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An 18-year-old man presented to our hospital with muscular pain, diffuse petechiae, spontaneous thigh ecchymosis, edema and pain of the right knee, bilateral pretibial subcutaneous nodules, and gingival hypertrophy and hemorrhage. His history was positive for a mixed anxiety-depressive disorder and a restrictive diet caused by self-diagnosed food allergies. Skin lesions appeared like hyperkeratotic papules with coiled hairs and perifollicular hemorrhages. A diagnosis of scurvy was made upon demonstration of low serum levels of ascorbic acid. An allergy evaluation found cross-reactivity between pollens and food, related to the presence of panallergens. Moreover, we found that our patient was also affected by celiac disease. In conclusion, scurvy should be considered in the differential diagnosis of patients with petechiae and ecchymosis, especially when food restriction, malabsorption, or psychiatric disorders are present

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Background: Sortilin is a 95-kDa protein which has recently been linked to circulating cholesterol concentration and lifetime risk of developing significant atherosclerotic disease. Sortilin is found inside different cell types and circulating in blood. Higher circulating sortilin concentration has been found in patients with coronary atherosclerosis compared to control subjects. Sortilin concentration is influenced by statin therapy. Methods: We enrolled statin-naïve subjects with type 2 diabetes mellitus and we performed a cross-sectional study to evaluate the association between sortilin levels and the presence of clinically significant lower limb peripheral artery disease (PAD) in a population of statin-free diabetic subjects. Results: Out of the 154 patients enrolled in our study, 80 patients were free from PAD, while 74 had clinically significant PAD. Sortilin concentration was significantly higher in the latter group compared to the former (1.61 ± 0.54 ng/mL versus 0.67 ± 0.30 ng/mL, P < 0.01) and there was a trend toward increased sortilin levels as disease severity increased. The association of sortilin levels with PAD remained after adjusting for major risk factors in a multivariate analysis. Conclusions: We showed that sortilin is significantly and independently associated with the presence of lower limb PAD in a statin-free diabetic population and it may be a promising marker for clinically significant atherosclerosis of the lower limbs. Further studies are needed to confirm this finding and to evaluate its clinical usefulness.

Background: Clostridium difficile infection (CDI) is characterized by a relevant intestinal neutrophil infiltrate. So far, role of fecal calprotectin in CDI, has been investigated only in few studies, mainly focused on diagnosis of the disease. Aim: By a longitudinal design, we assess fecal calprotectin concentrations (FCCs) in subjects with CDI, evaluating the correlation between fecal marker and response to therapy. Methods: Clinical (diarrhea scoring) and laboratory (FCCs and leucocytes count) evaluation was performed in 56 subjects with CDI at time of diagnosis (T0) and after a week from starting of therapy (T1). Clinical response to therapy at T1was related with both T0and T1FCC values. FCCs were also related to all-cause 30-day mortality, recurrence and death, both of them within 90 days. Results: FCCs at T1were significantly increased in subjects with persistence of diarrhea in respect to the other ones (285.5 ± 270 µg/g vs 150.7 ± 147 µg/g, respectively; p 

RATIONALE: Fever of unknown origin (FUO) can be determined by different conditions among which infectious diseases represent the main cause. PATIENT CONCERNS: A young woman, with a history of aortic stenosis, was admitted to our unit for a month of intermittent fever associated with a new diastolic heart murmur and splenomegaly. Laboratory tests were negative for infectious screening. The total body computed tomography (CT) scan excluded abscesses, occulted neoplasia, or lymphadenopathy. DIAGNOSES: The transthoracic and transesophageal echocardiogram showed an aortic valve vegetation. Three sets of blood cultures were negative for all microorganisms tested. According to these findings, Bartonella endocarditis was suspected and the serology tests performed were positive. Finally, real-time polymerase chain reaction (RT-PCR) detected Bartonella henselae DNA on tissue valve. INTERVENTIONS: The patient underwent heart valve surgery and a treatment of Ampicillin, Gentamicin, and oral Doxycycline was prescribed for 16 days and, successively, with Doxycycline and Ceftriaxone for 6 weeks. OUTCOMES: After surgery and antibiotic therapy, patient continued to do well. LESSONS: Bartonella species are frequently the cause of negative blood culture endocarditis. Molecular biology techniques are the only useful tool for diagnosis. Valvular replacement is often necessary and antibiotic regimen with Gentamicin and either Ceftriaxone or Doxycycline is suggested as treatment.Echocardiogram and blood cultures must be performed in all cases of FUO. When blood cultures are negative and echocardiographic tools are indicative, early use of Bartonella serology is recommended.

Peripheral arterial disease (PAD), is a major health problem. Many studies have been focused on the possibilities of treatment offered by vascular regeneration. Human adipose-derived stem cells (HASCs), multipotent CD34 + stem cells found in the stromal-vascular fraction of adipose tissues, which are capable to differentiate into multiple mesenchymal cell types. The High mobility group box 1 protein (HMGB1) is a nuclear protein involved in angiogenesis. The aim of the study was to define the role of HMGB1 in cell therapy with HASCs, in an animal model of PAD. We induced unilateral ischemia in mice and we treated them with HASCs, with the specific HMGB1-inihibitor BoxA, with HMGB1 protein, and with the specific VEGF inhibitor sFlt1, alternately or concurrently. We measured the blood flow recovery in all mice. Immunohistochemical and ELISA analyses was performed to evaluate the number of vessels and the VEGF tissue content. None auto-amputation occurred and there have been no rejection reactions to the administration of HASCs. Animals co-treated with HASCs and HMGB1 protein had an improved blood flow recovery, compared to HASCs-treated mice. The post-ischemic angiogenesis was reduced when the HMGB1 pathway was blocked or when the VEGF activity was inhibited, in mice co-treated with HASCs and HMGB1. In conclusion, the HASCs treatment can be used in a mouse model of PAD to induce post-ischemic angiogenesis, modulating angiogenesis by HMGB1. This effect is mediated by VEGF activity. Although further data are needed, these findings shed light on possible new cell treatments for patients with PAD.

