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Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammation-mediated disease of the nasal mucosa and paranasal sinuses that often coexists with asthma. The role of atopy in the development and severity of CRSwNP is still a controversial issue. Objective: The aim of our study was to propose a systematic allergy workup to identify atopic patients in the context of CRSwNP and to characterize their allergen sensitization profile (sources/molecules). Methods: Patients with a diagnosis of CRSwNP (n = 97) were studied in the otorhinolaryngologist and allergy settings. Demographic and clinical data were collected for each patient. Different allergen sensitization profiles (sources/molecules) were evaluated in atopic CRSwNP patients by using component-resolved diagnosis (CRD). Results: In our cohort of patients, the CRSwNP was frequently diagnosed during adulthood with significant impact on health-related quality of life. Asthma and atopy were the most common comorbidities with a prevalence of asthma in the atopic group. In CRSwNP patients sensitized to grass pollens and/or to house dust mites, the CRD analysis revealed a prevalence of sensitization to species-specific allergens of Phleum pratense (Phl p1, Phl p2, and Phl p5) or Dermatophagoides pteronyssinus (Der p1 and Der p2) rather than to cross-reactive ones. Conclusion: To define the allergen sensitization profile in atopic CRSwNP patients by CRD, it may be useful to better characterize type 2 inflammation, thus providing a personalized endotype-driven treatment.

Background: Although liver biopsy remains the gold standard for the diagnosis and the monitoring of liver disease, non-invasive biomarkers have been recently suggested to predict liver disease severity, progression, and response to therapy. We investigated multiple tissue and circulating markers of angiogenesis in predicting the severity of biopsy-validated chronic liver diseases in patients with chronic hepatitis C virus (HCV) and in NAFLD/NASH patients. Methods: We studied samples from forty-six patients with HCV and/or NAFLD who underwent liver biopsy, liver ultrasonography, and liver stiffness measurement. Ishak and Brunt scores were calculated. Expression of selective genes and luminex analyses of 17 different circulating pro-angiogenic factors were performed. Results: The phenotype of NAFLD/NASH or HCV subjects was similar, except for insulin, which was expressed at higher levels in NAFLD/NASH patients. A Mann–Whitney test showed significant differences for the circulating levels of HB-EGF and for follistatin between HCV and NAFLD/NASH patients. In HCV patients, we found an inverse correlation between disease stage and BMP-9 and VEGF-A circulating levels, while in NASH/NAFLD direct correlations between stage and BMP-9 and VEGF-A circulating levels were noted. The K-means algorithm divided HCV and NASH/NAFLD patients in two clusters with significant differences between them. Logistic regression models showed a positive relationship with BMP-9 levels for NASH/NAFLD and with HB-EGF circulating concentrations for HCV. ROC analysis showed for BMP-9 > 1188 pg/mL a worse disease in NASH/NAFLD, whereas for HB-EGF < 61 pg/mL a higher severity of disease in HCV. Conclusion: Our data show that circulating biomarker profiles can identify the severity of chronic liver disease of NAFLD/NASH or HCV origin.

COVID-19 is a respiratory-centered systemic disorder caused by SARS-CoV-2. The disease can progress into a severe form causing acute lung injury.CD48 is a co-signaling receptor, existing as both membrane-bound and soluble forms reported to be dysregulated in several inflammatory conditions. Therefore, we reasoned that CD48 could be deregulated in COVID-19 as well.Here we analyzed CD48 expression in autoptic sections and peripheral blood leukocytes and sera of COVID-19 patients by gene expression profiling (HTG® autoimmune panel), immunohistochemistry, flow cytometry and ELISA.Lung tissue of COVID-19 patients showed increased CD48 mRNA expression and infiltration of CD48+ lymphocytes. In the peripheral blood, mCD48 was considerably increased on all evaluated cells, and additionally, sCD48 levels were significantly higher in COVID-19 patients independently of disease severity. Considering the alterations of mCD48 and sCD48, a specific role for CD48 in COVID-19 can be assumed, suggesting it as a potential target for therapy.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can progress into a severe form of acute lung injury. The cosignaling receptor cluster of differentiation 48 (CD48) exists in membrane-bound (mCD48) and soluble (sCD48) forms and has been reported to be implicated in antiviral immunity and dysregulated in several inflammatory conditions. Therefore, CD48 dysregulation may be a putative feature in COVID-19-associated inflammation that deserves consideration.To analyze CD48 expression in lung autopsies and peripheral blood leukocytes and sera of patients with COVID-19. The expression of the CD48 ligand 2B4 on the membrane of peripheral blood leukocytes was also assessed.Twenty-eight lung tissue samples obtained from COVID-19 autopsies were assessed for CD48 expression using gene expression profiling immunohistochemistry (HTG autoimmune panel). Peripheral whole blood was collected from 111 patients with COVID-19, and the expression of mCD48 and of membrane-bound 2B4 was analyzed by flow cytometry. Serum levels of sCD48 were assessed by enzyme-linked immunosorbent assay.Lung tissue of patients with COVID-19 showed increased CD48 messenger RNA expression and infiltration of CD48+ lymphocytes. In the peripheral blood, mCD48 was considerably increased on all evaluated cell types. In addition, sCD48 levels were significantly higher in patients with COVID-19, independently of disease severity.Considering the changes of mCD48 and sCD48, a role for CD48 in COVID-19 can be assumed and needs to be further investigated.

