Hormonal deficiencies in heart failure with preserved ejection fraction: prevalence and impact on diastolic dysfunction: a pilot study.

OBJECTIVE: In heart failure with reduced ejection fraction, catabolic mechanisms have a strong negative impact on mortality and morbidity. The relationship between anabolic hormonal deficiency, thyroid function, and heart failure with preserved ejection fraction (HFpEF) has still been poorly investigated. Therefore, we aimed to define the multi-hormonal deficiency prevalence in HFpEF patients and the relationships between hormonal deficiency and echocardiographic indexes. PATIENTS AND METHODS: Plasma levels of N-terminal pro-brain natriuretic peptide, fasting glucose, thyroid-stimulating hormone, free triiodothyronine (T3), free thyroxine, insulin-like growth factor-1, dehydroepiandrosterone-sulfate (DHEA-S), total testosterone (only in male subjects) in 40 patients with HFpEF were evaluated. An echocardiographic evaluation was performed. RESULTS: One (2.5%) patient (2.5%) had no hormonal deficiencies; 8 (20%) patients had deficits of one hormone, 18 patients (45%) of two axes, 12 patients (30%) of three axes, and one patient (2.5%) of all four axes. Among them, 97.5% had DHEA-S deficiency, 67.5% IGF-1 deficiency, 37% testosterone deficiency, 22.5% a "Low T3 syndrome", and 20% subclinical hypothyroidism. Patients with IGF-1 deficit showed higher left atrial volume values, systolic pulmonary artery pressure (SPAP), tricuspid peak velocity (TPV), and lower tricuspid annular plane systolic excursion (TAPSE) and TAPSE/SPAP ratio values. Patients with testosterone deficiency had higher SPAP and TPV. Patients with low T3 syndrome had higher value of right ventricular mid cavity diameter. Hormonal dysfunction was independent from the presence of comorbidities and no difference between male and female subjects was noted. CONCLUSIONS: Multi-hormonal deficiencies are associated with right ventricular dysfunction and diastolic dysfunction in patients with HFpEF.

MEDS score and vitamin D status are independent predictors of mortality in a cohort of Internal Medicine patients with microbiological identified sepsis.

OBJECTIVE: Sepsis is a life-threatening disease resulting from the interaction between pathogen and host response; its dysregulation causes organ dysfunction, high morbidity, and mortality. Despite the increase of septic patients admitted to Internal Medicine wards, data about clinical predictors of mortality in this setting are still lacking. The aim of this study was to evaluate the role of MEDS score and vitamin D as predictors of mortality (28-day and 90-day) in septic patients admitted to the Internal Medicine department. PATIENT S AND METHODS: Prospectively collected clinical data, lab tests including vitamin D, and clinical scores (SIRS, MEDS, SCS, REMS, SOFA, qSOFA) were retrospectively analyzed. Eighty-eight microbiologically identified septic patients (median age 75 years old, IQR 65-82 years old; range 37-94 years old) were evaluated. RESULTS: Twenty-three patients (26.1%) died at 28 days, 33 (37.5%) died at 90 days. The logistic regression showed a positive effect of MEDS score (p=0.006; OR 1.24, 95% CI 1.08-1.49), and a negative effect of low vitamin D levels (p=0.008, OR 0.83, 95% CI 0.72-0.94) on mortality. Moreover, the cut-off of 7 points for MEDS score and of 7 ng/ml for vitamin D levels significantly predicted poor prognosis at 28 and 90 days. CONCLUSIONS: MEDS score and vitamin D levels represent independent predictors of mortality in a cohort of Internal Medicine septic patients. Further studies on larger samples are needed to confirm our results and to clarify the pathophysiological mechanisms at the basis of vitamin D deficiency as a predictor of mortality in septic patients.

Scurvy as cause of purpura in the XXI century: a review on this "ancient" disease.