AIMS: Charcot Neuroarthropathy (CN) is a disabling complication, culminating in bone destruction and involving joints and articular cartilage with high inflammatory environment. Its real pathogenesis is unknown yet. In autoinflammatory diseases, as rheumatoid arthritis, characterized by inflammation and joints involvement, autoantibodies against post-translationally modified (ox-PTM) collagen type I (CI) and Type II (CII) were detected. Therefore, the aim of our study was to assess the potential involvement of autoimmunity in CN, investigating the presence of autoantibodies ox-PTM-CI and -CII, in subjects with CN. METHODS: In this case-control study, we enrolled 124 subjects with type 2 diabetes mellitus (47 with CN, 37 with diabetic peripheral neuropathy without CN, and 40 withuncomplicated diabetes), and 32 healthy controls. CI and CII were modified with ribose and other oxidant species and the modifications were evaluated with SDS-PAGE. Binding of sera from the subjects were analyzed with ELISA. RESULTS: Age, body mass index, waist and hip circumferences, and lipid profile were similar across the four groups, as well as glycated hemoglobin and duration of diabetes among people with diabetes. An increased binding to both native and all oxidative-modified forms of CII was found in subjects with CN and DN. Conversely, for CI, an aspecific increased reactivity was noted. CONCLUSIONS: Our results detected the presence of autoantibodies against oxidative posttranslational modified collagen, particularly CII, in subjects with CN and DN, suggesting the possible involvement of autoimmunity. Further studies are required to understand the role of autoimmunity in the pathogenesis of CN.

Chronic diarrhea in a patient with severe vitamin B12 deficiency: a rare clinical manifestation

Alterations of intestinal microflora may significantly contribute to the pathogenesis of different inflammatory and autoimmune disorders. There is emerging interest on the role of selective modulation of microflora in inducing benefits in inflammatory intestinal disorders, by as probiotics, prebiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). To summarize recent evidences on microflora modulation in main intestinal inflammatory disorders, PubMed was searched using terms microbiota, intestinal flora, probiotics, prebiotics, fecal transplantation. More than three hundred articles published up to 2015 were selected and reviewed. Randomized placebo-controlled trials and meta-analysis were firstly included, mainly for probiotics. A meta-analysis was not performed because of the heterogeneity of these studies. Most of relevant data derived from studies on probiotics, reporting some efficacy in ulcerative colitis and in pouchitis, while disappointing results are available for Crohn's disease. Probiotic supplementation may significantly reduce rates of rotavirus diarrhea. Efficacy of probiotics in NSAID enteropathy and irritable bowel syndrome is still controversial. Finally, FMT has been recently recognized as an efficacious treatment for recurrent Clostridium difficile infection. Modulation of intestinal flora represents a very interesting therapeutic target, although it still deserves some doubts and limitations. Future studies should be encouraged to provide new understanding about its therapeutical role.

To study the 3' immunoglobulin heavy-chain regulatory region (3'RR) enhancer complex, active in class switching recombination and in B-cells, in Crohn's disease. PATIENTS AND METHODS: A total of 167 patients [79 females (47.3%) and 88 males (52.7%)] affected by Crohn's disease were enrolled in the study. As a control, we included 64 healthy subjects, age and sex matched, from the same geographical area. Blood tests were performed on all subjects to determine their antibody levels and to detect the presence of any possible infections. We conducted a selective PCR, which amplified the hs1.2-A region. The nested second PCR to amplify the polymorphic core of the enhancer was performed. RESULTS: No differences between cases and controls were observed with respect to sex distribution (43.8% females among controls and 49.5% among cases), age, tTG IgA, RF, serum or secretory IgA, IgG1, IgG2 and IgG3. No correlation was found between both seric and secretory immunoglobulins levels, with except of statistically significant differences between cases and controls with respect to IgA and IgG ASCA positivity (p<0.001), serum IgG4 (p<0.001) and IgD (p=0.001). CONCLUSIONS: We have demonstrated that in Crohn's disease, the HS1,2 immunoglobulins enhancer is not implicated in the disease pathogenesis. Moreover, we have found that IgG4 levels are lower in Crohn's disease patients than in controls; these data may be related to an impairment of number and function of Tregs, further linked to the presence of tissue inflammation. Crohn's disease is a complex multifactorial disease. The pathogenesis of Crohn's disease is incompletely understood although it is clear that the disease involves multiple interacting agents.