Simple Summary The development of hypersensitivity reactions to platinum agents in patients with gynecological cancers limits the use of platinum re-treatment for recurrent disease. In those patients who developed a hypersensitivity reactions during treatment with platinum agents it could be safer to undergo allergy diagnosis. This approach includes the in-vivo skin tests before re-exposure to the platinum agent, especially in those patients who have to undergo a 2nd or 3rd line therapy. In our experience, skin test for platinum agents resulted in a simple and sensitive tool for the diagnosis and prevention of hypersensitivity reactions to platinum agents. In addition, this approach identified a sub-group of patients that became sensitized to the platinum agent during the previous platinum-based therapy. Abstract Background: Hypersensitivity reactions (HSR)s to platinum agents are increasing in frequency, due to their extensive use and repeated exposures in patients with increased life expectancy. The aims of our study are to analyze the frequency of both type I and type IV HSRs in patients with gynecological cancer treated with (CBDCA) carboplatin and/or (CDDP) cisplatin, to evaluate the role of skin tests in the diagnosis and prevention of HSRs. Methods: From 2011 to 2018, we evaluated 124 consecutive female patients previously treated with CBDCA and/or CDDP for gynecological cancer. All patients, including those with and without HSR to previous platinum-based therapy, underwent in-vivo skin tests for platinum agents before starting the second or more therapeutic lines. To reduce the risk of false negative results, patients with a negative skin test at the first evaluation were re-tested after 3 weeks from the platinum re-exposure. Results: Among the 124 patients evaluated, 58 (47%) experienced HSRs to at least one platinum agent: 35% were to CBDCA, 5% to CDDP, 7% to both. Fifty-six of the 58 HSRs were classified as immediate and two delayed. Skin tests confirmed an IgE-dependent mechanism in 67% of patients with immediate-HSRs to CBDCA and identified a cross-reactivity between platinum agents in 18% of patients. Moreover, among those who had never developed an HSRs during platinum-based therapy, in-vivo skin tests identified 12% of sensitized patients. Conclusions: On the basis of our findings, skin test for platinum agents is a simple and sensitive tool for the diagnosis and prevention of HSRs to CBDCA and/or CDDP and can be useful for detecting possible cross-reactivity among platinum agents.

Background: Red blood cells (RBCs) contain the majority of α-synuclein (α-syn) in blood, representing an interesting model for studying the peripheral pathological alterations proved in neurodegeneration. Objective: The current study aimed to investigate the diagnostic value of total α-syn, amyloid-β (Aβ1–42), tau, and their heteroaggregates in RBCs of Lewy body dementia (LBD) and Alzheimer’s disease (AD) patients compared to healthy controls (HC). Methods: By the use of enzyme-linked immunosorbent assays, RBCs concentrations of total α-syn, Aβ1–42, tau, and their heteroaggregates (α-syn/Aβ1–42 and α-syn/tau) were measured in 27 individuals with LBD (Parkinson’s disease dementia, n = 17; dementia with Lewy bodies, n = 10), 51 individuals with AD (AD dementia, n = 37; prodromal AD, n = 14), and HC (n = 60). Results: The total α-syn and tau concentrations as well as α-syn/tau heterodimers were significantly lower in the LBD group and the AD group compared with HC, whereas α-syn/Aβ1–42 concentrations were significantly lower in the AD dementia group only. RBC α-syn/tau heterodimers had a higher diagnostic accuracy for differentiating patients with LBD versus HC (AUROC = 0.80). Conclusion: RBC α-syn heteromers may be useful for differentiating between neurodegenerative dementias (LBD and AD) and HC. In particular, RBC α-syn/tau heterodimers have demonstrated good diagnostic accuracy for differentiating LBD from HC. However, they are not consistently different between LBD and AD. Our findings also suggest that α-syn, Aβ1–42, and tau interact in vivo to promote the aggregation and accumulation of each other.

Background Chronic kidney disease (CKD) shows different clinical features in Types1 (T1D) and 2 diabetes (T2D). Metabolomics have recently provided useful contribution to the identification of biomarkers of CKD progression in either form of the disease. However, no studies have so far compared plasma metabolomics between T1D and T2D in order to identify differential signatures of progression of estimated glomerular filtration rate (eGFR) decline. Methods We used two large cohorts of T1D (from Finland) and T2D (from Italy) patients followed up to 7 and 3 years, respectively. In both groups, progression was defined as the top quartile of yearly decline in eGFR. Pooled data from the two groups were analysed by univariate and bivariate random forest (RF), and confirmed by bivariate partial least squares (PLS) analysis, the response variables being type of diabetes and eGFR progression. Results In progressors, yearly eGFR loss was significantly larger in T2D [−5.3 (3.0), median (interquartile range)mL/min/1.73 m2/year] than T1D [−3.7 (3.1) mL/min/1.73 m2/year ; P = 0.018]. Out of several hundreds, bivariate RF extracted 22 metabolites associated with diabetes type (all higher in T1D than T2D except for 5-methylthioadenosine, pyruvate and β-hydroxypyruvate) and 13 molecules associated with eGFR progression (all higher in progressors than non-progressors except for sphyngomyelin). Three of the selected metabolites (histidylphenylalanine, leucylphenylalanine, tryptophylasparagine) showed a significant interaction between disease type and progression. Only eight metabolites were common to both bivariate RF and PLS. Conclusions Identification of metabolomic signatures of CKD progression is partially dependent on the statistical model. Dual analysis identified molecules specifically associated with progressive renal impairment in both T1D and T2D.

ObjectivesIn patients with systemic autoimmune rheumatic disorders (SARDs), vaccination with SARS-CoV-2 mRNA vaccines has been proposed. The aim of this study is to evaluate the immune response elicited by vaccination with mRNA vaccine, testing IgM, IgA and IgG antibodies to SARS-CoV-2 receptor-binding domain (RBD) and measuring neutralising antibodies.MethodsIgG, IgM and IgA anti-RBD antibodies were measured in 101 patients with SARDs. Antibodies inhibiting the interaction between RBD and ACE2 were evaluated. Antibody avidity was tested in a chaotropic ELISA using urea. Twenty-one healthcare workers vaccinated with mRNA vaccine served as control group.ResultsAnti-RBD IgG and IgA were produced after the first dose (69% and 64% of the patients) and after the boost (93% and 83%). Antibodies inhibiting the interaction of RBD with ACE2 were detectable in 40% of the patients after the first dose and 87% after boost, compared with 100% in healthy controls (pConclusionsThese data show that double-dose vaccination induced in patients with SARDs anti-RBD IgG and IgA antibodies in amounts not significantly different from controls, and, most interestingly, characterised by high avidity and endowed with neutralising activity.

