Comprehensive analysis of PTEN status in Sezary syndrome.

Sézary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma characterized by recurrent chromosomal alterations, among which, chromosome 10q deletion is very frequent. In this study, we investigated the PTEN status, on locus 10q23, in 44 SS patients; our findings show that PTEN is deleted in 36% of SS cases, whereas PTEN downregulation is observed in almost all of the samples evaluated by quantitative reverse-transcriptase polymerase chain reaction and Western blotting analysis. Neither DNA sequence mutation nor promoter hypermethylation were found at the PTEN locus, but we demonstrate that PTEN level can be also reduced by a group of miRs previously found upregulated and of prognostic relevance in SS; particularly, miR-21, miR-106b, and miR-486 were able to control PTEN abundance either in vitro or in vivo. Finally, because reduced PTEN activates the PI3/AKT-mediated pathway of cell growth and survival, we demonstrate that PTEN deficiency is associated with activated AKT in skin resident but not circulating SS cells, suggesting that the cutaneous milieu may strongly contribute to the SS cell growth. To our knowledge, this is the first study fully exploring the PTEN status in a large cohort of SS patients, unveiling potential elements of clinical utility in this malignancy.

Intracerebellar administration of the chemokine Cxcl3 reduces the volume of medulloblastoma lesions at an advanced stage by promoting the migration and differentiation of preneoplastic precursor cells.

The prognosis for many pediatric brain tumors, including cerebellar medulloblastoma (MB), remains dismal but there is promise in new therapies. We have previously generated a mouse model developing spontaneous MB at high frequency, Ptch1+/-/Tis21-/-. In this model, reproducing human tumorigenesis, we identified the decline of the Cxcl3 chemokine in cerebellar granule cell precursors (GCPs) as responsible for a migration defect, which causes GCPs to stay longer in the proliferative area rather than differentiate and migrate internally, making them targets of transforming insults. We demonstrated that 4-week Cxcl3 infusion in cerebella of 1-month-old mice, at the initial stage of MB formation, forces preneoplastic GCPs (pGCPs) to leave lesions and differentiate, with a complete suppression of MB development. In this study, we sought to verify the effect of 4-week Cxcl3 treatment in 3-month-old Ptch1+/-/Tis21-/- mice, when MB lesions are at an advanced, irreversible stage. We found that Cxcl3 treatment reduces tumor volumes by sevenfold and stimulates the migration and differentiation of pGCPs from the lesion to the internal cerebellar layers. We also tested whether the pro-migratory action of Cxcl3 favors metastases formation, by xenografting DAOY human MB cells in the cerebellum of immunosuppressed mice. We showed that DAOY cells express the Cxcl3 receptor, Cxcr2, and that Cxcl3 triggers their migration. However, Cxcl3 did not significantly affect the frequency of metastases or the growth of DAOY-generated MBs. Finally, we mapped the expression of the Cxcr2 receptor in human MBs, by evaluating a well-characterized series of 52 human MBs belonging to different MB molecular subgroups. We found that Cxcr2 was variably expressed in all MB subgroups, suggesting that Cxcl3 could be used for therapy of different MBs.

Formation and function of acute stroke-ready hospitals within a stroke system of care recommendations from the brain attack coalition.

BACKGROUND AND PURPOSE: Many patients with an acute stroke live in areas without ready access to a Primary or Comprehensive Stroke Center. The formation of care facilities that meet the needs of these patients might improve their care and outcomes and guide them and emergency responders to such centers within a stroke system of care. METHODS: The Brain Attack Coalition conducted an electronic search of the English medical literature from January 2000 to December 2012 to identify care elements and processes shown to be beneficial for acute stroke care. We used evidence grading and consensus paradigms to synthesize recommendations for Acute Stroke-Ready Hospitals (ASRHs). RESULTS: Several key elements for an ASRH were identified, including acute stroke teams, written care protocols, involvement of emergency medical services and emergency department, and rapid laboratory and neuroimaging testing. Unique aspects include the use of telemedicine, hospital transfer protocols, and drip and ship therapies. Emergent therapies include the use of intravenous tissue-type plasminogen activator and the reversal of coagulopathies. Although many of the care elements are similar to those of a Primary Stroke Center, compliance rates of ≥67% are suggested in recognition of the staffing, logistical, and financial challenges faced by rural facilities. CONCLUSIONS: ASRHs will form the foundation for acute stroke care in many settings. Recommended elements of an ASRH build on those proven to improve care and outcomes at Primary Stroke Centers. The ASRH will be a key component for patient care within an evolving stroke system of care.