OBJECTIVE: RANKL is a member of the TNF superfamily that stimulates chemokine release, monocyte/macrophage matrix migration and matrix metalloproteinase activity and plays an important role in atherosclerosis. In our study, we have evaluated whether RANKL gene polymorphisms are involved in ischemic stroke in Italian subjects. PATIENTS AND METHODS: In a retrospective study we have included 487 patients (242 males, 245 females) with history of ischemic stroke and 543 control subjects without history of ischemic stroke (277 males, 276 females). The rs9533156, and rs2277438 gene polymorphisms of the RANKL gene were analyzed by PCR and restriction fragment length polymorphism. RESULTS: We found that the rs9533156 gene polymorphism of the RANKL gene was significantly (55.0% versus 36.5%, p < 0.0001) and independently (adjusted OR 6.28 [2.34-4.21]) associated with history of ischemic stroke. No statistically significant difference was found between the two groups in our population for the rs2277438 gene polymorphism (p = 439). Furthermore, we have confirmed that rs 3134069, rs 2073617 and rs 2073618 polymorphisms of the OPG gene were significantly and independently associated with cerebrovascular disorders. CONCLUSIONS: The present study identifyes, for the first time, the genetic variant of RANKL as an independent risk factor for ischemic stroke.

OBJECTIVE: Fibroblast growth factor 23 (FGF23) was demonstrated to be involved in the occurrence and development of cardiovascular disease (CVD). The aim of this study was to investigate the potential role of FGF23 on presence and severity of peripheral arterial disease (PAD) in type 2 diabetic patients. PATIENTS AND METHODS: In this study, we analyzed FGF23 serum levels in 413 type 2 diabetic patients with PAD and in 598 diabetic controls without lower limbs atherosclerosis. RESULTS: We found that FGF23 median serum levels were significantly higher in patients than in diabetic controls (69.3 (58.8-75.1) pg/mL in PAD and 42.98 (37.1-49.8) pg/mL in subjects without PAD (p < 0.001) and were significantly and independently associated with critical limb ischemia (CLI) [OR, 7.69 (2.64-16.31); p = 0.001]. CONCLUSIONS: We have found, for the first time, that FGF23 could be associated with presence and severity of PAD in Italian patients with type 2 diabetes.

Venous thromboembolism (VTE) represents the third leading cause of cardiovascular mortality, and it is the main cause of preventable mortality in hospitalized patients. Among VTE, there is the unique case of isolated distal deep vein thrombosis (IDDVT), which still lacks an agreement in terms of optimal therapeutic strategy. Although most IDDVTs are self-limiting and associated with a very low risk of embolic complications, still not all IDDVTs can be safely identified as stable. Lack of strong scientific evidence, fear of thromboembolic complications, and risk of bleeding upon initiation of anticoagulant treatment result in very heterogeneous therapeutic strategies among physicians. Here, we provide a comprehensive review of the literature, highlight the many controversial issues regarding IDDVTs, and call for a consensus of experts aimed to shed new light on the gray areas of IDDVT management and therapy.

Overuse of thromboprophylaxis is not an infrequent behavior in internal medicine. However, differently from underuse, overuse of thromboprophylaxis is rarely taken into account, and only few studies have addressed this issue. The purpose of our study was to try to understand the reasons behind this phenomenon.

Worldwide, Streptococcus Pneumoniae is responsible for a considerable burden of illness especially in elderly and in people affected by chronic diseases. Vaccination reduces the burden of disease and two vaccines are currently available: a polysaccharide (PPV23) and a conjugate one (PCV13). Notwithstanding national recommendations to vaccinate people at risk, reaching them is not easy, especially in adulthood. For this reason a project was launched in Italy with an unrestricted grant of Pfizer in order to catch people at risk in the hospital setting. Description of the problem Vaccination of adults at risk is a relevant challenge for Public Health. The primary goal of this study is to estimate the prevalence of people at risk for pneumococcal diseases who have access to the hospital and are not vaccinated and to offer them the opportunity to be vaccinated in the hospital. For this purpose, all patients 50 years old or older who are admitted to the Department of Medical Sciences of the Teaching Hospital ‘A. Gemelli’ are interviewed through a questionnaire in order to identify eligibility to vaccination and, in that case, offer them PCV13. Results The project is ongoing but, at the present, it is showing that the prevalence of people at risk for pneumococcal diseases admitted to the hospital is very high and that the most of them did not receive any recommendation to be vaccinated. Beyond providing epidemiological data, the project is expected to increase the awareness of the need of vaccination, to provide eligible people with the vaccine and to support decision making in the identification of new strategies for setting up vaccination programs. Lessons Pneumococcal vaccination has been already proved to reduce the incidence of pneumococcal diseases and to be costeffective. This project will contribute to increase the knowledge of the current status of pneumococcal vaccination and its awareness and to disclose possible ways to increase vaccination coverage. Key messag

BACKGROUND: The object of this study was to investigate the potential role of FGF23 on plaque stability in type 2 diabetic patients with internal carotid artery stenosis. METHODS: In this retrospective observational study, we analyzed FGF23 serum level in 361 type 2 diabetic patients with internal carotid artery stenosis undergoing carotid endarterectomy and in 598 diabetic controls without carotid atherosclerosis. RESULTS: We found that FGF23 median serum levels was significantly higher in patients than in diabetic controls [67.7 (59.5-77.8) pg/mL and 43.89 (37.5-50.4), P < 0.001] and was significantly and independently associated with unstable plaque in patients with internal carotid artery stenosis [OR, 5,71 (95% CI, 2.09-15.29]. CONCLUSIONS: We have found, for the first time, that FGF23 could be associated with unstable plaque in type 2 diabetic patients with internal carotid artery stenosis.

