Clinical Impact and Safety of Anticoagulants for Portal Vein Thrombosis in Cirrhosis.

OBJECTIVES: Portal vein thrombosis (PVT) is a frequent complication of cirrhosis. Benefit, safety, and duration of anticoagulant treatment in this setting are controversial issues. The aim of this study was to analyze the course of PVT in a large cohort of cirrhotic patients undergoing or not anticoagulation therapy. METHODS: The data of 182 patients who presented between January 2008 and March 2016 with cirrhosis and PVT with at least 3 months of follow-up after the first PVT detection were analyzed. Eighty-one patients received anticoagulants and 101 were untreated per physician discretion. RESULTS: The extension of the thrombosis decreased by >50% in 46 (56.8%, with complete recanalization in 31/46) patients under anticoagulation and in 26 (25.7%) untreated patients. Of the 46 patients who underwent recanalization, 17 (36%) suffered recurrent thrombosis after stopping anticoagulation therapy. Kaplan-Meier analysis showed a higher survival rate in the treated group (p = 0.010). At multivariate analysis, anticoagulation was an independent factor associated with longer survival (HR:0.30, CI:0.10-0.91, p = 0.014). The Child-Turcotte-Pugh classes B/C negatively influenced survival (hazard ratio, (HR):3.09, confidence interval (CI):1.14-8.36, p = 0.027 for Child-Turcotte-Pugh B and HR:9.27, CI:2.67-32.23, p < 0.001 for Child-Turcotte-Pugh C). Bleeding complications occurred in 22 (21.8%) untreated and 16 (19.7%) treated patients, but in only four cases was it judged to be related to the anticoagulant treatment. No death was reported as a consequence of the bleeding events. CONCLUSIONS: Anticoagulant treatment is a safe and effective treatment leading to partial or complete recanalization of the portal venous system in 56.8% of cases, improving the survival of patients with cirrhosis and PVT. Discontinuation of the therapy is associated with a high rate of PVT recurrence.

MRI detection of soleus muscle injuries in professional football players.

OBJECTIVES: To describe magnetic resonance imaging (MRI) characteristics of soleus muscle injuries in symptomatic professional football players stratified according to both the Munich consensus statement and the British Athletics Muscle Injury Classification (BAMIC), and to investigate the association between specific MRI features and the "return to play" (RTP). MATERIALS AND METHODS: Professional football players with an episode of acute posterior calf pain and impaired function, subsequent to sports activity, underwent ultrasound followed by MRI examination reviewed by two different radiologists with more than 10 years of experience in the musculoskeletal system. MRI features and RTP outcome were evaluated for all types of injuries. RESULTS: During a 36-month period, a total of 20 professional football players were evaluated. According to the Munich consensus, 11 were type 3A, 8 were type 3B, and 1 was type 4, whereas according to the BAMIC, 11 lesions were considered grade 1, 4 grade 2, 4 grade 3, and 1 grade 4. RTP data were available for all patients (mean 3.3 ± 1.6 weeks). Both the Munich consensus and the BAMIC correlated with RTP (Spearman correlation = 0.982 and p < 0.0001 and 0.886 and p < 0.0001 respectively). Extension of edema was an independent prognostic factor for RTP in two different models of multivariate regression analysis (p = 0.044 model A; p = 0.031 model B). CONCLUSIONS: The Munich consensus and BAMIC grading systems are useful tools for defining the patient's prognosis and proper rehabilitation time after injury. The MRI feature that we should carefully look for is the extension of edema, as it seems to significantly affect the RTP.

NADPH oxidase activation and 4-hydroxy-2-nonenal/aquaporin-4 adducts as possible new players in oxidative neuronal damage presents in drug-resistant epilepsy.