Revised and updated recommendations for the establishment of primary stroke centers: a summary statement from the brain attack coalition.

BACKGROUND AND PURPOSE: The formation and certification of Primary Stroke Centers has progressed rapidly since the Brain Attack Coalition's original recommendations in 2000. The purpose of this article is to revise and update our recommendations for Primary Stroke Centers to reflect the latest data and experience. METHODS: We conducted a literature review using MEDLINE and PubMed from March 2000 to January 2011. The review focused on studies that were relevant for acute stroke diagnosis, treatment, and care. Original references as well as meta-analyses and other care guidelines were also reviewed and included if found to be valid and relevant. Levels of evidence were added to reflect current guideline development practices. RESULTS: Based on the literature review and experience at Primary Stroke Centers, the importance of some elements has been further strengthened, and several new areas have been added. These include (1) the importance of acute stroke teams; (2) the importance of Stroke Units with telemetry monitoring; (3) performance of brain imaging with MRI and diffusion-weighted sequences; (4) assessment of cerebral vasculature with MR angiography or CT angiography; (5) cardiac imaging; (6) early initiation of rehabilitation therapies; and (7) certification by an independent body, including a site visit and disease performance measures. CONCLUSIONS: Based on the evidence, several elements of Primary Stroke Centers are particularly important for improving the care of patients with an acute stroke. Additional elements focus on imaging of the brain, the cerebral vasculature, and the heart. These new elements may improve the care and outcomes for patients with stroke cared for at a Primary Stroke Center.

One-year treatment with rosuvastatin reduces intima-media thickness in 45 hypercholesterolemic subjects with asymptomatic carotid artery disease.

AIM: An increase in carotid intima-media thickness (CIMT) represents an early phase of the atherosclerotic process. The aim of our study was to evaluate whether a reduction in CIMT could be seen with 1-year treatment with rosuvastatin (10 mg/day). METHODS AND RESULTS: Forty-five patients with hypercholesterolemia and asymptomatic carotid atherosclerosis on baseline carotid ultrasound investigation (CUI) were examined with repeat CUI after 1 year of treatment (rosuvastatin 10 mg/day). Demographic and lifestyle data were collected. A physical examination was performed, and fasting venous blood samples were obtained. Total cholesterol, low-density lipoprotein cholesterol and triglycerides decreased significantly (p < 0.001), while high-density lipoprotein cholesterol increased significantly (p < 0.001) during the intervention. The mean decreases in the IMT of the right and left common carotid arteries (CCAs) were 0.29 and 0.26 mm, respectively (p < 0.05 for each). Age and lipid profile parameters were significant predictors of change in CIMT in linear regression analyses after adjustment for established atherosclerosis risk factors. CONCLUSIONS: One-year treatment with rosuvastatin in hypercholesterolemic adults with evidenceof subclinical atherosclerosis significantly reduced the CIMT of both CCAs and improved the lipid and lipoprotein levels.

Leukotrienes in atherosclerosis: new target insights and future therapy perspectives.

Atherosclerosis represents an important chronic inflammatory process associated with several pathophysiological reactions in the vascular wall. The arachidonic acid, released by phospholipase A2, is an important substrate for the production of a group of lipid mediators known as leukotrienes, which induce proinflammatory signaling through the activation of specific BLT and CysLT receptors. The interaction of these substances in the vascular wall determines important morphological alterations like the early lipid retention and the accumulation of foam cells, the development of intimal hyperplasia, and advanced atherosclerotic lesions, and it plays an important role in the rupture of atherosclerotic plaque. Many studies regarding myocardial ischemia and reperfusion show that leukotriene signaling may be involved in the development of ischemic injury. For these, reasons both leukotriene synthesis inhibitors and leukotriene receptor antagonists have been suggested for inducing beneficial effects at different stages of the atherosclerosis process and may represent a new therapeutic target in the treatment of atherosclerotic vessel diseases, in particular in acute coronary syndrome.