Although mild traumatic brain injury (MTBI) in people on oral anticoagulant treatment (OAT) is a frequent challenge for Emergency Department (ED), strong guidelines recommendations are lacking. In the attempt to assess the safety profile of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs), we have recruited 473 patients with a MTBI on OAT (43.6% males; age 81.8 ± 8.7 years), admitted to the Pisa’s University Hospital ED (Jan 2016—Oct 2018). All patients underwent a head CT scan with those with no sign of acute bleedings remaining under clinical observation for the ensuing 24 h. Fifty patients (10.6%, 95% CI: 8.1–13.7%) had immediate intracranial hemorrhage (ICH), with a prevalence of patient-important outcomes due to immediate ICH of 1.1% (95% CI 0.4–2.4%); 3 patients died (0.6%, 95% CI 0.2–1.8) and 2 required neurosurgical intervention. Immediate ICHs were more frequent in VKA-treated than in DOAC-treated patients (15.9 vs. 6.4%. RR 2.5. 95%CI 1.4–4.4. p

Highlights • Subjects with obesity affected by COVID-19 require longer hospitalization compared to subjects without obesity. • Subjects with obesity require more time to clear from SARS-COV-2 shedding compared to subjects without obesity. • Subjects with obesity affected by COVID-19 have higher inflammatory markers compared to subjects without obesity., Introduction On the last three months the new SARS-COV-2 coronavirus has created a pandemic, rapidly spreading all around the world. The aim of the study is to investigate whether obesity impacts on COVID-19 morbidity. Methods One hundred consecutive patients with COVID-19 pneumonia admitted in our Medical Unit were evaluated. Anthropometric parameters and past medical history were registered. Nasopharyngeal swab samples and biochemical analysis were obtained at admission and during hospital stay. Results Patients with (OB, 29) and without obesity (N-OB, 71) were similar in age, gender and comorbidities, with the exception of hypertension that was more frequent in OB group. At admission, inflammatory markers were higher in OB than N-OB group. OB group showed a worse pulmonary clinical picture, with lower PaO2 (57 ± 15 vs. 68 ± 14 mmHg, p = 0.042), and SaO2 (88 ± 6 vs. 92 ± 5%, p = 0.049) at admission consequently requiring higher volumes of oxygen (Fi02: 38 ± 15 vs. 29 ± 19%, p = 0.047) and a longer period to achieve oxygen weaning (10 ± 6 vs. 15 ± 7 days, p = 0.03). OB group also had positive swabs for longer time (19 ± 8 vs. 13 ± 7, days, p = 0.002), and required longer hospital stay (21 ± 8 vs. 13 ± 8, days, p = 0.0008). Partial least square regression analysis showed that BMI, age and CRP at admission were related to longer length of hospital stay, and time for negative swab. On the contrary, in this cohort, obesity did not predict higher mortality. Conclusions Subjects with obesity affected by COVID-19 require longer hospitalization, more intensive and longer oxygen treatment, and they may have longer SARS-COV-2 shedding.

To assess the impact of bariatric surgery on remission and relapse of type 2 diabetes mellitus (T2DM) at 10 years of follow-up and analyze predictive factors.Eighty-eight obese subjects undergoing Roux-en-Y gastric bypass (RYGB) and 25 subjects assigned to medical therapy (MT) were evaluated every year for 10 years. T2DM remission was defined by the American Diabetes Association criteria.Body mass index (BMI), fasting glucose, and haemoglobin A1c (HbA1c) improved more markedly in RYGB than MT patients throughout the 10-year period. Post-surgery remission rates were 74% and 53% at 1 and 10 years, respectively, while remission did not occur in MT patients. One-year post-surgery, BMI decreased more in subjects with remission than in those without, but no further decrease was observed thereafter. By partial-least-squares analysis, T2DM duration, baseline HbA1c, and ensuing insulin therapy were the strongest predictors of remission. Remission was achieved at one year in 91% of patients with T2DM duration4 years, and 79% of them remained in remission at 10 years. On the contrary only 42% of patients with T2DM duration ≥ 4 years achieved remission, which was maintained only in 6% at the end of 10 years. By survival analysis, patients with T2DM duration4 years had higher remission rates than those with duration ≥ 4 years (hazards ratio (HR) 3.1 [95%CI 1.8-5.7]). Relapse did not occur before two years post-surgery and was much less frequent in patients with4- vs ≥ 4-year duration (HR 11.8 [4.9-29.4]).Short T2DM duration and good glycemic control before RYGB surgery were the best requisites for a long-lasting T2DM remission, whereas weight loss had no impact on the long-term relapse of T2DM.

OBJECTIVE Coronary artery disease (CAD) is a major challenge in patients with type 2 diabetes (T2D). Coronary computed tomography angiography (CCTA) provides a detailed anatomic map of the coronary circulation. Proteomics are increasingly used to improve diagnostic and therapeutic algorithms. We hypothesized that the protein panel is differentially associated with T2D and CAD. RESEARCH DESIGN AND METHODS In CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation—a cohort of 528 individuals with no previous cardiovascular event undergoing CCTA), participants were grouped into CAD− (clean coronaries) and CAD+ (diffuse lumen narrowing or plaques). Plasma proteins were screened by aptamer analysis. Two-way partial least squares was used to simultaneously rank proteins by diabetes status and CAD. RESULTS Though CAD+ was more prevalent among participants with T2D (HbA1c 6.7 ± 1.1%) than those without diabetes (56 vs. 30%, P < 0.0001), CCTA-based atherosclerosis burden did not differ. Of the 20 top-ranking proteins, 15 were associated with both T2D and CAD, and 3 (osteomodulin, cartilage intermediate-layer protein 2, and HTRA1) were selectively associated with T2D only and 2 (epidermal growth factor receptor and contactin-1) with CAD only. Elevated renin and GDF15, and lower adiponectin, were independently associated with both T2D and CAD. In multivariate analysis adjusting for the Framingham risk panel, patients with T2D were “protected” from CAD if female (P = 0.007), younger (P = 0.021), and with lower renin levels (P = 0.02). CONCLUSIONS We concluded that 1) CAD severity and quality do not differ between participants with T2D and without diabetes; 2) renin, GDF15, and adiponectin are shared markers by T2D and CAD; 3) several proteins are specifically associated with T2D or CAD; and 4) in T2D, lower renin levels may protect against CAD.