A correlation between epilepsy and cellular redox imbalance has been suggested, although the mechanism by which oxidative stress (OS) can be implicated in this disorder is not clear. In the present study several oxidative stress markers and enzymes involved in OS have been determined. In particular, we examined the levels of 4-hydroxy-2-nonenal protein adducts (HNE-PA), a by-product of lipid peroxidation, and the activation of NADPH oxidase 2 (NOX2), as cellular source of superoxide (O(2)(-)), in surgically resected epileptic tissue from drug-resistant patients (N=50). In addition, we investigated whether oxidative-mediated protein damage can affect aquaporin-4 (AQP4), a water channel implicated in brain excitability and epilepsy. Results showed high levels of HNE-PA in epileptic hippocampus, in both neurons and glial cells and cytoplasmic positivity for p47(phox) and p67(phox) suggesting NOX2 activation. Interestingly, in epileptic tissue immunohistochemical localization of AQP4 was identified not only in perivascular astrocytic endfeet, but also in neurons. Nevertheless, negativity for AQP4 was observed in neurons in degeneration. Of note, HNE-mediated post-translational modifications of AQP4 were increased in epileptic tissues and double immunofluorescence clearly demonstrated co-localization of AQP4 and HNE-PA in epileptic hippocampal structures. The idea is that sudden, disorderly, and excessive neuronal discharges activates NOX2 with O(2)(-) production, leading to lipid peroxidation. The resulting generation of HNE targets AQP4, affecting water and ion balance. Therefore, we suggest that seizure induces oxidative damage as well as neuronal loss, thereby promoting neuronal hyperexcitability, also affecting water and ion balance by AQP4 modulation, and thus generating a vicious cycle.

Incidental pancreatic cystic lesions: comparison between CT with model-based algorithm and MRI.

INTRODUCTION: The present study aims to compare low-kV CT reconstructed with MBIR technique with MRI in detecting high-risk stigmata and worrisome features in patients with pancreatic cystic lesions. METHODS: We retrospective enrolled 75 patients who underwent low-kV CT with contrast media injection for general abdominal disorders and MRI with MRCP sequences. The reviewer, blinded to clinical and histopathological data, recorded the overall number of pancreatic cystic lesions, size, location, presence of calcifications, septa, or solid enhancing or non-enhancing components, main pancreatic duct (MPD) communication, and MPD dilatation. Mean differences with 95% limits of agreement, ICC, and κ statistics were used to compare CT and MRI. RESULTS: More pancreatic cystic lesions were detected with MRI than with CT, however, the ICC value of 0.81 suggested a good agreement. According to the evaluated target lesion, a very good agreement (ICC = 0.98) was found regarding the diameter (21.4 mm CT vs 21.8 mm MRI), the location (κ = 0.90), the detection of MPD dilatation (κ = 1), the presence of septa (κ = 0.86) and the MPD communication (κ = 0.87). A moderate agreement on the assessment of enhanced components was noted (κ = 0.44), while there was only a fair agreement about the presence of calcifications (κ = 0.87). CONCLUSION: MDCT can be considered almost equivalent to MRI with MRCP in the evaluation of worrisome features and high-risk stigmata, offering detailed morphologic features helpful for their characterization. IMPLICATIONS FOR PRACTICE: Even if MRI is considered the reference standard in pancreatic cystic lesions characterization, CT can be considered a useful tool as a first-line imaging technique to identify worrisome features and high-risk stigmata.

Glucocorticoid receptor mRNA expression in peripheral blood mononuclear cells in high trained compared to low trained athletes and untrained subjects.