The gut is able to maintain tolerance to microbial and food antigens. The intestine minimizes the number of harmful bacteria by shaping the microbiota through a symbiotic relationship. In healthy human intestine, a constant homeostasis is maintained by the perfect regulation of microbial load and the immune response generated against it. Failure of this balance may result in various pathological conditions. Innate immune sensors, such as Toll-like receptors (TLRs), may be considered an interface among intestinal epithelial barrier, microbiota, and immune system. TLRs pathway, activated by pathogens, is involved in the pathogenesis of several infectious and inflammatory diseases. The alteration of the homeostasis between physiologic and pathogenic bacteria of intestinal flora causes a condition called dysbiosis. The breakdown of homeostasis by dysbiosis may increase susceptibility to inflammatory bowel diseases. It is evident that environment, genetics, and host immunity form a highly interactive regulatory triad that controls TLR function. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes, such as in IBD, colitis, and colorectal cancer. The study of interactions between different components of the immune systems and intestinal microbiota will open new horizons in the knowledge of gut inflammation.

Hydroxyurea as an indirect antithrombotic agent: In Myeloproliferative neoplasms (MPNs) thrombosis is an important cause of morbidity and mortality and some experimental studies reported an indirect, but significant, anti-thrombotic efficacy of hydroxyurea (HU), currently the most used cytoreductive agent in these disorders (1-2). HU was studied in important randomized clinical trials, one carried out in Polycitemia Vera (PV) and two in Esssential Thrombocytemia (ET) patients (3). In summary Finazzi describes these last studies, one trial comparing HU with a randomized untreated control group performed in 114 patients with ET and a high risk of thrombosis, and another comparing HU plus low-dose aspirin with anagrelide plus low-dose aspirin in 809 ET high-risk. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. Hydroxyurea mediated release of nitric oxide in myeloproliferative neoplasms patients: Effects on platelet-leukocyte interaction - ResearchGate. Available from: http://www.researchgate.net/publication/277081198_Hydroxyurea_mediated_release_of_nitric_oxide_in_myeloproliferative_neoplasms_patients_Effects_on_platelet-leukocyte_interaction [accessed Oct 12, 2015].

Celiac disease (CD) is an immune-mediated enteropathy, triggered by dietary wheat gluten and similar proteins of barley and rye in genetically susceptible individuals. This is a complex disorder involving both environmental and immune-genetic factors. The major genetic risk factor for CD is determined by HLA-DQ genes. Dysfunction of the innate and adaptive immune systems can conceivably cause impairment of mucosal barrier function and development of localized or systemic inflammatory and autoimmune processes. Exposure to gluten is the main environmental trigger responsible for the signs and symptoms of the disease, but exposure to gluten does not fully explain the manifestation of CD. Thus, both genetic determination and environmental exposure to gluten are necessary for the full manifestation of CD; neither of them is sufficient alone. Epidemiological and clinical data suggest that other environmental factors, including infections, alterations in the intestinal microbiota composition, and early feeding practices, might also play a role in disease development. Thus, this interaction is the condicio sine qua non celiac disease can develop. The breakdown of the interaction among microbiota, innate immunity, and genetic and dietary factors leads to disruption of homeostasis and inflammation; and tissue damage occurs. Focusing attention on this interaction and its breakdown may allow a better understanding of the CD pathogenesis and lead to novel translational avenues for preventing and treating this widespread disease.

The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein.

The rising prevalence of obesity is a major global health problem. In severe obesity, bariatric surgery (BS) allows to obtain a significant weight loss and comorbidities improvement, among them one of the factors is the thrombotic risk. In this observational study, we measured indices of leukocyte activation in severely obese patients as markers of increased thrombotic risk in relation with serum markers of inflammation before and after BS.Frequency of polymorphonuclear neutrophil-platelet (PLT) and monocyte (MONO)-PLT aggregates as well as of tissue factor (TF) expressing MONOs was measured in the peripheral blood of 58 consecutive obese patients and 30 healthy controls. In 31 of the 58 obese patients, data obtained at the enrollment were compared with those obtained at 3, 6, and 12 months after BS.Compared with healthy controls, obese patients showed a higher frequency of polymorphonuclear leukocyte (PMNL)-PLT aggregates (7.47 ± 2.45 [6.82-8.11]% vs 5.85 ± 1.89 [5.14-6.55]%, P = 0.001), MONO-PLT aggregates (12.31 ± 7.33 [10.38-14.24]% vs 8.14 ± 2.22 [7.31-8.97]%, P < 0.001), and TF expressing MONOs (4.01 ± 2.11 [3.45-4.56]% vs 2.64 ± 1.65 [2.02-3.25]%, P = 0.002). PMNL-PLT and MONO-PLT aggregate frequency was positively correlated with TF expressing MONOs (R = 0.260, P = 0.049 and R = 0.318, P = 0.015, respectively).BS was performed in 31 patients and induced a significant reduction of the body mass index, and waist and hip circumferences. These effects were associated with a significant decrease of PMNL-PLT aggregates at 12 months (7.58 ± 2.27 [6.75-8.42]% vs 4.47 ± 1.11 [3.93-5.01]%, P < 0.001), and a reduction of TF expressing MONOs at 6 (3.82 ± 2.04 [3.07-4.57]% vs 1.60 ± 1.69 [0.30-2.90]%, P = 0.008) and 12 months (3.82 ± 2.04 [3.07-4.57]% vs 1.71 ± 0.54 [1.45-1.97]%, P = 0.001) after BS.These data suggest that leukocyte-PLT aggregate formation and MONO activation represent an important mechanism underlying the increased thrombotic risk of obese patients. We

Catheter-related bloodstream infections (CRBI) represent a frequent complication of immune-compromised hosts with a high mortality rate. In this setting, opportunistic pathogens can create a biofilm on implanted devices, being the source of infection. We provide a mini-review of the literature, starting from the description of two cases of CRBI by opportunistic pathogens in poly-morbid patients, successfully treated by antibiotic lock-therapy.