Aim of the present study is to compare the synchronization of the classical Kuramoto system and the reaction - diffusion space time Landau - Ginzburg model, in order to describe the alternation of REM (rapid eye movement) and NREM (non-rapid eye movement) sleep across the night. These types of sleep are considered as produced by the cyclic oscillation of two neuronal populations that, alternatively, promote and inhibit the REM sleep. Even if experimental data will be necessary, a possible interpretation of the results has been proposed.

In the above article, all mentions of “cartilage intermediate-layer protein” refer to “cartilage intermediate-layer protein 2.” The isoform number was misstated in the abstract and one place in the …

Background: Dysregulated production of cytokines has a critical role in systemic lupus. The aim of this work is to identify, by a comprehensive analysis of IL-1 family cytokines and receptors in serum, correlation between cytokines/receptors' levels and the clinical and serological features of the disease.Methods: A full clinical evaluation was performed in 74 patients with systemic lupus erythematosus (SLE). C3, C4, anti-dsDNA and anti-C1q antibodies were measured. Cytokines of the IL-1 family (IL-1α, IL-1β, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, ST2/sIL-1R4) and antagonists (IL-1Ra, IL-18 binding protein (IL-18BP)) were measured in serum by multiarray ELISA. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Data were analysed by non-parametric tests and by multivariate analysis, using partial least squares (PLS) models.Results: Total IL-18, IL-18BP, sIL-1R4 and IL-1Ra levels were higher in SLE vs. controls. Total and free IL-18 and sIL-1R4 were higher in patients with active vs. inactive disease and correlated with ECLAM, anti-C1q and anti-dsDNA antibodies. sIL-1R2 was higher in patients with inactive disease, was negatively correlated with ECLAM and anti-C1q antibodies and was positively correlated with C3 levels. PLS identified sIL-1R4, sIL-1R2 and anti-dsDNA as variables distinguishing patients with active from those with inactive disease; sIL-1R4, IL-18BP and anti-dsDNA identified patients with active nephritis; sIL-1R4, C3, IL-18 and free IL-18 identified patients with haematological involvement.Conclusion: The data support the use of IL-18, sIL-1R2 and sIL-1R4 as biomarkers of disease activity and organ involvement, and suggest that failure in the inhibition of IL-1 activation may be a critical event in the active stages of SLE.

Objectives Anti-citrullinated protein/peptide antibodies (ACPA) represent an important tool for the diagnosis of rheumatoid arthritis (RA) and the presence of multiple ACPA specificities is highly correlated with the evolution towards RA. However, little is known about the association of single specificities with disease manifestations and response to therapy in established RA. The aim of this work is to evaluate in a retrospective study the clinico-serological association of ACPA detected using VCP1 and VCP2 (EBV-derived citrullinated peptides) and HCP1 and HCP2 (histone-H4-derived citrulinated peptides) in established RA. Methods In 413 RA patients, anti-VCP1, -VCP2, -HCP1, -HCP2 were measured by ELISA. Patients were evaluated for systemic involvement, disease activity/severity, ongoing and past therapies. Data were analyzed by cluster analysis (CA) and principal component analysis (PCA). Results Anti-VCP1 were detected in 44% of RA patients; anti-VCP2 in 52%; anti-HCP1 in 46% and anti-HCP2 in 63%. CA and PCA independently demonstrated that ACPA levels are associated with RF positivity, and lung involvement. Subdividing patients in 5 groups according to the number of anti-peptide antibodies, mean antibody level and RF positivity, as well as the frequency of lung involvement, progressively increase in parallel with the number of ACPA specificities. Conclusions Higher number/levels of ACPA subtypes is associated with lung involvement but not with erosive disease. Moreover, a broader ACPA repertoire may identify patients treated with biological therapy, probably affected by a more severe disease. In conclusion, ACPA typing might be relevant for a better characterization of some disease features in established RA.

High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction.

Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n=41) or insulin resistant (IR, n=41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P=0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance.

Background Anti-citrullinated protein/peptide antibodies (ACPA) represent an important tool for the diagnosis of RA and the presence of multiple ACPA specificities is highly correlated with the evolution towards RA. 1 However, a limited amount of information is available on the predictive value of single specificities on disease manifestations and response to therapy in established RA The aim of the present work is to evaluate the diagnostic and prognostic value of the combined use of four well established citrullinated peptides as antigens for ACPA detection: VCP1 and VCP2 (derived from EBV proteins) and HCP1 and HCP2 (derived from histone H4). 2,3 Materials and methods Four hundred and forty-eight RA patients, followed in the Clinical Immunology Unit, University of Pisa, and in the Rheumatology Unit, University of Perugia, were recruited. RA patients were evaluated for systemic involvement, disease activity and severity, ongoing and past therapies. Anti-VCP1, -VCP2, -HCP1, -HCP2 were measured by home-made ELISA. Data were analysed by cluster analysis and principal component analysis. Results Antibodies to VCP1 were detected in 52% of RA patients; anti-VCP2 in 59,5%; anti-HCP1 in 57% and anti-HCP2 in 57,5% Cluster analysis and principal component analysis identify two subpopulations, that differ for ACPA levels, RF positivity, lung involvement and higher use of biological therapy. Patients were also subdivided in 5 groups according to the number of anti-peptide antibodies (negative for any, positive for one, for two, for three, for four). Mean antibody level and RF positivity progressively increased from the first to the last group, as well as the frequency of lung involvement. Conclusions ACPA are a family of antibodies with overlapping specificities. The results obtained with citrullinated peptides from EBV proteins and histone H4 suggest that fingerprinting of ACPA may be informative in established RA. A higher number of ACPA subtypes is predictive of lung involvement. Moreover, a broader ACPA repertoire also emerged as a feature of patients treated with biological therapy, thus probably affected by a more severe form of the disease. In conclusion, ACPA typing may be relevant for a better characterisation of some disease features in established RA. References 1. Brink M, Hansson M, Mathsson L, et al . Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis Rheum. 2013;65(4):899–910 2. Panza F, Pratesi F, Valoriani D, et al . Immunoglobulin G subclass profile of anticitrullinated peptide antibodies specific for Epstein Barr virus-derived and histone-derived citrullinated peptides. J Rheumatol2014;41(2): 407–8. 3. Johansson L, Pratesi F, Brink M, et al . Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis. Arthritis Res Ther2016;18(1):127.