BACKGROUND: Physiological needs during prolonged exercise are a potent stimulus for the hypothalamic-pituitary-adrenal (HPA) axis. Hence, athletes undergoing daily endurance training sessions may have frequent and prolonged phases of endogenous hypercortisolism. Since chronic glucocorticoids treatment leads to down-regulation of glucocorticoid receptor alpha (GR-alpha) mRNA expression, endurance training could lead to modulation of GR expression. AIM: The aim of the study was to evaluate GR-alpha and GR-beta mRNA expressions in peripheral blood mononuclear cells and plasma cortisol, ACTH and cortisol binding globulin (CBG) concentrations at rest in subjects undergoing different training regimes. SUBJECTS AND METHODS: Nine high trained (HT) swimmers (training volume: 21.6+/-1.7 hours/week in 10-12 sessions) were compared with two age-matched control groups represented by 8 low trained (LT) runners (training volume: 6.4+/-2.6 h/week in 3-5 sessions) and 9 untrained subjects. Expression of GR was determined by RT-PCR of total RNA. Hormone levels were determined by radioimmunoassay methods. RESULTS: HT athletes showed 10 times less GR-alpha mRNA expression than the untrained subjects, while LT athletes exhibited values about twofold less than the untrained subjects. GR-beta mRNA expression was undetectable in all subjects. No differences were observed among the three groups in hormone levels. CONCLUSIONS: GR- alpha mRNA expression is repressed in proportion to the amount and frequency of the stressful stimuli due to training. Hence, this down-regulation may be a consequence of the frequent and prolonged exposure to cortisol acute elevations induced by training. GR-beta did not play an important role in inducing the down-regulation of GR-alpha mRNA expression observed.

MRI characteristics of adductor longus lesions in professional football players and prognostic factors for return to play.

PURPOSE: To correctly define through Magnetic Resonance Imaging (MRI), diagnosis, staging and prognosis of the adductor longus (AL) acute lesions and to identify a correlation between Return to Play (RTP) and sport-related injury predisposing conditions and complications. MATERIALS AND METHODS: Twenty professional football players with acute groin pain and clinical suspicion of AL injury subsequent to sport's activity were evaluated. MRI examinations were performed by one and reviewed by other two radiologists with more than 10 years of experience. Lesions were stratified according to both Munich consensus statement and British Athletics Muscle Injury Classification (BAMIC). Patients were monitored until clinical recovery occurred. RESULTS: According to the Munich consensus statement, 75% of lesions were defined as type 3 and 25%as type 4; while according to the BAMIC, 45% were considered as Grade 1, 20% as Grade 2, 10% as Grade 3, and 25% as Grade 4. RTP was 1-2 weeks for minor lesions (45%), 4-6 weeks for moderate lesions (30%), and more than 6 weeks for complete lesions (25%). Both BAMIC and Munich consensus significantly correlated with RTP (R = 0.958 and 0.974, respectively). The extent of gap was the only independent prognosticator of RTP always present in all three different models of multivariate analysis (p < 0.006, p < 0.002, and p < 0.001, respectively). CONCLUSIONS: MRI represents the gold standard imaging technique for the evaluation of AL due to its ability not only to recognize but also to classify acute lesions and define patient's prognosis. MRI is also useful to detect potential predisposing conditions and complications, which may correlate with RTP.

Detection of a transforming gene in spontaneous reticulum cell sarcoma of SJL/J mice: genetically linked and host-dependent neoplasia.

Spontaneous reticulum cell sarcoma (RCS) tumor induction occurs in 90% of SJL/J mice of 8-13 months of age. Tumor induction and growth has been shown to be under the influence of both H-2 and non-H-2 genes as well as the presence of an intact host T-cell system. We postulated that cellular oncogenes may play a role in the induction, growth, and characteristics of RCS. DNA-mediated gene transfer protocols were adopted to investigate the presence of transforming genes in DNA from RCS of SJL/J mice. High molecular weight DNA was isolated from these tumors as well as from brains and livers of control tumor-free SJL/J mice and transfected into NIH-3T3 mouse and F2408 rat fibroblast cell lines. Foci of transformed cells with a peculiar round morphology were scored in both rat and mouse cultures given tumor DNA, but not in those receiving DNA from normal tissues. DNA from first-cycle transformants was transfected in further cycles of transfection, giving rise to foci with similar morphological appearances and growth properties. These experiments suggest that a transforming gene, present in RCS spontaneous tumors, is involved in the malignant conversion of the transfected normal fibroblasts. The implication of these results with respect to the induction and growth properties of RCS is discussed.

MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction.

Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. Here we show that elevated mtDNA mutagenesis in mice with a proof-reading deficient mtDNA polymerase (PolG) leads to incomplete mitochondrial clearance, with asynchronized iron loading in erythroid precursors, and increased total and free cellular iron content. The resulting Fenton chemistry leads to oxidative damage and premature destruction of erythrocytes by splenic macrophages. Our data indicate that mitochondria actively contribute to their own elimination in reticulocytes and modulate iron loading. Asynchrony of this sequence of events causes severe mitochondrial anaemia by depleting the organism of red blood cells and the bone marrow of iron. Our findings account for the anaemia development in a progeroid mouse model and may have direct relevance to the anemias associated with human mitochondrial disease and ageing.

[Role of parenteral feeding in an operative protocol of total artificial nutrition]. / Ruolo della nutrizione enterale nel protocollo operativo di una NAT.

Two cases of enterocutaneous fistula treated with mixed artificial diet (NP + NE) where enteral nutrition played the principal role in weaning from i.v. nutrition have been examined. Gradual transit was possible to normal diet, demonstrating ease of use and effectiveness of the nutritional contribution.

[Oxidative stress and Rett syndrome]. / La sindrome di Rett: ruolo dello stress ossidativo.

The oxidative stress (OS) hypothesis is able to explain several features of Rett syndrome (RTT), a pervasive development disorder almost exclusively affecting females mainly caused by a mutation in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. In particular, the generation of an OS imbalance is related to MeCP2 gene mutation type, as well as natural history, clinical heterogeneity of the disease, and is compatible with the potential reversibility of the disease observed in the RTT animal models. In addition, our findings indicate the importance of blood as a suitable biological fluid for detecting markers of central nervous system oxidative damage in RTT and underline the key role of interaction between organic chemists, OS biochemists, and clinicians in revealing potential new markers of the disease and identifying potential new targets and interventional strategies aimed at improving the quality of life of these patients, affected by a so far incurable disease. Further efforts in the near future are needed in order to dissect the "black box" of the molecular events likely linking the MeCP2 gene mutation to OS derangement and subsequent disease expression.

Endothelin receptor A expression in human inflammatory cells.

Most inflammatory diseases show elevated levels of endothelin-1 (ET-1) probably due to an alteration in vascular structure and function with activation/accumulation of inflammatory cells. The ET receptors (ET(A), ET(B)) are widely expressed in all human vessels, consistent with the main role of ET-1 in maintaining physiological vascular tone. Previous findings have shown the expression on inflammatory cells such as neutrophils (PMNs) and macrophages (MØs) of ET-1 and endothelin-converting enzyme-1 (ECE-1) (the key enzyme in the biosynthesis of ET-1). Therefore the role of ET-1 cannot be related only to the vasoactivity. Our study was aimed to determine the expression and the cellular location of ET receptors in both human PMNs and MØs by the use of RT-PCR assay, Western blot analysis and immunocytological methods. Our results showed for the first time that PMNs and MØs clearly expressed ET(A) (mRNA and protein). Considering that the overproduction of ET-1 following endothelial dysfunction and inflammation, contributes to pathophysiological processes such as vascular hypertrophy, cell proliferation and fibrosis, our results suggest that PMNs and MØs can also play a key role in vascular dysfunctions via the possible formation of an autocrine loop between ET-1 and ET(A).

Beta-carotene prevents ozone-induced proinflammatory markers in murine skin.