OBJECTIVE: Scurvy is defined as a deficiency of ascorbic acid, which is an essential exogenous vitamin in humans. Vitamin C is involved in collagen synthesis and its deficit can cause disorders of connective tissue. The most frequent symptoms are weakness, arthralgias, anorexia and depression, commonly associated with follicular hyperkeratosis and perifollicular hemorrhage, with purpura. PATIENTS AND METHODS: A young woman, with a history of malnutrition, manifested purpura and hematoma of the left lower limb. The laboratory tests didn't detect alterations either in coagulation, the platelet count or in the autoimmunity. The total body TC scan didn't show neoplasia or other suspected lesions. Excluding the most important causes of purpura, in consideration of malnutrition, scurvy was suspected. RESULTS: A skin biopsy confirmed the diagnosis. Accordingly to this finding, a treatment with a daily intravenous infusion of vitamin C was started with consequent improvement of hematoma and purpura. CONCLUSIONS: Scurvy is a re-emerging disease, also in western countries. When purpura appears in young adults, scurvy has to be investigated, especially when a history of malnutrition is present. The treatment with vitamin C infusions should be started as soon as possible in order to prevent any complications.

Association between peripheral arterial disease and cardiovascular risk factors: role of ultrasonography versus ankle-brachial index.

OBJECTIVE: Most studies on atherosclerotic processes include peripheral arterial disease diagnosis only if patients report symptoms suggestive of peripheral arterial disease and/or an instrumental demonstration of lower limbs perfusion deficit is provided, rather than the sole presence of atherosclerotic lesions localized at lower limbs, this attitude leading to ignore early stages of the disease. To overcome these limitations, we have proposed a new ultrasonographic semiquantitative score to better identify all disease stages. The aim of this study is to compare ultrasonography versus ankle-brachial index in the association between peripheral arterial disease and cardiovascular risk factors. PATIENTS AND METHODS: This cross-sectional observational study included subjects undergoing lower limbs evaluation through ultrasonography and ankle-brachial index determination because of symptoms suggestive of peripheral arterial disease or presence of known cardiovascular risk factors. Associations between ultrasonography and ankle-brachial index with cardiovascular risk factors were assessed by first fitting logistic regression models and then comparing the respective areas under the Receiver Operating Characteristic and 95% confidence intervals. RESULTS: The areas under the Receiver Operating Characteristic for each cardiovascular risk factors were consistently larger in magnitude for ultrasonography compared with ankle-brachial index, this comparison being statistically significant for age, male gender, smoking status, hypertension, diabetes mellitus and previous cardiovascular events. CONCLUSIONS: Our study demonstrates that ultrasonography is a better method to screen peripheral arterial disease respect to ankle-brachial index in order to identify all disease stages. These findings are useful in particular when including peripheral arterial disease as organ damage marker in cardiovascular risk stratification.

Anthracycline and trastuzumab-induced cardiotoxicity in breast cancer.

OBJECTIVE: Breast cancer is the most common cancer among women. In the last twenty years early diagnosis, neoadjuvant and adjuvant systemic treatment that targeted to specific molecular targets have significantly reduced the mortality from breast cancer. However, the increase in survival has allowed to observe the cardiotoxic effects of anticancer therapy and increased mortality from cardiovascular causes, resulting in a large literature where experts try to identify the correct management of this critical problem. Even thought the increased attention in this field, many questions have not yet answers and new studies are needed. MATERIALS AND METHODS: We conducted a broad search of the English-language literature in Medline using the following search terms: cardiotoxicity, anthracyclines, trastuzumab, breast cancer, left ventricular dysfunction, heart failure. A manual examination of the articles found has been performed. RESULTS: We provide a comprehensive assessment of the current knowledge about cardiotoxicity induced by anthracycline plus trastuzumab in women affected by breast cancer. CONCLUSIONS: Early identification and prompt treatment of subclinical cardiotoxicity may improve cardiologic prognosis of these patients and may allow oncologists to avoid withdrawal of chemotherapy. That is why it becomes always more important the creation of multidisciplinary teams where cardiologists and oncologists work together to ensure optimal care to oncologic patients treated with cardiotoxic agents.

