Nicolò Gentiloni Silveri

Cardiopulmonary bypass in man: role of the intestine in a self-limiting inflammatory response with demonstrable bacterial translocation

BACKGROUND Cardiopulmonary bypass provokes a systemic inflammatory reaction that, in 1% to 2% of all cases, leads to multiorgan disfunction. The aim of this study was to evaluate the possible role of the intestine in the pathogenesis and development of this reaction. METHODS Eleven selected patients scheduled for elective coronary artery bypass graft surgery were enrolled in a open, prospective clinical study. Gastric tonometry, chromium-labeled test and double sugar intestinal absorption tests, polymerase chain reaction microbial DNA test, and measurement of cytokines and transcriptional factor (nuclear factor kappaB) activation were performed. RESULTS During the postoperative period, gastric pH remained stable (range,7.2 to 7.3). The partial pressure for carbon dioxide gradient between the gastric mucosa and arterial blood increased significantly (from 1 to 23 mm Hg), peaking in the sixth postoperative hour. Interleukin 6 increased significantly over basal levels, peaking 3 hours after cardiopulmonary bypass (96.3 versus 24 pg/mL). Nuclear factor kappaB never reached levels higher than those observed after lipopolysaccharide stimulation. Escherichia coli translocation was documented in 10 patients: in eight cases from removal of aortic cross-clamps and in two cases from the first postoperative hour. With respect to basal value (6.4%), the urine collection revealed a significant increase in excretion of the radioisotope during the first 24 hours after surgery (39.1%), although there were no significant variations with the double sugar test. CONCLUSIONS The results obtained showed a correlation between the damage of the gastrointestinal mucosa, subsequent increased permeability, E coli bacteremia, and the activation of a self-limited inflammatory response in the absence of significant macrocirculatory changes and postoperative complications.

Efficacy of different Helicobacter pylori eradication regimens in patients affected by insulin-dependent diabetes mellitus.

Background: Patients with insulin-dependent diabetes mellitus (IDDM) are often affected by chronic infections; antibiotic absorption, however, may be influenced by the disease. H. pylori eradication appears to be reduced in IDDM patients. The aim of the study was to evaluate the efficacy of the most common H. pylori eradication regimens in a population of IDDM-infected patients. Methods: One hundred and seventy-two IDDM patients were evaluated. H. pylori infection was assessed through the 13C-urea breath test. Infected patients were randomly assigned to three different standard 7-day eradication regimens: 1) amoxicillin, clarithromycin, pantoprazole; 2) tinidazole, clarithromycin, ranitidine bismuth citrate; or 3) tinidazole, clarithromycin, pantoprazole. Patients in whom eradication was not successful in the first cycle were subsequently submitted to a 7-day therapy with tinidazole, tetracycline, bismuth, and pantoprazole. Results: Thirty-seven per cent of IDDM patients were infected. None of the triple therapies used provided an eradication higher than 62%. Conversely, the quadruple regimen was successful in 88% of the patients. Ten per cent of the subjects undergoing the triple therapies showed minor side effects, without significant differences among groups, whereas side effects occurred in 25% of the patients treated with the quadruple therapy (P < 0.05). Conclusions: IDDM patients show a low H. pylori eradication rate with a standard triple therapy regardless of the regimen utilized, the dosage and/or the duration of the therapy used appearing not to be sufficient to eradicate the infection efficiently. The use of a quadruple regimen leads to the cure of a large percentage of the infected patients in whom the eradication was unsuccessful in the first therapy, although it is accompanied by a greater incidence of minor side effects.BACKGROUND Patients with insulin-dependent diabetes mellitus (IDDM) are often affected by chronic infections; antibiotic absorption, however, may be influenced by the disease. H. pylori eradication appears to be reduced in IDDM patients. The aim of the study was to evaluate the efficacy of the most common H. pylori eradication regimens in a population of IDDM-infected patients. METHODS One hundred and seventy-two IDDM patients were evaluated. H. pylori infection was assessed through the 13C-urea breath test. Infected patients were randomly assigned to three different standard 7-day eradication regimens: 1) amoxicillin, clarithromycin, pantoprazole; 2) tinidazole, clarithromycin, ranitidine bismuth citrate; or 3) tinidazole, clarithromycin, pantoprazole. Patients in whom eradication was not successful in the first cycle were subsequently submitted to a 7-day therapy with tinidazole, tetracycline, bismuth, and pantoprazole. RESULTS Thirty-seven per cent of IDDM patients were infected. None of the triple therapies used provided an eradication higher than 62%. Conversely, the quadruple regimen was successful in 88% of the patients. Ten per cent of the subjects undergoing the triple therapies showed minor side effects, without significant differences among groups, whereas side effects occurred in 25% of the patients treated with the quadruple therapy (P < 0.05). CONCLUSIONS IDDM patients show a low H. pylori eradication rate with a standard triple therapy regardless of the regimen utilized, the dosage and/or the duration of the therapy used appearing not to be sufficient to eradicate the infection efficiently. The use of a quadruple regimen leads to the cure of a large percentage of the infected patients in whom the eradication was unsuccessful in the first therapy, although it is accompanied by a greater incidence of minor side effects.