Received: 6 May 2015 / Accepted: 14 May 2015 SIMI 2015 A 36-year-old man with no relevant past medical history was referred to our Internal Medicine outpatients Unit because of shortness of breath gradually occurred during the last 12 months. He was working as a security agent and was experiencing this symptomatology during sports activities, in particular during scuba diving. Notably, the patient had gained about 8 kilos in the prior year. The patient’s general appearance was good: he was eupnoeic and comfortable with no respiratory distress while resting. Blood pressure was 118/72 mmHg, pulse rate was 58 beats/min, respiratory rate was 13 breaths/min with an oxygen saturation of 98 %. At physical examination, a reduced murmur at the left lower lung field was found. A chest X-ray study showed a marked elevation of the left hemi-diaphragm, and a significant right shift of the mediastinum, with no signs of pneumothorax or pleural effusion (Fig. 1a). An US scan showed the absence of diaphragmatic thickening during inspiration. A chest MRI (Fig. 1b, c) confirmed the marked elevation of the left hemi-diaphragm up to a plane passing through the carina. The diaphragmatic dome was normal without signs of diaphragmatic rupture. The midline was significantly shifted to the right. The spleen, small bowel, transverse colon, pancreatic tail and left lobe of the liver were in the thorax with an ‘‘upside down’’ stomach. Relaxatio diaphragmatica, also called diaphragmatic elevation, is an anomalous position of the diaphragmatic dome in the chest and represents a rare case of exertional dyspnoea [1]. It can be a congenital or acquired condition; this lasts mostly due to phrenic nerve palsy or post-traumatic rupture of the diaphragm. The diagnostic workup requires a complete medical history and diagnostic tests [2, 3]. A pleural effusion can be excluded by chest X-ray study or US scan. Diaphragmatic motility can be assessed by chest radiograms (comparing inspiratory vs. expiratory i

BACKGROUND: Alcohol abuse represents the most common cause of liver disease in the Western countries. Pre-clinical and clinical studies showed that alcohol consumption affects amount and composition of gut microbiota. Moreover, gut flora plays an important role in the pathogenesis of alcoholic liver injury. AIM: To review the relationship between alcohol administration and changes on gut microbiota, its involvement in the pathogenesis of alcoholic liver disease, and how gut microbiota modulation could be a target for the treatment of alcoholic liver disease. METHODS: Articles were identified using the PubMed database with the search terms 'Alcohol', 'Gut Microbiota', 'Alcoholic liver disease', 'Probiotic', 'Prebiotic', 'Symbiotic' and 'Antibiotic'. English-language articles were screened for relevance. Full review of publications for the relevant studies was conducted, including additional publications that were identified from individual article reference lists. RESULTS: Alcohol abuse induces changes in the composition of gut microbiota, although the exact mechanism for this alteration is not well known. The translocation of bacterial products into the portal blood appears to play a key role in alcohol-induced liver damage. Several studies show that the modulation of gut microbiota seem to be a promising strategy to reduce alcohol-induced liver injury. CONCLUSIONS: Further studies are needed to better understand the relationship between alcohol administration and changes in gut microbiota, and its involvement in alcoholic liver disease. Moreover larger studies are needed to confirm the preliminary results on the therapeutic effects of gut microbiota modulation.

The best strategy for managing patients with resolved hepatitis B virus infection (HBsAg negative, anti-HBc antibodies positive with or without anti-HBs antibodies) and hematological malignancies under immunosuppressive therapies has not been defined. The aim of this study was to prospectively analyze the risk of hepatitis B virus reactivation in these patients.

Screening for and prophylaxis of venous thromboembolism in severe carbon monoxide poisoning?

Rivaroxaban, un nuovo inibitore orale diretto del fattore Xa, è stato recentemente approvato per il trattamento del tromboembolismo venoso (TEV) e per la prevenzione dell’ictus nei pazienti con fibrillazione atriale (FA) non valvolare. Un gruppo di specialisti italiani, composto da internisti, ematologi, angiologi, cardiologi, neurologi e coordinato da un panel di esperti, ha analizzato mediante metodo “Delphi” modificato la gestione di tali condizioni cliniche nella pratica clinica di differenti contesti sanitari ed hanno discusso i limiti e le discrepanze riscontrate negli studi clinici e nelle linee guida, nonché il ruolo di rivaroxaban nel trattamento del TEV e della FA non valvolare. Tale indagine, denominata “progetto EXTRA”, è stata suddivisa in due sezioni (EXTRA-TEV, EXTRA-FA) e si è svolta in due fasi: la prima comprendeva la compilazione di un questionario online, mentre nella seconda è stato organizzato un incontro al quale hanno preso parte tutti gli specialisti coinvolti al fine di discutere gli argomenti maggiormente controversi. Quasi tutti i partecipanti sono stati concordi nel riconoscere a rivaroxaban un ruolo fondamentale nella prevenzione dell’ictus e nel trattamento del TEV, in virtù del suo prevedibile profilo farmacocinetico e farmacodinamico, dell’ampia finestra terapeutica, dell’assenza di interazioni con molti dei farmaci più frequentemente prescritti, del fatto che non necessita di monitoraggio routinario del livello di anticoagulazione e della buona tollerabilità in un ampio spettro di pazienti ad elevato rischio di complicanze. Vengono qui riportati i risultati dell’indagine, unitamente alle opzioni attuali di utilizzo di rivaroxaban nei diversi contesti e alle prospettive cliniche future.

