Novel therapeutic approaches based on the pathological role of gut dysbiosis on the link between nonalcoholic fatty liver disease and insulin resistance.

The growing global epidemic of obesity and type 2 diabetes mellitus has determined an increased prevalence of NAFLD (non-alcoholic fatty liver disease), making it the most common chronic liver disease in the Western world and a leading cause of liver transplantation. In the last few years, a rising number of studies conducted both on animal and human models have shown the existence of a close association between insulin resistance (IR), dysbiosis, and steatosis. However, all the mechanisms that lead to impaired permeability, inflammation, and fibrosis have not been fully clarified. Recently, new possible treatment modalities have received much attention. To reach the review purpose, a broad-ranging literature search on multidisciplinary research databases was performed using the following terms alone or in combination: "NAFLD", "gut dysbiosis", "insulin resistance", "inflammation", "probiotics", "Chinese herbs". The use of probiotics, prebiotics, symbiotics, postbiotics, fecal microbiota transplant (FMT), Chinese herbal medicine, antibiotics, diet (polyphenols and fasting diets), and minor therapies such as carbon nanoparticles, the MCJ protein, water rich in molecular hydrogen, seems to be able to improve the phenotypic pattern in NAFLD patients. In this review, we provide an overview of how IR and dysbiosis contribute to the development and progression of NAFLD, as well as the therapeutic strategies currently in use.

Impact of statins on the coagulation status of type 2 diabetes patients evaluated by a novel thrombin-generation assay.

PURPOSE: Dyslipidemia is common in type 2 diabetes (T2D) and contributes to cardiovascular disease (CVD) by exacerbating atherosclerosis and hypercoagulability. Statins can stabilize atherosclerotic plaque and reduce prothrombotic status. In the present study we aimed to evaluate the coagulation activity and the effect of statins on procoagulant state of T2D patients using a novel activated protein C (APC)-dependent thrombin-generation assay. METHODS: Procoagulant status (by HemosIL ThromboPath (ThP) assay) and in vivo platelet activation (by plasma soluble (s)CD40L levels) were analyzed in a retrospective, cross-sectional study of 198 patients with long-standing T2D and 198 controls. RESULTS: Procoagulant status of T2D patients was enhanced when compared to control subjects (p < 0.0001). Similarly, sCD40L levels were increased in T2D (p < 0.0001). When testing ThP as the dependent variable in a multivariate regression model, sCD40L (p < 0.0001) and statin treatment (p = 0.019) were independent predictors of the procoagulant state of T2D patients. Subgroup analysis showed a significant improvement of coagulability in T2D patients on statins (p = 0.012). CONCLUSIONS: The use of a standardized, easy-to-run, and commercially available APC-dependent thrombin-generation assay detected the presence of a procoagulant status in a large series of patients with long-standing T2D and demonstrated a significant impact of statins in the coagulation status of patients with T2D.

Surveillance Programme for Healthcare Associated Infections in the State of São Paulo, Brazil. Implementation and the first three years' results.

Governmental programmes should be developed to collect and analyse data on healthcare associated infections (HAIs). This study describes the healthcare setting and both the implementation and preliminary results of the Programme for Surveillance of Healthcare Associated Infections in the State of São Paulo (PSHAISP), Brazil, from 2004 to 2006. Characterisation of the healthcare settings was carried out using a national database. The PSHAISP was implemented using components for acute care hospitals (ACH) or long term care facilities (LTCF). The components for surveillance in ACHs were surgical unit, intensive care unit and high risk nursery. The infections included in the surveillance were surgical site infection in clean surgery, pneumonia, urinary tract infection and device-associated bloodstream infections. Regarding the LTCF component, pneumonia, scabies and gastroenteritis in all inpatients were reported. In the first year of the programme there were 457 participating healthcare settings, representing 51.1% of the hospitals registered in the national database. Data obtained in this study are the initial results and have already been used for education in both surveillance and the prevention of HAI. The results of the PSHAISP show that it is feasible to collect data from a large number of hospitals. This will assist the State of São Paulo in assessing the impact of interventions and in resource allocation.

[Small bowel diverticula in adults: clinical and therapeutic features. Report of 2 cases and review of the literature]. / I diverticoli del tenue nell'adulto. Aspetti clinici e terapeutici. Presentazione di 2 casi e revisione della letteratura.