Beta-carotene has been thought to protect against oxidative stress generated by ultraviolet radiation and thus prevents skin cancer and skin aging (Biesalski and Obermueller-Jevic, 2001). However, nothing is known about its potential effects against other environmental sources of oxidative stress such as ozone (O3) in skin. Intake of oral beta-carotene supplements before exposure to sunlight (and thus inevitably also to (O3) has been recommended on a population-wide basis. However, although some studies have shown beta-carotene as providing skin protection as an antioxidant, other studies using skin cells in culture have shown that beta-carotene may have unexpected prooxidant properties (Obermüller-Jevic, et al., 2001). Given this, there is an ongoing debate regarding the protective or potentially harmful role(s) of beta-carotene in human skin. In this study, the effect of beta-carotene on ozone's effects on the skin of hairless mice was assessed. After feeding a diet supplemented with 0.5% beta-carotene for 1 month, mice were subjected to O3 exposure (0.8 ppm 6 h/day; 7 days) and the induction of proinflammatory markers such as tumor necrosis factor-alpha (TNFalpha), macrophage inflammatory protein 2 (MIP2), and inducible nitric oxide synthase (iNOS), and markers of oxidative stress, heme-oxygenase-1 (HO-1), were quantitated. The data showed that beta-carotene downregulated the induction of TNFalpha, MIP2, iNOS, and HO-1 in response to O3. We conclude that beta-carotene provides protection against O3-induced skin oxidative stress in vivo, which is consistent with a protective role for beta-carotene in the skin.

Endothelin-1 and endothelin-converting enzyme-1 in human granulomatous pathology of eyelid: an immunohistochemical and in situ hybridization study in chalazia.

Endothelin-1 (ET-1), a potent vasoconstrictor peptide, is involved in several functions of eye pathophysiology, such as regulation of intraocular tension and retinal reactive vasoconstriction. As ET-1 pro-inflammatory and fibrosing activity is emerging in different fields of pathology, we investigated the expression of ET-1 and endothelin-converting enzyme-1 (ECE-1) in chalazia, granulomatous lesions of the eyelid. ET-1 and ECE-1 were analyzed by immunohistochemistry (IHC) in twenty surgically removed chalazia, with regard to expression in eyelid structures and inflammatory infiltrate. Phenotype of ET-1 expressing inflammatory cells was established by double immunofluorescence. The cellular localization of prepro-ET-1 (pp-ET-1) mRNA and ECE-1 mRNA was studied by nonisotopic in situ hybridization (ISH). Neutrophils (PMNs), macrophages and T-lymphocytes were scattered in stroma, around alveoli and grouped in lipogranulomas. PMNs, macrophages, basal epithelium of meibomian adenomers and central ducts immunostained for ET-1. ECE-1 protein was found in meibomian adenomers, conjunctival epithelium, tarsal mucous glands and in inflammatory cells. Hybridization signals for pp-ET-1 mRNA and ECE-1 mRNA were recognized in healthy and degenerating meibomian ducts, adenomers, inflammatory cells, as well as in vessel walls. ECE-1 mRNA was also present in conjunctival epithelium and Henle's crypts. Our findings suggest that the multifunctional peptide ET-1 may have a role in molecular genesis of tissue damage in chalazia. ET-1 cytokine activity is likely to support the migration of inflammatory cells and the setting of lipogranulomas; ET-1 stimulation might contribute to proliferation of fibroblasts and collagen synthesis. ET-1 upregulation on meibomian adenomers and ducts may further enhance granulomas formation by stimulating lipid release.

Bacterial lipopolysaccharide and gamma interferon induce transcription of beta interferon mRNA and interferon secretion in murine macrophages.