Ultrasound M-mode assessment of diaphragmatic kinetics by anterior transverse scanning in healthy subjects.

The purpose of this study was to set an effective standardized method to assess diaphragmatic kinetics by ultrasound. Forty healthy volunteers were submitted to a B- and M-mode ultrasound study using a convex transducer positioned in the subcostal anterior area for transverse scanning. Ultrasound examination was completed in 38/40 cases (95%), spending on average <10 min for examination. The resting and forced diaphragmatic excursions were 18.4 ± 7.6 and 78.8 ± 13.3 mm, respectively, unrelated to demographic or anthropometric parameters: intraobserver variability on three successive measurements resulted in 6.0% and in 3.9%, respectively. An inexperienced sonographer completed the ultrasound examination in 37/40 cases, spending on average >15 min, with significant, although marginal, interobserver variability (31.9% and 14.7% for resting and forced diaphragmatic excursion, respectively). Bedside ultrasonography by an anterior subcostal transverse scanning on semi-recumbent patient proves to be a safe, feasible, reliable, fast, relatively easy and reproducible way to assess diaphragm movement.

Potential Therapeutic Effect of Antioxidants in Experimental Diabetic Retina: A Comparison between Chronic Taurine and Vitamin E Plus Selenium Supplementations

Although good glycaemic control can delay the development and progression of diabetic retinopathy, new therapies are needed to obtain a better control of this diabetic complication. Oxidative stress seems to be a contributing factor in diabetic retinal alterations, therefore, it has been suggested that antioxidants may be beneficial in reducing diabetic retinal changes. However, many questions are still open. In fact, it remains to be ascertained which antioxidants are the most active when they are chronically administered in vivo and their effective dosages. Therefore, we compared the effect of chronic taurine supplementations versus a mixture of vitamin E+selenium on biochemical retinal changes induced by diabetes at different stages of the disease. Briefly, streptozotocin (STZ) diabetic rats ware administered for 4 months following the dietary supplements: (a) 2% (w/w) taurine; (b) 5% (w/w) taurine; (c) 200 IU vitamin E+8 mg selenium/kg diet (d) 500 IU vitamin E+8 mg selenium/kg diet. In STZ diabetic rat in poor metabolic control (i.e. serum glucose >16.5 mmol/l), at 2, 4, 8, 16 weeks following the onset of diabetes, retinal conjugated dienes (CD) and lipid hydroperoxides (LP) were significantly and progressively increased, while sodium pump activity was gradually and significantly reduced. In taurine and vitamin E+selenium supplemented diabetic rats, glycaemia and body weight were not significantly different from those of non-supplemented diabetic animals. In diabetic rats, 2 and 5% taurine significantly decreased CD. This reduction is long lasting. Regarding CD, both vitamin E+selenium supplementations reduced CD only during the first 4 weeks of diabetes. Two percent taurine supplementation significantly lowered LP for the first 8 weeks of the disease while 5% taurine-induced-reduction lasted for the whole experimental time. A 200 IU vitamin E+8 mg selenium supplementation did not significantly modify LP, while 500 IU vitamin E+8 mg selenium significantly lowered them for the whole studied period. Finally, taurine preserved ATPase activity being more effective at 5% than 2%. Two hundred IU vitamin E+8 mg selenium did not generally modify pump activity, while 500 IU vitamin E+8 mg selenium partially prevented the decrease in pump activity. We conclude that taurine and vitamin E+selenium supplementations ameliorate biochemical retinal abnormalities caused by diabetes. These effects are dose- and time-dependent. Moreover, the effect of taurine on CD is longer lasting than that of vitamin E+selenium. In addition, taurine seems to better preserve ATPase activity in comparison with vitamin E+selenium. Finally, in diabetic animals a negative correlation is found between CD and LP on one side and Na + K + ATPase activity on the other; thus, lipid peroxidation and pump activity seem to be associated. The same inverse correlations are present in vitamin E+selenium supplemented diabetic rats, but are lost in taurine supplemented animals. Therefore, taurine effects may not be simply mediated by its antioxidant activity. Thus, chronical (4 months) taurine and vitamin E+selenium supplementations reduce biochemical retinal alterations in diabetic rat in poor metabolic control.