Objective To evaluate prognostic factors for canine acute pancreatitis (AP) based on clinical and laboratory data that can be easily assessed in veterinary practice. Design Retrospective study between January 2010 and December 2013. Methods The diagnosis of AP was based on clinical signs and an abnormal SNAP® cPL™ test result, concurrently with an ultrasound pattern suggestive of pancreatitis. Dogs were divided into survivors and non-survivors. We evaluated 12 clinical and laboratory parameters: respiratory rate, rectal temperature, white blood cells, haematocrit, total serum proteins, albumin, creatinine, cholesterol, total and ionised calcium, sodium and potassium. Clinical and clinicopathological data were statistically compared between survivors and non-survivors. A value of P

Renal disease in type 2 diabetes mellitus (T2DM) is associated with excess morbidity/mortality. Although estimated glomerular filtration rate (eGFR) and albuminuria are routine for assessing renal impairment, novel biomarkers could improve risk stratification and prediction.To identify specific biomarkers of progression of renal dysfunction.Prospective observational.Academic diabetes clinics.A total of 286 T2DM patients (age, 62 ± 8 y; glycosylated hemoglobin, 7.2 ± 0.9%; eGFR, 85 ± 20 mL · min(-1) · 1.73 m(2)).None.Progression of eGFR and albuminuria.We performed screening metabolomics in serum and urine samples by gas chromatography/mass spectroscopy (MS) and ultra-high performance liquid chromatography/MS/MS. Biomarker identification was performed by random forest using an eGFR cutoff of60 mL · min(-1) · 1.73 m(2) or an albumin/creatinine ratio (ACR) cutoff ≥ 30 mg/g as response variables. At follow-up, eGFR had declined by 16 [9] (median [interquartile ratio]) mL · min(-1) · 1.73 m(2), and ACR had increased by 41 [135] mg/g in patients in the respective top quartile of changes from baseline. Clinical parameters (gender, age, fasting glucose, and baseline eGFR) predicted outcome, with receiver operator characteristics curve (ROC) = 0.671. The five serum metabolites best correlated with either eGFR60 or ACR ≥ 30 at baseline were tested for their ability to improve clinical prediction. The sum of C-glycosyl tryptophan, pseudouridine, and N-acetylthreonine (MetIndex) raised the ROC to 0.739 (P.0001). eGFR decline was predicted by the top MetIndex quartile (odds ratio = 5.48 [95% confidence interval, 2.23-14.47]). MetIndex also predicted an ACR increase with an odds ratio of 2.82 [1.20-7.03] and a ROC of 0.750. Top urine metabolites did not add significant predictivity.A limited number of circulating intermediates of amino acid and nucleotide pathways carry clinically significant predictivity for deterioration of renal function in well-controlled T2DM.

Oxidative damage accumulates in the DNA of the human brain over time, and is supposed to play a critical role in the pathogenesis of Alzheimer's disease (AD). It has been suggested that the brain in AD might be subjected to the double insult of increased oxidative stress, as well as deficiencies in repair mechanisms responsible for the removal of oxidized bases. The type of damage that is most likely to occur in neuronal cells is oxidative DNA damage which is primarily removed by the base excision repair (BER) pathway, and a decrease in BER activity was observed in post-mortem brain regions of AD individuals, especially in the activity of 8-oxoguanine DNA glycosylase. There is evidence that the Ser326Cys polymorphism of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene is associated with a reduced DNA repair activity. However, although a deficient BER was proposed in the etiology of AD by several authors, polymorphisms of BER genes have not been studied in AD yet. We performed a case-control study including 178 patients with sporadic AD (sAD) and 146 matched controls to evaluate the role of the Ser326Cys polymorphism as a risk factor for sAD. In the present study we failed to find any association between allele (chi2=0.03, p=0.86) or genotype (chi2=0.25, p=0.882) frequencies of hOGG1 Ser326Cys and the risk of sAD. Present results suggest that the Ser326Cys polymorphism of the hOGG1 gene is not an independent risk factor for sAD.

Several investigations have documented an increased incidence of right-to-left shunt (RLS) in migraine with aura (MA) and have emphasised its role in the physiopathology of aura; so far, however, no data are available concerning a possible correlation between the extent of the RLS and the clinical picture of MA patients. To investigate the possible relationship between the extent of the RLS, revealed by the number of microbubbles (MB) detected during transcranial Doppler with IV injection of ultrasound contrast (TCDc), and the clinical characteristics of MA (age at first onset of migraine, mean annual frequency of attacks and mean duration of the aura phase), 30 consecutive patients with typical aura and migraine headache positive on TCDc evaluation for RLS were enrolled. Permanent RLS was found in 12 patients and latent RLS was found in 18 patients; of these, 6 had a high-grade RLS, 5 medium-grade RLS and 7 low-grade RLS. No correlation has been documented between the number of MBs and the clinical parameters of both patients with latent shunts and those with permanent ones, nor between the clinical parameters of the two groups of patients. These data show that RLS does not seem to affect the clinical manifestation of MA and that the extent of RLS fails to correlate with the severity of the clinical picture of the disorder.