STUDY QUESTION: How does endothelial function change in women with endometriosis after surgical treatment? SUMMARY ANSWER: Surgical treatment of endometriosis leads to endothelial function improvement, resulting in reduction of cardiovascular risk. WHAT IS KNOWN ALREADY: Some recent studies have demonstrated that in young women with endometriosis, even if structural alterations are absent, endothelial dysfunction, expressed as flow-mediated dilation (FMD) impairment, can nevertheless occur. However, there are no data about changes of endothelial function in women with endometriosis after surgical treatment of endometriosis. STUDY DESIGN, SIZE, DURATION: This is a follow-up study carried out in 68 women enrolled in a previous study. Endothelial function was evaluated 2 years after surgical procedure and compared with baseline values. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-two patients who had undergone surgical treatment of endometriosis (named as patients with STE) and 10 control subjects without endometriosis, from the original study sample participated in this follow-up study. Assessment of endothelial function by FMD evaluation and measurements of serum markers of endothelial activation and inflammation were done in all these subjects. MAIN RESULTS AND THE ROLE OF CHANCE: After a 2-year follow-up period, FMD increased significantly with respect to baseline values among patients with STE [average pre- to post-difference: 5.07%, 95% confidence intervals (CI) 3.50, 6.63%; P < 0.001] but not among controls (average pre- to post-difference: 1.56%, 95% CI -0.55, 3.67%; P = 0.13). Follow-up FMD values were not significantly different between patients with STE and controls (average difference 1.50%, 95% CI -1.24, 4.23%; P = 0.27). Follow-up markers of inflammation and endothelial cells activation were similar among patients with STE and controls. LIMITATIONS, REASONS FOR CAUTION: Although this study represents the first in the literature assessing endothelial f

Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. OPG has been hypothesized to modulate vascular functions; however, its role in mediating atherosclerosis is controversial. Epidemiological data in patients with cardiovascular disease (CVD) indicate that OPG serum levels are associated with several inflammatory markers, myocardial infarction events, and calcium scores, suggesting that OPG may be causative for CVD.

Multimorbidity and polypharmacy in the elderly: lessons from REPOSI

Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. OPG has been hypothesized to modulate vascular functions; however, its role in mediating atherosclerosis is controversial. Epidemiological data in patients with cardiovascular disease (CVD) indicate that OPG serum levels are associated with several inflammatory markers, myocardial infarction events, and calcium scores, suggesting that OPG may be causative for CVD.

Prophylaxis against venous thromboembolism in patients with cancer.

Background/Aim. Uncomplicated diverticular disease (UDD) is a frequent condition in adults. The pathogenesis of symptoms remains unknown. Bacteria are able to interact with Toll-like receptors (TLRs) and to induce inflammation through both innate immunity and T-cell recruitment. We investigated the pattern of TLRs 2 and 4 and the intestinal homing in patients with UDD before and after a course of Rifaximin. Methods. Forty consecutive patients with UDD and 20 healthy asymptomatic subjects were enrolled. Among UDD patients, 20 were assigned to a 2-month course of treatment with Rifaximin 1.2 g/day for 15 days/month and 20 received placebo. Blood sample and colonic biopsies were obtained from patients and controls. The samples were collected and analyzed at baseline and at the end of treatment. Flow cytometry was performed using monoclonal antibodies (CD3, CD4, CD8, CD103, TCR-gamma/delta, CD14, TLR2, and TLR4). Results. In UDD, TLR2 and TLR4 expression on immune cell subpopulations from blood and mucosa of the affected colon are altered as compared with controls. Rifaximin treatment induced significant modifications of altered conditions. Conclusions. Our data show the role of TLRs in the development of inflammation in UDD. TLRs distribution is altered in UDD and these alterations are reversed after antibiotic treatment. This trial is registered with ClinicalTrials.gov: NCT02068482.

'Doctor, treat your patient, not your monitor!' Tremor-induced ECG artefacts mimicking torsades de pointes

How does endothelial function change in women with endometriosis after surgical treatment?