Anti-tissue transglutaminase antibodies from celiac patients are responsible for trophoblast damage via apoptosis in vitro

OBJECTIVES:The association between maternal celiac disease (CD) and both reduced fertility and increased risk of adverse pregnancy-related events has been long documented. However, no evidences are available regarding the pathogenic mechanisms of this link. The aim of this study was to determine whether anti-tissue transglutaminase (anti-tTG) antibodies are involved in the damage of trophoblastic cells in vitro.METHODS:Human primary trophoblastic cells, isolated from term placenta, were exposed to anti-tTG immunoglobulin G (IgG) antibodies, both commercially available and separated from sera of three untreated celiac women. The ability of anti-tTG antibodies to bind to trophoblastic cells, invasiveness of placental cells through a layer of extracellular matrix, and the activity of cellular matrix metalloprotease (MMP) and cellular apoptosis were evaluated, as indicators of trophoblast damage, by TdT-mediated dUTP digoxigenin nick end labeling (TUNEL) and annexin V expression.RESULTS:Anti-tTG IgG showed a specific dose- and time-dependent binding to human trophoblast. In addition, trophoblastic cells, after being exposed to anti-tTG IgG antibodies, both commercially available and separated from sera of celiac women, showed an impaired invasiveness, a decreased activity of cellular MMP, and a greater percentage of TUNEL positivity and annexin V positivity.CONCLUSIONS:We showed that the binding of anti-tTG antibodies to trophoblast might represent a key mechanism by which the embryo implantation and pregnancy outcome are impaired in untreated celiac pregnant women. Because healthy trophoblast development is essential for placental and fetal development, these data provide a novel mechanism for CD-induced infertility, early pregnancy loss, and intrauterine growth retardation.

Coronary atherosclerotic burden in patients with infection by CagA-positive strains of Helicobacter pylori

ObjectivesCytotoxic associated gene-A (CagA)-positive strains of Helicobacter pylori emerged as a possible atherosclerotic stimulus. Nevertheless, whether CagA-positivity is associated with more extensive or severe atherosclerotic coronary burden has never been studied. MethodsForty consecutive patients with coronary artery disease (CAD) and twenty consecutive patients with normal coronary arteries undergoing coronary angiography were enrolled. All patients underwent evaluation of classical atherogenic risk factors and assessment of anti-urease B and anti-CagA antibodies titer. Either the severity of coronary stenosis (stenosis score) or the extent of coronary atherosclerosis (extent score) was evaluated in CAD patients. ResultsThe anti-CagA antibody titer was significantly higher in patients with CAD as compared with normal coronary arteries patients [85 (10–108.75) vs. 47.3 (17–64) RU/ml, P=0.02], whereas there were no differences in anti-urease B titer between the two groups. A significant correlation was found between anti-CagA antibody titer and extent score (R=0.35, P=0.03), whereas stenosis score was similar (R=0.25, P=0.11). On the contrary, no significant correlation was found between anti-urease B antibody titer and either extent or stenosis score. Moreover, CagA-positive patients had a more extensive CAD (P=0.029) when compared with CagA-negative patients. Interestingly, whereas serum glucose, LDL levels, anti-urease B, and anti-CagA antibodies were predictors of extent score at univariate analysis, at multivariate analysis anti-CagA antibody titer only was an independent predictor of the extent of coronary atherosclerosis (B=0.051, standard error of B=0.042, P=0.04). ConclusionThese results support the association between CagA-positive H. pylori infection and coronary atherosclerotic burden. Further studies are needed to better elucidate the mechanism by which CagA-positive strains may promote atherosclerosis.

Utility of Procalcitonin (PCT) and Mid regional pro-Adrenomedullin (MR-proADM) in risk stratification of critically ill febrile patients in Emergency Department (ED). A comparison with APACHE II score