The true diverticula of the small bowell are a very rare observation in clinical practice; they have a malformative origin and, occasionally, are acquired, contrary to what observed in the colon, where they are frequently an acquired pathology. They can involve the small bowel as a single lesion (Meckel's diverticulum), or as a segmentary disease (duodenal diverticula), or as a diffused diverticulosis. Generally they are asymptomatic and rarely they produce a true pathology. The symptomatic disease is primarily found in pediatric age and it requires a surgical procedure. This makes even more rare the diverticular pathology in the adult. The authors report 1 case of intestinal occlusion due to ileoileo-colic invagination arising from a Meckel's diverticulum and 1 case of intestinal occlusion in presence of a severe and acute diffuse diverticulosis of the small bowell, both in adult patients.

p53, cyclin-D1, PCNA, AgNOR expression in squamous cell cancer of the lip: a multicenter study.

BACKGROUND: The development of squamous cell carcinoma of the lower lip is an interesting model of photocarcinogenesis because of the structural and topographic characteristics of the lips. The purpose of this study was to evaluate the expression of immunohistochemical markers on the lips of patients with lower lip squamous cell carcinoma (LLSCC), compared with a control population. METHODS: Of the 98 subjects involved in the study, 58 were suffering from squamous cell carcinoma of the lower lip. The remaining 40 acted as a control. The case studies were taken from six university and hospital dermatology and plastic surgery departments. Questionnaires were administered to assess the risk factors for LLSCC. The cases involving squamous cell carcinoma underwent surgical excision and punch biopsy specimens were obtained from 20 control patients. Tissues were prepared in 5-microm-thick sections to carry out the following immunohistochemical study: PCNA, p53, AgNOR, cyclin-D1, bcl-2. RESULTS: The lower lip was the predominant location of squamous cell carcinoma, with the following factors playing important roles: chronic sun exposure, history of smoking, alcohol use and familial risk of cutaneous tumors. The male/female ratio in our survey was 5:1. The p53 protein was positive in approximately 50% of SCC cases and in 20% of controls. This protein is mostly associated with chronically photoexposed skin areas. AgNOR positivity increased with the loss of cellular differentiation; a progressive increase in size and a poorly defined shape were evident in poorly differentiated carcinomas. CONCLUSIONS: The results of this multicenter study showed that there is a noticeable difference in the expression of PCNA, p53, cyclin-D1, and AgNOR in tissues from patients with LLSCC and controls.

Selection, establishment and characterization of cell lines derived from a chemically-induced rat mammary heterogeneous tumor, by flow cytometry, transmission electron microscopy, and immunohistochemistry.

In order to isolate, characterize, and establish culture cell lines with different diagnostic and prognostic significance, derived from multiclonal neoplasms, a ductal infiltrating mammary tumor was induced in rats by 7,12-dimethylbenz[a]anthracene. Clones with different DNA/protein content, being the DI of 1.16, 1.30, and 1.60, respectively, were observed in the primary tumor. Biparametric flow cytometry suggested that the clone at 1.30 is made up of two subpopulations with different protein and slightly different DNA contents. The culture, after a few passages, exhibited the presence of aneuploid cells and the absence of diploid components, demonstrating that only tumor cells survived. The limiting dilution method gave rise to four lines with DI of 1.16, 1.25, 1.30, and 1.50; a mean chromosome number of 45, 46, 47, and 88, respectively; and different morphological and ultrastructural features. These characteristics were stable during the experimental procedure, that is, for about 20 passages. Conversely, the detection of cytoskeletal proteins indicated that the tumor epithelial cells underwent early dedifferentiation into sarcoma-like cells showing markers of stromal cell type and thus exhibiting phenotypic instability in vitro, a feature reported in many advanced human breast cancers in vivo. In conclusion, this cellular model represents the in vivo situation and appears suitable for in vitro studies of tumor cell characteristics and might be used to predict clinical behavior.

In vitro proliferation and in vivo malignancy of cell lines simultaneously derived from a chemically-induced heterogeneous rat mammary tumor.