Atherosclerosis and cardiovascular involvement in celiac disease: the role of autoimmunity and inflammation.

OBJECTIVE: The aim of this review is to explore the evidence about the association among celiac disease (CD), atherosclerosis (AS) and cardiovascular (CV) diseases, and the role of inflammation in this connection. MATERIALS AND METHODS: A systematic literature search was conducted using PubMed, EMBASE, and Cochrane Library for the association among CD, AS and CV diseases. RESULTS: Several studies reported the association of CD with accelerated AS, as evidenced by the alterations of a number of parameters indicative of subclinical AS, as increased carotid artery intima-media thickness, endothelial dysfunction and increased arterial stiffness. In addition, recent evidence reported an increase of CV diseases prevalence in CD patients respect to controls, many of which including ischemic diseases as acute myocardial infarction and angina pectoris, as well as death from ischemic heart disease, and, more rarely, stroke for cerebrovascular involvement. Other not-ischemic CV diseases associated with CD are represented by dilated cardiomyopathy, atrial fibrillation, and myocarditis. CONCLUSIONS: On the basis of the reported association among CD, AS and CV diseases, we suggest to perform a more detailed CV risk assessment in all CD patients than what is currently being achieved in clinical practice, in order to scan and treat modifiable CV risk factors in these patients. In particular, we suggest to resort to instrumental techniques to detect AS in the subclinical stage, in order to prevent AS development and CV diseases in CD patients.

RANK/RANKL/OPG pathway: genetic association with history of ischemic stroke in Italian population.

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 identifies, for the first time, the genetic variant of RANKL as an independent risk factor for ischemic stroke.

Fibroblast growth factor 23 serum level in type 2 diabetic italian subjects with peripheral arterial disease and critical limb ischemia.

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.

The involvement of IgH enhancer HS1.2 in the pathogenesis of Crohn's disease: how the immune system can influence a multifactorial disease.

OBJECTIVE: 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.

Catheter-related bloodstream infections by opportunistic pathogens in immunocompromised hosts.

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.

The Interaction among Microbiota, Immunity, and Genetic and Dietary Factors Is the Condicio Sine Qua Non Celiac Disease Can Develop.

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.

Review article: Alcohol and gut microbiota - the possible role of gut microbiota modulation in the treatment of alcoholic liver disease.

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.

Sonic hedgehog gene therapy increases the ability of the dystrophic skeletal muscle to regenerate after injury.

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.

Baclofen in the treatment of persistent hiccup: a case series.

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.

Role of fecal calprotectin in gastrointestinal disorders.

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.

New insights on the role of T cells in the pathogenesis of celiac disease.

Despite intense investigation, the pathogenetic mechanisms leading to villous atrophy in Celiac disease (CD) remain not completely understood. The traditional interpretation is that CD4 cells recognize gliadin and develop an inflammatory reaction by production of Th1 cytokines at the mucosa level inducing CD8 cells to kill mucosal cells by a direct cytotoxic mechanism or by Fas-mediated apoptosis. Recent data, however, have shown that novel CD4 T-cells subpopulations, CD4+ CD25+ Regulatory T cells (Tregs) and Th17 cells also play a role in the ongoing inflammatory process. Both Tregs and Th17 cells are increased in active CD. However, because Tregs have a suppressive activity on inflammation, their role is controversial. In this editorial we discuss these recent findings and the hypothesis formulated to explain the increase of Tregs. To understand the pathogenesis of tissue damage of CD, we have focused on the duodenal micro-environment, introducing the new concept of immunological niche that in CD summarizes cellular and cytokine interactions in duodenal mucosa, where a high plasticity of T-cell subsets is present. CD is often complicated by T-cell lymphomas, especially in cases of refractory CD.