An 85-year-old man with acute-onset of confusion and dyspnea after a fall: a diagnostic challenge

Thromboprophylaxis in patients with stroke: A delicate decision

Hypokalemia is a common biochemical abnormality. Severe Hypokalemia can produce cardiac rhythm alterations and neurologic manifestations. Early detection and treatment allow clinician to prevent morbidity and mortality from cardiac arrhythmias and respiratory failure. Here we describe a case of severe hypokalemia inducing pseudo ischemic electrocardiographic (ECG) alterations and quadriplegia in a patient affected by chronic diarrhea. Electrocardiographic alterations and neurologic manifestations completely disappeared after potassium replacement: however, prolonged potassium supplementation was required to achieve the normalization of plasmatic potassium levels. Consecutive figures show ECG improvement until normalization of ECG findings. Hypokalemia is a common biochemical abnormality in approximately 11% of patients admitted to the emergency department (ED) (1). Early detection and treatment allow clinician to prevent morbidity and mortality from cardiac arrhythmias and respiratory failure. Moreover a relationship between hypokalemia and quadriplegia has been reported in some cases (2). Here we describe a case of severe hypokalemia inducing pseudo ischemic ECG alterations and quadriplegia. A 77-year-old woman presented to the ED complaining of epigastric pain, vomiting, generalized weakness, impossibility to walk and dysphagia. Epigastric pain and vomiting acutely appeared 3 hours before to the ED arrival, whereas weakness and dysphagia progressively developed in 48 hours. The patient had undergone duodenocephalopancreasectomy 6 weeks before because of duodenal adenocarcinoma. Few days after discharge from surgery clinic, diarrhea developed with approximately 6 to 8 stool emission per day. The patient was also affected diabetes mellitus and mild aortic stenosis (a preoperatory balloon valvuloplasty downstaged the stenosis from severe mild). Her drug therapy included pantoprazole, metformin, insulin-determir, aspirin and pancreatic enzymes. At the ED, blood pressu

The Hedgehog (Hh) pathway is a crucial regulator of muscle development during embryogenesis. We have previously demonstrated that Sonic hedgehog (Shh) regulates postnatal myogenesis in the adult skeletal muscle both directly, by acting on muscle satellite cells, and indirectly, by promoting the production of growth factors from interstitial fibroblasts. Here, we show that in mdx mice, the murine equivalent of Duchenne muscular dystrophy in humans, progression of the dystrophic pathology corresponds to progressive inhibition of the Hh signaling pathway in the skeletal muscle. We also show that the upregulation of the Hh pathway in response to injury and during regeneration is significantly impaired in mdx muscle. Shh treatment increases the proliferative potential of satellite cells isolated from the muscles of mdx mice. This treatment also increases the production of proregenerative factors, such as insulin-like growth factor-1 and vascular endothelial growth factor, from fibroblasts isolated from the muscle of mdx mice. In vivo, overexpression of the Hh pathway using a plasmid encoding the human Shh gene promotes successful regeneration after injury in terms of increased number of proliferating myogenic cells and newly formed myofibers, as well as enhanced vascularization and decreased fibrosis.Gene Therapy advance online publication, 27 February 2014; doi:10.1038/gt.2014.13.

Previous investigations of the relationship between characteristics of immunoproteins on red blood cells (RBCs) and the occurrence of autoimmune haemolysis yielded divergent results. Here, we studied these characteristics in autoimmune haemolytic anaemias (AIHAs) to determine their relationship with the degree of anaemia at diagnosis. We studied at diagnosis 52 cases of warm AIHA with positive direct antiglobulin test. Immunohaematological testing and determination of immunoglobulin class, complement, and immunoglobulin G (IgG) were performed using gel technology (GCT). Median haemoglobin (Hb) levels significantly differed between cases with IgG1 only or negative for IgG subclasses (7.4 g/dl), those with IgG3 or IgG1 + IgG3 (6.5 g/dl), and those with multiple immunoglobulins (5 g/dl). Logistic regression indicated that IgG3 detection was the only variable significantly related to the occurrence of RBC transfusion in AIHA (odds ratio 4.05, 95 % CI 1.1-14.7). In our study, the type of immunoprotein(s) on the RBC surface was associated with different Hb levels at AIHA diagnosis. IgG3 and multiple immunoglobulins were associated with lower Hb levels; IgG3 was also associated with a higher percentage of patient transfusions in the first week after diagnosis. Thus, qualitative differences in these immunoproteins may lead to deeper and more prolonged anaemia levels, influencing the need for RBC transfusion.

Superior vena cava syndrome is characterised by dyspnoea, headache, facial oedema, and venous distention in the neck, upper chest and arms. These symptoms are bilateral. A 47-year-old woman reported the appearance of venous ectasias in the right side of her chest, face and neck. The patient was affected by systemic lupus erythematous with antiphospholipid syndrome and end-stage renal disease. She was on haemodialysis via a right subclavian central venous silicone, double-lumen, tunnelled catheter (central venous catheter, CVC) because of a previous thrombosis of arteriovenous fistula. Although this type of CVC has a higher risk of complications (ie, thrombosis), the reason of this choice was not clear, since the patient was treated at another haemodialysis service. At physical examination, the patient's clinical condition was discrete; right side of the face appeared slightly swollen; distension of the right external jugular vein and superficial ectasic veins of the right hemithorax were present (figure 1). Ultrasound scan showed a fibrotic right internal jugular vein, without Doppler signal. Neck and chest CT confirmed the lack of contrast enhancement of the right internal jugular vein in its distal tract (5.5 cm) until the confluence with the subclavian vein (figures 2A, B) and the presence of multiple ectasic veins of the subcutaneous tissue of the right anterior chest wall and neck (figures 3 and 4). The CVC was passing through the brachiocephalic vein to the right atrium.