Identification of clones in primary tumors responsible for proliferation, invasion, and metastasis was carried out. Four different aneuploid established cell lines derived from a ductal infiltrating mammary rat tumor induced by 7,12-dimethylbenz[a]anthracene were studied for proliferative and growth features in vitro and for tumorigenic and metastatic potential in vivo in nude mice. Clones, named RM1, RM2, RM3, and RM4, were characterized by different proliferative activity. Clone RM1 showed the highest proliferative activity by both tritiated thymidine incorporation and S-phase flow cytometry, followed by clone RM4. Conversely, clones RM2 and RM3 showed a lower proliferation rate. Growth-promoting activity, tested on 3T3 Swiss cells, was high in all clones, although RM1 showed significantly lower growth factors-releasing activity. Nude mice tumorigenesis demonstrated a strong tumor induction of line RM1 (100% of the mice after 47 +/- 7 d) and a slightly lower tumor induction of line RM4 (70% of the mice after 69 +/- 9 d). Line RM3 showed tumor induction in 40% of the mice after 186 +/- 16 d. Lines RM2 showed no tumor induction. Metastasis occurred in mice treated with line RM1 only. Therefore, tumorigenesis and metastasis correlate with proliferation but not with the release of growth factors. In conclusion, flow cytometry monitoring of clones from heterogeneous primary tumors proved to be a suitable model for the study of in vivo malignancy and in vitro proliferation.

[Immunotherapy of solid tumors. Current status and prospects]. / Immunoterapia dei tumori solidi. Stato attuale e prospettive.

Immunotherapy is the most recent therapeutic strategy in the treatment of cancer. It has not yet achieved an elevated curative efficiency and a wide clinical application. Nevertheless the possibilities of improvement seem very promising. The knowledge of the immune response mechanisms and the first clinical trials have determined a more efficient immunotherapy. Here we will critically analyze current immunotherapeutic strategies by reviewing the latest and the most important experimental works. The latest protocols of immunotherapy have been aimed to be more integrated in the physiological immune response schemes. The orientation of the experimental works have been changed from non specific immunotherapy using lymphokines to immunotherapy with specific lymphocytes expanded in vitro and, finally, the active specific immunotherapy in vivo by modificated tumoral vaccines or by variously manipulated tumoral antigens.

[Immunotherapy of solid tumors. Clinical studies]. / Immunoterapia dei tumori solidi. Studi clinici.

In this study we analyze the major clinical trials of immunotherapy for solid tumors. Much progress have been made in reducing the side effects and the percentage of patients which respond has increased. In immunotherapy with lymphokines the innovative orientation consist in the administration of low doses or decreasing doses and by alternative ways as regards infusion and systemically. The use of immunotherapy to stimulate the specific immune response seems to represent the most promising field from a therapeutic point of view. Studies in the field of in vitro expansion of immunocompetent cells have obtained results in the simplification of the technique and in an increase of its efficiency; moreover, at the moment, many clinical trials are involving specific immunotherapy using autologous neoplastic cells altered with adjuvant substance and the results are promising with very few side effects. In the near future immunotherapy with specific tumor antigens is sure it will play a major role.

Systemic specific active immunotherapy for solid tumors. An overview about cancer vaccinetherapy.

Augmentation of specific immunity is one of the most promising immunotherapeutical approaches against solid tumors. Protocols using autologous tumor cells or tumor associated antigens are easily performed and not charged by severe side effects. Recently some clinical trials suggested good results from immunotherapeutical protocols applied as an adjuvant to surgery in terms of disease free interval, survival and progression time in different stages. In this review the authors report the results of the most important clinical trials of vaccinetherapy in solid tumors. Little is known about the possibility of this new approach to oncology since we are at the real beginning of a new clinical treatment but in the considered trial its effectiveness seems to suggest a future wider application.

[Sudden infant death syndrome. A case with accessory atrio-ventricular pathways and fetal ring tissue remnants]. / Morte improvvisa del lattante (SIDS). Un caso con vie accessorie atrio-ventricolari e persistenza di "ring tissue" fetale.

A 55 day-old male infant dying suddenly is diagnosed as sudden infant death syndrome (SIDS). Important modifications of the cardiac conduction system were found; such as: splitting-His bundle dispersion, accessory atrioventricular pathways of Mahaim type, and remnants of fetal "ring tissue" anastomosing with ordinary myocardium. These changes can be considered as arrhythmogenic in nature.

[Arrhythmogenic Takayasu disease]. / Malattia di Takayasu ad impronta aritmogena.

The Authors report a case of Takayasu disease in a woman who died at the age of forty-six, in whom the histological examination of the cardio-vascular system revealed giant cells granulomatous arteritis localized in the aortic arch and collateral arteries; endocarditis and granulomatous coronaritis. The bases of arrhythmogenic alterations, in this study, take into account the thrombosis of the conduction system arteriolar vessels and the phlogosis extending to the cardiac plexus.