, its biological properties, and potential use as therapeutic agents. In this context, identifying and utilizing small portions of NGF is of great interest and involves several human diseases including Alzheimer's disease. Here we report the specific action of the peptide encompassing the 1-14 sequence of the human NGF (NGF(1-14)), identified on the basis of scattered indications present in literature. The biological activity of NGF(1-14) was tested on PC12 cells, and its binding with TrkA was predicted by means of a computational approach. NGF(1-14) does not elicit the neurite outgrowth promoting activity, typical of the whole protein, and it only has a moderate action on PC12 proliferation. However, this peptide exerts, in a dose and time dependent fashion, an effective and specific NGF-like action on some highly conserved and biologically crucial intermediates of its intracellular targets such as Akt and CREB. These findings indicate that not all TrkA pathways must be at all times operative, and open the possibility of testing each of them in relation with specific NGF needs, biological actions, and potential therapeutic use.

Splanchnic vein thrombosis and variceal rebleeding in patients with cirrhosis.

OBJECTIVES: Splanchnic vein thrombosis (SVT) affects the short-term prognosis of acute variceal bleeding in cirrhotic patients. This study evaluated whether SVT also affects the rebleeding rate of patients included in a program of secondary prophylaxis after variceal bleeding. PATIENTS AND METHODS: A total of 387 patients with variceal bleeding were included from January 2001 to December 2010. Band ligation was carried out every 3-4 weeks. Follow-up included endoscopy at 1, 3, and every 6 months, Echo-Doppler, and biochemical examination every 6 months. From 2005, patients with SVT received anticoagulation with enoxaparin 200 UI/kg/day for at least 6 months. The therapy was started after variceal eradication. RESULTS: SVT was diagnosed in 41 patients at variceal bleeding, in eight before and in 18 patients during the follow-up. Variceal eradication was achieved in 89.2 and 86.6% in no-SVT and SVT patients. Rebleeding occurred in 9.5 and 11.9% of no-SVT and SVT patients at 12 months. Varices relapsed more frequently in SVT than in no-SVT patients (25.4 vs. 14.67%, P=0.03). The rates of variceal rebleeding and relapse were similar in patients who received or did not receive anticoagulation, but mortality was significantly lower in patients who received anticoagulation. CONCLUSION: SVT favors the relapse of esophageal varices, but rebleeding can be effectively prevented by standard scheduled band ligations. Anticoagulation does not prevent variceal relapse. The improvement in the survival of patients treated with anticoagulation needs to be confirmed in future studies.