Giant cell arteritis and polymyalgia rheumatica after influenza vaccination: report of 10 cases and review of the literature.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory rheumatic diseases common in people over the age of 50 years. Herein, we report 10 cases of previously healthy subjects who developed GCA/PMR within 3 months of influenza vaccination (Inf-V). A Medline search uncovered additional 11 isolated cases of GCA/PMR occurring after Inf-V. We discuss the role of individual susceptibility, the potential function of immune adjuvants as triggers of autoimmunity post-vaccination, and the correlation of our observation with the 'ASIA' syndrome, i.e. autoimmune/inflammatory syndrome induced by adjuvants and including post-vaccination phenomena.

The immune response to tumors as a tool toward immunotherapy.

Until recently cancer medical therapy was limited to chemotherapy that could not differentiate cancer cells from normal cells. More recently with the remarkable mushroom of immunology, newer tools became available, resulting in the novel possibility to attack cancer with the specificity of the immune system. Herein we will review some of the recent achievement of immunotherapy in such aggressive cancers as melanoma, prostatic cancer, colorectal carcinoma, and hematologic malignancies. Immunotherapy of tumors has developed several techniques: immune cell transfer, vaccines, immunobiological molecules such as monoclonal antibodies that improve the immune responses to tumors. This can be achieved by blocking pathways limiting the immune response, such as CTLA-4 or Tregs. Immunotherapy may also use cytokines especially proinflammatory cytokines to enhance the activity of cytotoxic T cells (CTLs) derived from tumor infiltrating lymphocytes (TILs). The role of newly discovered cytokines remains to be investigated. Alternatively, an other mechanism consists in enhancing the expression of TAAs on tumor cells. Finally, monoclonal antibodies may be used to target oncogenes.

Skewed T-cell receptor repertoire: more than a marker of malignancy, a tool to dissect the immunopathology of inflammatory diseases.

The highly diverse heterodimeric surface T cell receptor (TCR) gives the T lymphocyte its specificity for MHC-bound peptides needed to initiate antigen-recognition. In normal peripheral blood, spleen and lymph nodes, the TCR repertoire of the T lymphocytes is usually polyclonal. However, in malignancies such as leukemias, as well as in lymphoproliferative diseases of mature T cells, the TCR is a reflection of the clonality of the malignant cells and is therefore monoclonal. Several clinical conditions (mainly solid tumors and autoimmune diseases) have been described where the TCR repertoire is restricted. The ability to demonstrate clonal TCR usage provides a useful tool to dissect the immunopathology of inflammatory diseases. In this review we discuss these findings and propose to sub-divide diseases with restricted TCR repertoire into a group of conditions in which there is a known TCR ligand, as opposed to diseases in which the restricted TCR repertoire is the result of impaired T-cell development. This classification sheds light on the pathogenesis of several inflammatory diseases.

Italian intersociety consensus statement on antithrombotic prophylaxis in hip and knee replacement and in femoral neck fracture surgery.

Anticoagulant prophylaxis for preventing venous thrombembolism (VTE) is a worldwide established procedure in hip (HR) and knee replacement (KR) surgery, as well as in the treatment of femoral neck fractures (FNF). Different guidelines are available in the literature, with quite different recommendations. None of them is a multidisciplinary effort as the one presented. The Italian Society for Studies on Hemostasis and Thrombosis, the Italian Society of Orthopedics and Traumatology, the association of Orthopedic Traumatology of Italian Hospitals, together with the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care have set down easy and quick suggestions for VTE prophylaxis in HR and KR surgery as well as in FNF treatment. This inter-society consensus statement aims at simplifying the grading system reported in the literature, and thus at improving its proper application. Special focus is given to fragile patients, those with high bleeding risk, and on those receiving chronic antiplatelet and vitamin K antagonists treatment. A special chapter is dedicated to regional anesthesia and VTE prophylaxis.