The aim of the study was to evaluate the safety and functional outcome of a small incision, sutureless vitrectomy in the treatment of idiopathic epiretinal membranes (ERM) compared with a standard 20-gauge vitrectomy system.Forty-six consecutive patients with idiopathic ERM were recruited for this study and prospectively evaluated. In group 1 (n=26) we used a transconjunctival sutureless 25-gauge vitrectomy system (TSV), patients in group 2 (n=20) were operated on using a standard 20-gauge vitrectomy system. The ERM was removed and the internal limiting membrane (ILM) was peeled in all eyes. Surgery-related complications, operating time, intraoperative balanced salt solution (BSS) consumption, postoperative discomfort, postoperative intraocular inflammation, lens opacification, and long-term visual outcome are reported and compared.No surgery-related complications were observed in either group. Operating time was shorter in group 1 compared with group 2 (mean 15.6 and 29.6 min respectively). Intraoperative amount of BSS consumption was less in group 1 (mean 28 ml in group 1 and 42 ml in group 2). Postoperative discomfort and intraocular inflammation were significantly reduced in the 25-gauge group. In the 20-gauge group cataract formation requiring surgery was observed in two eyes. Visual acuity improved significantly in both groups. The 25-gauge group improved on average by more lines of vision and the improvement in vision was more rapid.The TSV system is a safe and efficient surgical technique for ERM surgery. Operating time is significantly reduced, minimizing surgery-induced trauma, and reducing postoperative intraocular inflammation and the patients' discomfort. The incidence of cataract formation may be less using TSV. Postoperative recovery is accelerated.

The increased tendency to fall asleep during the daytime together with increased wakefulness during the night has been demonstrated in patients with advanced Alzheimer's disease (AD). The aim of this study was to assess daytime sleep propensity in a cohort of patients with mild/moderate AD and to correlate it with cognitive impairment. Twenty drug-free AD patients meeting the NINCDS-ADRDA criteria for probable AD were evaluated. According to their Clinical Dementia Rating scores, subjects were classified into mild (CDR1; n=11) and moderate (CDR2; n=9) dementia patients. A group of 12 healthy subjects was taken as controls. The subjects were evaluated by the multiple sleep latency test (MSLT) after their nocturnal sleep pattern had been assessed by a polysomnographic recording throughout the night before. Both groups of AD patients showed a higher level of daytime sleepiness, which was statistically significant for mean daytime sleep latency (MDSL) (controls versus CDR1 and versus CDR2, CDR1 versus CDR2) and for 10:00 and 12:00 hour naps (controls versus CDR1, controls versus CDR2). In the entire group of AD patients, MDSL was significantly related with MMSE, De Renzi's Token test, verbal fluency, verbal digit span, story recall, Raven's Progressive Matrices, Weigl test and Benton's three-dimensional test. These data indicate that an increased sleep propensity during daytime occurs also in patients with mild/moderate AD detected by objective neurophysiological techniques.

Lormetazepam is a hypnotic benzodiazepine currently used in the treatment of insomnia. When this agent is used appropriately, its pharmacologic properties predict a high therapeutic index with a good tolerability profile.The primary aim of this study was to compare the effects on psychomotor performance of lormetazepam and placebo in healthy young adult subjects. A secondary objective was to evaluate the clinical tolerability of lormetazepam.This was a randomized, double-blind,placebo-controlled, crossover study in healthy young adult volunteers. All volunteers received single doses of lormetazepam 1 mg and placebo, with a 1-week interval between doses. The primary study variables were visual simple reaction time (VSRT) and visual choice reaction time (VCRT), measured before dosing with lormetazepam or placebo and at 20, 60, 120, 180, 240, and 360 minutes after dosing using a standard computerized apparatus. To increase the sensitivity of the results, visual reaction times were also recorded using a validated mobile computerized device. Secondary variables were the duration and quality of sleep on the night before each study session, rated by subjects using a 100-mm visual analog scale; the Epworth Sleepiness Scale for daytime drowsiness; and the Critical Flicker Fusion Threshold test. Spontaneously reported adverse events were recorded and monitored throughout the study.The study included 18 healthy young adult volunteers (12 women, 6 men; mean [SD] age, 26.7 [2.8] years [range, 21-30 years]; mean body weight, 58 [9.5] kg). There were no significant differences in either VSRT or VCRT after administration of lormetazepam or placebo. Independent of study drug but consistent with the accepted range of variability between the 2 devices, overall reaction times were significantly shorter with the use of the mobile device compared with the standard apparatus (P0.01). Analysis of the results showed no sequence effects or other evidence of learning. There were no changes in the secondary study variables after administration of the test drugs. Administration of lormetazepam was associated with dizziness in 2 subjects, in 1 case occurring in association with somnolence. These adverse events were mild and subsided spontaneously 3 hours after drug intake. After administration of placebo, 1 subject reported slight somnolence 60 minutes after dosing that persisted through 180 minutes.In this small, selected group of healthy young adult subjects, a single dose of lormetazepam 1 mg did not affect psychomotor performance, assessed in terms of visual reaction times, compared with placebo.

Summary: Purpose: Limited research has focused to date on objective neurophysiological evaluation of daytime sleepiness in patients treated with newer antiepileptic drugs (AEDs), especially when used as monotherapy. This study was aimed at assessing occurrence of daytime sleepiness in newly diagnosed, drug-naive patients with partial epilepsy receiving initial topiramate (TPM) monotherapy. Methods: Daytime vigilance was assessed in 14 consecutive, newly diagnosed and never medicated adult patients with focal epilepsy, receiving monotherapy with TPM. At baseline and 2 months after slowly titrated therapy with TPM, 200 mg/day, patients underwent the Multiple Sleep Latency Test (MSLT), visual simple and choice reaction times (VRT), and self-rated their own degree of sleepiness with the Epworth Sleepiness Scale. A group of 14 age- and gender-matched healthy volunteers served as controls. Results: At baseline, mean daytime sleep latencies on the MSLT were comparable in patients and in controls. Two months after TPM monotherapy, MSLT scores did not significantly change in patients as compared with pretreatment values. Accordingly, subjective daytime sleepiness and VRTs, which were comparable in controls and in untreated patients at baseline, did not change in patients after TPM monotherapy. Conclusions: Study results suggest that an initial short-course monotherapy with TPM, 200 mg/day, does not impair daytime vigilance in newly diagnosed adult patients with partial seizures.