In a previous report, we investigated the capability of commercially available immunohematology tests based on gel technology to add useful information for the diagnosis of autoimmune hemolytic anemia (AIHA). In this report, we analyzed the same casuistic to find useful information on the importance of different immunohematology tests for the AIHA diagnosis, but using the artificial neural network (ANN) analysis. We studied 588 samples with a positive direct antiglobulin test (DAT), of which 52 samples came from patients with AIHA. The samples were analyzed with the ANN using the multilayer perceptron with the backpropagation algorithm. Using the ANN in the observed data set, the predictive value for the presence of AIHAs was 94.7%. The rate of DAT-positive cases that were not AIHA and that were correctly classified was 99.4%. The receiver operating curve area for the model was 0.99. The independent variable importance analysis found that the gel centrifugation test anti-IgG titer was an important contributor to the network performance, but other variables such as the IgG subclasses can also be considered important. The use of the ANN permitted us to identify immunohematology tests that were "hidden" with the common statistical models used previously. This was the case for the IgG subclasses. However, it is very likely that the information given to the network from those tests is quantitative rather than qualitative.

BACKGROUND: Persistent hiccup is a worrying symptom both for patients, because of reduced quality of life, and for physicians, because of frustration for unsuccessful treatments. AIM: To test baclofen administration for the treatment of persistent hiccup. METHOD: We report a series of seven patients affected by persistent hiccup successfully treated with baclofen. RESULTS: Hiccup stopped in all patients after a single administration of the drug. CONCLUSIONS: Baclofen is a GABA(B) receptor agonist. It is conceivable that the reduction of dopamine release by GABA(B) receptor stimulation is able to interrupt hiccup's reflex arc.

BACKGROUND: Fecal calprotectin (FC) has been proposed as a useful and non-invasive marker of acute intestinal inflammation. AIM: We summarize recent evidences on FC, providing practical perspectives on its diagnostic and prognostic role in different gastrointestinal conditions. MATERIALS AND METHODS: We performed a MEDLINE search for all articles published on FC in human gastroenterology field up to December 2011. We chose evidences from well-designed and controlled studies when available. A meta-analysis was not performed because of the heterogeneity of these studies. RESULTS: Most of relevant data derived from studies on inflammatory bowel disease (IBD). FC concentrations (FCCs) showed a good diagnostic precision for separating organic and functional intestinal diseases and well correlated with IBD activity. FCCs were higher in subjects with NSAID enteropathy, but the actual correlation between FC and endoscopy is under investigation. FCCs can not be recommended for colorectal neoplasia population screening purpose. Few and heterogeneous studies have been performed in order to evaluate role of FC in other gastrointestinal conditions. CONCLUSIONS: FC has been widely proposed as a filter to avoid unnecessary endoscopies. Nevertheless, it should not be considered as a marker of organic intestinal disease at all; rather it represents a marker of "neutrophilic intestinal inflammation". In IBD, more and larger studies are needed to confirm FC's capacity to correlate with IBD extent, to predict response to therapy and relapse, and the presence of a subclinical intestinal inflammation in asymptomatic first-degree relatives of patients. For NSAID enteropathy, the actual correlation between FC and endoscopic results needs further confirmation. Finally, as regarding other gastrointestinal conditions, available data are still insufficient to draw any final conclusion and further studies should be encouraged.

Many concerns about liver transplantation in alcoholic patients are related to the risk of alcohol recidivism. Starting from 2002, an Alcohol Addiction Unit (AAU) was formed within the liver transplant center for the management of alcoholic patients affected by end-stage liver disease and included in the waiting list for transplantation. We evaluated retrospectively the impact of the AAU on alcohol recidivism after transplantation. The relationship between alcohol recidivism and the duration of alcohol abstinence before transplant was evaluated as well.

Many concerns about liver transplantation in alcoholic patients are related to the risk of alcohol recidivism. Starting from 2002, an Alcohol Addiction Unit (AAU) was formed within the liver transplant center for the management of alcoholic patients affected by end-stage liver disease and included in the waiting list for transplantation. We evaluated retrospectively the impact of the AAU on alcohol recidivism after transplantation. The relationship between alcohol recidivism and the duration of alcohol abstinence before transplant was evaluated as well.

Dystrophin, the missing or defective protein in Duchenne muscular dystrophy, is expressed not only in muscle cells but also in vascular endothelial cells (ECs). In this study, we assessed the effects of dystrophin deficiency on the angiogenic capacities of ECs.

An 84-year-old woman, affected by Alzheimer's disease, presented to the emergency department with intense dyspnoea. Since ECG was showing T wave inversion in anterior leads and troponin-T was high, the patient was admitted to our unit with a diagnosis of anterior non-ST elevation myocardial infarction. However, the patient's medical history and a further review of the ECG led us to suspect a pulmonary embolism (PE) as a possible differential clinical diagnosis. We tested this alternative hypothesis: echocardiography as well as contrast-enhanced CT scan confirmed the diagnosis of PE. We describe these misleading ECG findings together with a brief discussion of electrocardiographical changes in pulmonary embolism.

I-scan technology is the newly developed endoscopic tool that works in real time and utilizes a digital contrast method to enhance endoscopic image.

Sorafenib has become the standard first-line treatment for patients with advanced HCC and acts by inducing alterations in tumor vascularity. We wanted to evaluate the feasibility of dynamic CEUS (D-CEUS) as a predictor of early tumor response to sorafenib and to correlate functional parameters with clinical efficacy end points.