Bacterial lipopolysaccharide (LPS) induces interferon (IFN) secretion and an antiviral state in murine peritoneal macrophages (PM). These cells secrete predominantly IFN-beta, as shown by neutralization assays with monoclonal antibodies. Secretion of IFN-beta is also induced in PM by IFN-gamma. LPS and IFN-gamma synergistically stimulated PM to produce IFN in amounts almost comparable to those induced by infection with Newcastle disease virus. Low levels of IFN-beta mRNA can be detected in freshly harvested PM by hybridization assays. The accumulation of this mRNA is markedly increased in PM treated with LPS or IFN-gamma, and it is further enhanced in the presence of the inhibitor of protein synthesis, cycloheximide. Similar studies were carried out on the RAW 264.7 line of transformed macrophages. These cells are induced to secrete IFN-beta by LPS but not by IFN-gamma, suggesting that this cytokine may elicit such specific response only in PM. IFN-beta mRNA is undetectable in untreated RAW 264.7 cells, and accumulation of this mRNA is induced by LPS but not by IFN-gamma. The secretion of IFN induced by these agents in PM and by LPS in RAW 264.7 cells and the corresponding accumulation of IFN-beta mRNA are blocked by an inhibitor of protein kinase C, staurosporine. The activity of this kinase is apparently necessary to stimulate accumulation of IFN-beta mRNA. The induction of IFN-beta by IFN-gamma appears to be a characteristic response of PM and may be at least in part responsible for the resistance of these cells to viral infections.

Doxazosin in the treatment of mild or moderate essential hypertension: an echocardiographic study.

Sixteen patients with mild or moderate essential hypertension received 1 to 8 mg/day of doxazosin (mean daily dose, 2.7 mg). Blood pressure reduction (supine and standing) was highly significant (p less than 0.001), and no significant changes in heart rate were observed. A significant reduction (p less than 0.01) in left ventricular mass was seen without a change in left ventricular systolic function. All side effects were mild, and only one patient withdrew from the study.

Estudio cruzado y evaluación ecocardiográfica de prazosin, propranolol e hidroclorotiazida en hipertensión arterial leve y moderada / Cross study and ecocardiographia evaluation of prazosin, propranolol and hydroclorothiazide in mild and moderate arterial hypertension

Veinte pacientes con hipertensión arterial esencial leve a moderada concluyeron un estudio cruzado distribuidos al azar en dos grupos: Grupo A: 10 pacientes que recibieron primero propranolol y posteriormente prazosin. Grupo B: 10 pacientes que recibieron inicialmente hidroclorotiazida y después prazosin. La reducción de la presión arterial en posición supina y de pie fue estadísticamente significativa y comparable con las tres drogas. Los efectos colaterales fueron menores con el prazosin. El análisis ecocardiográfico modo "M" en los pacientes con hipertrofia ventricular izquierda mostró reducción de la masa ventricular en 5 que recibieron propranolol y en 4 tratados con hidroclorotiazida. No encontramos reducción ulterior con el prazosin. La fracción de eyección y el acortamiento circunferencial de la fibra mejoraron en forma significativa con el prazosin (16 pacientes), no así con el propranolol ni con la hidroclorotiazida. Se concluye que el prazosin es una droga que puede ser utilizada como terapia inicial con pocos efectos secundarios a dosis bajas. Se propone el tratamiento secuencial de la hipertensión arterial leve a moderada en vez del esquema tradicional

Doxazosin en hipertensión arterial esencial leve a moderada: estudio ecocardiográfico / Doxazosin in mild to moderate essential hypertension: echocardiographic study

Trece pacientes con Hipertensión Arterial Esencial leve a moderada concluyeron un estudio abierto con Doxazosin en dosis de 1 a 8 mg. La reducción de la presión arterial en las diferentes posiciones fue altamente significativa (p < 0,001), mientras que la frecuencia del pulso y el peso corporal no se modificaron . Los effectos secundarios fueron leves y solamente un paciente fue retirado del estudio. No se presentaron cambios significativos en los exámenes de laboratorio. En el estudio ecocardiográfico Modo M realizado en ocho pacientes se observó una reducción significativa de la Masa Ventricular (p < 0,01), sin modificaciones en la función sistólica del ventrículo izquierdo. Concluimos que el Doxazosin, un nuevo bloqueante alfa 1 postsináptico, es efectivo en el tratamiento de los pacientes con hipertensión arterial esencial leve a moderada como monoterapia, con pocos efectos secundarios, que no modifica el metabolismo lipídico y que exhibe un efecto beneficioso sobre el corazón, al reducir la Masa Ventricular sin cambios en la función sistólica del ventrículo izquierdo