Patients with Alzheimer disease (AD) often exhibit psychotic symptoms associated with cognitive impairment. A few association studies have been carried out to determine if the serotonin transporter and receptor genes are potential risk factors for AD and/or associated psychopathology. The aim of this study was to investigate the association of a serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the 5-HT2A receptor T102C polymorphism with the risk of developing dementia and/or psychotic symptoms in a group of sporadic AD patients from Italy. No significant differences in the distribution of allele and genotype frequencies of 5-HTTLPR and 5-HT2A T102C were found between patient and control groups. However, a significant association between the C102/C102 5-HT2A genotype and psychotic symptoms (p0.001) was observed. Our data strongly confirm results from previous studies suggesting that the C102 allele of the 5-HT2A receptor is associated with the occurrence of psychotic symptoms in AD. On the contrary, the serotonin transporter does not appear to be a major susceptibility factor in the pathophysiology of the disease.

Plasma glucose thresholds for diagnosis of type 2 diabetes are currently based on outcome data (risk of retinopathy), an inherently ill-conditioned approach. A radically different approach is to consider the mechanisms that control plasma glucose, rather than its relation to an outcome. We developed a constraint optimization algorithm to find the minimal glucose levels associated with the maximized combination of insulin sensitivity and β-cell function, the two main mechanisms of glucose homeostasis. We used a training cohort of 1,474 subjects (22% prediabetic, 7.7% diabetic) in whom insulin sensitivity was measured by the clamp technique and β-cell function was determined by mathematical modeling of an oral glucose tolerance test. Optimized fasting glucose levels were ≤87 and ≤89 mg/dl in ≤45-yr-old women and men, respectively, and ≤92 and ≤95 mg/dl in >45-yr-old women and men, respectively; the corresponding optimized 2-h glucose levels were ≤96, ≤98, ≤103, and ≤105 mg/dl. These thresholds were validated in three prospective cohorts of nondiabetic subjects (Relationship Between Insulin Sensitivity and Cardiovascular Disease Study, Botnia Study, and Mexico City Diabetes Study) with baseline and follow-up oral glucose tolerance tests. Of 5,593 participants, 452 progressed to diabetes. Similarly, in the three cohorts, subjects with glucose levels above the estimated thresholds had an odds ratio of 3.74 (95% confidence interval = 2.64–5.48) of progressing, substantially higher than the risk carried by baseline conventionally defined prediabetes [odds ratio = 2.32 (95% confidence interval = 1.91–2.81)]. The concept that optimization of glucose concentrations by direct measures of insulin sensitivity and β-cell function identifies gender- and age-specific thresholds that bear on disease progression is proven in a physiologically sound, quantifiable manner.

Steinert's myotonic dystrophy (DM) is a genetic autosomal dominant disease and the most frequent muscular dystrophy in adulthood. Although causative mutation is recognized as a CTG trinucleotide expansion on 19q13.3, pathogenic mechanisms of multisystem involvement of DM are still under debate. It has been suggested that mitochondrial abnormalities can occur in this disease and deficiency of coenzyme Q 10 (CoQ10) has been considered one possible cause for this. The aim of this investigation was to evaluate, in 35 DM patients, CoQ10 blood levels and relate them to the degree of CTG expansion as well as to the amount of lactate production in exercising muscle as indicator of mitochondrial dysfunction. CoQ10 concentrations appeared significantly reduced with respect to normal controls: 0.85 +/- 0.25 vs. 1.58 +/- 0.28 microg/ml (p0.05). Mean values of blood lactate were significantly higher in DM patients than controls (p0.05) both in resting conditions (2.9 +/- 0.55 vs. 1.44 +/- 1.11 mmol/L) and at the exercise peak (6.77 +/- 1.79 vs. 4.90 +/- 0.59 mmol/L), while exercise lactate threshold was anticipated (30-50% vs. 60-70% of the predicted normal maximal power output, p0.05). Statistical analysis showed that serum CoQ10 levels were significantly (p0.05) inversely correlated with both CTG expansion degree and lactate values at exercise lactate threshold level. Our data indicates the occurrence of reduced CoQ10 levels in DM, possibly related to disease pathogenic mechanisms associated with abnormal CTG trinucleotide amplification.

Before the discovery of the myotonic dystrophy (DM) gene, the DM epidemiological rates could not be accurately estimated. The aim of this study was to calculate the DM prevalence rates in Padova (North-East Italy) and in four provinces of North-West Tuscany (Central Italy) and, as of 30 June 1999, to do so using molecular genetic testing. A minimum prevalence rate of 9.31x10(-5) inhabitants was found, consistent with epidemiological rates worldwide, and more than two times as high as those of two previous studies conducted in the same areas during the era prior to molecular genetic testing. This study, the first in Italy since the discovery of the DM gene, underlines the importance of direct genetic diagnosis of DM, especially in detecting mildly affected patients, a fundamental step in correctly estimating the risk of disease transmission in affected families.

The aim of this study was to evaluate the effects of an aerobic training program on the metabolic and sympathetic responses to exercise in 12 patients with mitochondrial myopathies. A 10-week course of aerobic training, consisting of supervised exercise every other day on an electrically braked pedal-rate bicycle ergometer was prescribed to each patient and four healthy controls. Venous lactate, epinephrine (EP) and norepinephrine (NEP) levels were assessed at baseline and after the aerobic training by means of constant-workload exercise performed at near lactate threshold (LT). In patients, a decrease in exercise peak values, significant for lactate (-38.6%, P < 0.01) but not for catecholamines (EP: -26.0%, NEP: -22.1%) was observed after training, findings confirmed by the lactate/EP and lactate/NEP area ratios. The results show that lactate accumulation during exercise is decreased after aerobic training in mitochondrial myopathies and that the effect is partially dissociated from the catecholaminergic response. This in turn suggests that the lactate decrease can be explained, at least in part, by the improved muscle oxidative metabolism consequent to the proposed training program.