BackgroundThe aim of our study was to evaluate the prognostic value of MR-proADM and PCT levels in febrile patients in the ED in comparison with a disease severity index score, the APACHE II score. We also evaluated the ability of MR-proADM and PCT to predict hospitalization.MethodsThis was an observational, multicentric study. We enrolled 128 patients referred to the ED with high fever and a suspicion of severe infection such as sepsis, lower respiratory tract infections, urinary tract infections, gastrointestinal infections, soft tissue infections, central nervous system infections, or osteomyelitis. The APACHE II score was calculated for each patient.ResultsMR-proADM median values in controls were 0.5 nmol/l as compared with 0.85 nmol/l in patients (P < 0.0001), while PCT values in controls were 0.06 ng/ml versus 0.56 ng/ml in patients (P < 0.0001). In all patients there was a statistically significant stepwise increase in MR-proADM levels in accordance with PCT values (P < 0.0001). MR-proADM and PCT levels were significantly increased in accordance with the Apache II quartiles (P < 0.0001 and P = 0.0012 respectively).In the respiratory infections, urinary infections, and sepsis-septic shock groups we found a correlation between the Apache II and MR-proADM respectively and MR-proADM and PCT respectively. We evaluated the ability of MR-proADM and PCT to predict hospitalization in patients admitted to our emergency departments complaining of fever. MR-proADM alone had an AUC of 0.694, while PCT alone had an AUC of 0.763. The combined use of PCT and MR-proADM instead showed an AUC of 0.79.ConclusionsThe present study highlights the way in which MR-proADM and PCT may be helpful to the febrile patient’s care in the ED. Our data support the prognostic role of MR-proADM and PCT in that setting, as demonstrated by the correlation with the APACHE II score. The combined use of the two biomarkers can predict a subsequent hospitalization of febrile patients. The rational use of these two molecules could lead to several advantages, such as faster diagnosis, more accurate risk stratification, and optimization of the treatment, with consequent benefit to the patient and considerably reduced costs.

Efficacy and Safety of Vernakalant in Recent-Onset Atrial Fibrillation After the European Medicines Agency Approval: Systematic Review and Meta-Analysis

Vernakalant is an emergent antiarrhythmic drug that, in preclinical studies, has demonstrated high efficacy in restoring sinus rhythm and safety in patients with rapid recent‐onset atrial fibrillation. The aim of this work was to evaluate the efficacy and safety of vernakalant for cardioversion of recent‐onset atrial fibrillation. PubMed, EMBASE, Clinical Trials Registry, and European Medicines Agency public reports were searched for randomized clinical trials, until May 2011, of vernakalant compared with controls (placebo/other antiarrhythmic drug) in enrolled patients with high ventricular rate atrial fibrillation. Five randomized trials that met inclusion criteria enrolled a total of 1099 patients. Among these, 810 had recent‐onset atrial fibrillation. When compared with controls (placebo/other oral antiarrhythmic drugs), vernakalant was associated with a significant increase in cardioversion within 90 minutes from drug infusion (relative risk, 8.4; 95% confidence interval, 4.4–16.3; P < .00001). Compared with controls, vernakalant was not associated with a significant difference in serious adverse events (relative risk, 0.9; 95% confidence interval, 0.6–1.4; P = .64). The authors conclude that compared with controls, vernakalant is effective and safe for rapidly converting recent‐onset atrial fibrillation. Questions remain surrounding safety because 1 unpublished trial was discontinued for this reason. Further cost‐effective analysis and comparison with other antiarrhythmic agents, such as class I antiarrhythmic agents, should be investigated, especially in the emergency department.

The role of H. pylori infection in diabetes

Helicobacter pylori [H. pylori], one of the most common chronic infections worldwide, is the main etiologic agent of gastritis, peptic ulcer and gastric cancer. Patients with diabetes mellitus are often affected by chronic infections. Many studies have evaluated the prevalence of H. pylori infection in diabetic patients and the possible role of this condition in their metabolic control. Some studies found a higher prevalence of the infection in diabetic patients and a reduced glycaemic control, while others did not support any correlation between metabolic control and H. pylori infection. There are only a few studies on the eradication rate of H. pylori in diabetic patients. Most of these papers concluded that standard antibiotic therapy allows a significantly lower H. pylori eradication rate than is observed in control groups matched for sex and age. Changes in the microvasculature of the stomach with a possible reduction of antibiotic absorption, the presence of gastroparesis and the frequent use of antibiotics for recurrent bacterial infections with the development of resistant strains could be some of the mechanisms underlying this phenomenon. A quadruple therapy may be used as the second line approach with a good eradication rate, even if an antibiotic selected according to a specific H. pylori antibiogram is considered the gold standard in these patients. As regards the gastrointestinal symptoms of H. pylori infected individuals, many studies showed that they are as frequent in patients with type 1 diabetes as in the general population. The incidence of H. pylori recurrence after 12 months follow-up is significantly higher in type 1 diabetic subjects when compared to controls. Reduced lymphocyte activity, neutrophil dysfunction with failure of chemotaxis and a possible reservoir of H. pylori in dental plaque may explain the higher rate of re-infection in these patients.

Saccharomyces cerevisiae-associated diarrhea in an immunocompetent patient with ulcerative colitis

Infectious diarrhea is common in cases of ulcerative colitis (UC), caused by resistance to treatment. In particular, it has been associated with cytomegalovirus or infection has rarely been observed in human beings, but has never been seen in immunocompetent patients. We report a case of intestinal infection presenting as acute diarrhea in a patient with a 10-year history of UC who was never treated with immunosuppressants.