Sympathetic system activation is considered one of the main factors influencing lactate production during exercise in normal individuals. In order to assess the role of such activation in mitochondrial myopathies, we compared blood catecholamine levels to those of lactate during an intermittent exercise performed at workloads near anaerobic lactate threshold. Following an initial increment, the patients (n = 10) exhibited a steady-state blood lactate shifted right relative to controls (n = 7), the peaks being respectively 665 +/- 29% and 322 +/- 11% of baseline. Plasma catecholamine increase in mitochondrial myopathies was 272 +/- 21% for norepinephrine and 261 +/- 18% for epinephrine, not statistically different from controls. Lactate/norepinephrine and lactate/epinephrine area ratios were significantly higher in the subjects than in controls (2.36 versus 1.48 and 2.40 versus 1.57, respectively). The study shows that the abnormal lactate production in mitochondrial myopathies is independent of the catecholaminergic response at the transition from aerobic to anaerobic exercise.

A molecular genetics-based epidemiological investigation was carried out in 1997 in the territory of North-West Tuscany, central Italy, to calculate incidence and prevalence rates of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Results were compared with a previous epidemiological study conducted in the same area in 1981, in the pre-dystrophin era. Routine adoption of methods of molecular diagnosis determined an increase in prevalence of BMD from 1.06 x 10(-5) to 2.42 x 10(-5) inhabitants, while cumulative incidence of DMD was markedly decreased from 23.12 x 10(-5) during the period 1965-1976 to 10.71 x 10(-5) male live births during the period 1977 1994. The combined reduction of DMD/BMD diagnostic error rate and familial recurrence could explain these results, providing the bases for a consistent redefinition of dystrophinopathy carrier frequency in the area considered.

The muscle changes occurring in Parkinson's disease (PD) may come about as a consequence of the modified pattern of motor unit activation and rigidity, which are characteristic of the disease. A tendency towards hypertrophy of type I fibers and, in some instances, atrophy of type II fibers has been observed. Fourteen patients affected by PD and 10 age-matched controls were studied in order to investigate these muscle changes. We indirectly evaluated muscle modifications by measuring muscle fiber conduction velocity (CV) and median frequency (MDF) of the power spectrum using automatic analysis of surface EMG. The tibialis anterior muscle was selected for the study of contractions electrically induced by 35 Hz pulse trains lasting 30 s; the myoelectric signal was detected using the 4-bar electrode technique described by Broman et al. (Broman, H., Bilotto, G. and De Luca, C.J. Myoelectric signal conduction velocity and spectral parameters: influence of force and time. J. Appl. Physiol., 1985, 58: 1428-1437). Muscle biopsy specimens were obtained in 4 PD patients by surgical excision at the site where the EMG recording electrode had been placed. The main difference observed between PD subjects and controls was the rate of change of MDF and CV during the course of stimulated contraction; patients with PD sustained a smaller fatigue related decrease in both parameters compared to controls. According to our histological data, this result can be explained by a type I fiber percentage which accounts for 79% of the myofiber population on average. As expected, the CV basal values correlated directly with type I fiber diameter. These data suggest that non-invasive surface EMG techniques are useful in assessing the modifications of muscle characteristics that are observed in PD patients and for analyzing some aspects of the peripheral fatigue in this disease.

In cancer patients mild-moderate non-chemotherapy-induced iron deficiency anemia (IDA) is usually treated with oral iron salts, mostly ferrous sulfate. In this study, we compare efficacy and toxicity of oral ferrous bisglycinate chelate and ferrous sulfate in cancer patients with mild IDA. Twenty-four patients operated on for solid tumors (10 breast, 12 colorectal, 2 gastric), aged 61±10 years (range 45-75), with non-chemotherapy-induced hemoglobin (Hb) values between 10 and 12 g/dL and ferritin lower than 30 ng/mL were randomized to receive oral ferrous bisglycinate chelate, 28 mg per day for 20 days, and then 14 mg per day for 40 days (12 patients) (A group) or oral ferrous sulphate, 105 mg per day for 60 days (12 patients) (B group). Values of hemoglobin and ferritin obtained at diagnosis, 1 and 2 months from the beginning of treatment were compared. Adverse events (AEs) related to the two treatments were recorded. In the 12 patients treated with ferrous bisglycinate chelate, basal hemoglobin and ferritin values (mean±SD) were 11.6±0.8 g/dL and 16.1±8.0 ng/mL. After 2 months of treatment, they were 13.0±1.4 g/dL and 33.8±22.0 ng/mL, respectively (P=0.0003 and P=0.020). In the group treated with ferrous sulphate, hemoglobin and ferritin mean values were 11.3±0.6 g/dL and 19.0±6.4 ng/mL basally, and 12.7±0.70 g/dL and 40.8±28.1 ng/mL (P

Background Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss. Objectives To examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on: (1) survival; (2) nutritional status; (3) quality of life; (4) minor and major complications of percutaneous endoscopic gastrostomy. Search methods We searched the Cochrane Neuromuscular Disease Group Trials Register (24 November 2009), MEDLINE (from January 1966 to September 2009), and EMBASE (from January 1980 to September 2009) for all papers on enteral tube feeding in amyotrophic lateral sclerosis/motor neuron disease. The results were screened to identify randomised controlled trials and to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles and enlisted personal communications to identify any additional references. Selection criteria A priori selection criteria included randomised and quasi-randomized controlled trials evaluating the efficacy of percutaneous endoscopic gastrostomy or other feeding tube placement. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review. Data collection and analysis We independently assessed study design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, (3) self-perceived quality of life and (4) safety of the procedure as indicated by minor and major complications of surgical or radiological guided PEG tube insertion. Main results We found no randomised controlled trials comparing the efficacy of enteral tube feeding with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective studies in the 'Discussion' section. Authors' conclusions There are no randomised controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for any of the outcome measures. The 'best' evidence to date suggests a survival advantage for some people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable. Quality of life has been addressed in studies and needs more attention. Based on a number of recent non-randomized studies comparing surgical and radiographic approaches to feeding tube insertion these two procedures for PEG tube insertion appear to be equivalent.