Antioxidant vitamin supplementation in cardiovascular diseases.

Cardiovascular disease is the most important adult health problem in wealthy countries, where biological factors such as obesity, hypertension, dyslipidemia, diabetes, inappropriate diet, cigarette smoking, and sedentary life-style have contributed to its dissemination. Research concerning nutritional regimens has shown that persons who consume large amounts of fruit and vegetables have lower incidences of cardiovascular diseases, stroke, and tumors, although the precise mechanisms for this protective effect are elusive. Possible explanations include (a) increased consumption of dietary fiber, (b) reduced consumption of dietary cholesterol and other lipids, and (c) increased intake of the antioxidant vitamins (A, C, and E). Numerous studies have raised the question whether vitamin supplements help to prevent cardiovascular diseases. Results of randomized controlled trials of antioxidant vitamin supplements in large numbers of participants has been ambiguous or contradictory. This minireview examines the relevant clinical reports on dietary supplements of vitamins A, C, and E to determine whether they support the premise that patients at risk of cardiovascular disease may be candidates for this therapeutic option.

Predictive value of biochemical markers in stroke.

Biochemical markers of cerebral ischemia and subsequent inflammation represent a potential diagnostic and predictive modality in acute ischemic stroke. Measurement of these markers may improve clinical functions ranging from diagnosis of ischemic stroke to prediction of functional outcome at 3 months. Predictive models, using various biochemical markers, continue to be investigated.

[Anastomotic dehiscence in colorectal surgery. Analysis of 1290 patients]. / Le deiscenze anastomotiche in chirurgia colo-rettale. Analisi su 1290 pazienti.

The most frightening complication following colorectal surgery is the anastomotic leakage which is associated with an high mortality rate, and the analysis of risk factors for the anastomotic leak is of great interest. The aim of this retrospective study is to evaluate the risk factor for the anastomotic leakage in personal series of patients who underwent colorectal surgery. We have analyzed a consecutive series of 1290 patients who underwent colorectal open surgery from 1970 to 2004. The associations between anastomotic leak and several risk factors were studied by univariate analysis. The variables considered were the following: age; sex; type of disease; elective or emergency surgery; type of surgery; type, design and site (intra or extra peritoneal) of the anastomosis; stapled or manual anastomosis; distance from anal verge of the colorectal anastomosis; intraoperative complications; protective stoma. The rate of anastomotic leakage was 4.8% (62/1290 patients). Significant factors were: the type of surgery (higher risk after restorative proctocolectomy or rectal resection), the site extra peritoneal of the anastomosis, the type of the anastomosis (higher risk after coloanal or ileal-pouch anal or colorectal), the stapled anastomosis, the intraoperative complications. After colorectal anastomosis the risk of leakage has progressively higher for low, ultra-low and coloanal anastomosis. In these conditions a protective stoma seems to be suitable.

Genetics and Autosomal Dominant Polycystic Kidney Disease Progression.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, accounting for 10% of European patients on renal replacement therapy. In the previous years, many approaches to slow the progression of ADPKD were studied and many clinical trials published. In addition to having diagnostic role, the description of the genotype is even important to predict the progression of the disease and contributes, combined with several other factors, to a more precise patients classification. With the availability of disease-modifying drugs, "fast progression factors" are needed to early recognize those patients who would likely progress, before cyst growth reaches a critical value. ERA-EDTA working group on inherited kidney disorders included a series of recommendations resulting in a hierarchical decision algorithm to select patients who are most likely to benefit from the treatment. Beyond diagnosis, we will also discuss the important role of genetics in ADPKD progression and management.

Metabolic syndrome: contributing factors and treatment strategies.

Metabolic syndrome is associated with increased risk for cardiovascular and cerebrovascular disease. The World Health Organization and National Cholesterol Education Program Adult Treatment Panel III have identified physiologic abnormalities associated with metabolic syndrome, including impaired glucose metabolism, high blood pressure, elevated cholesterol levels, and abdominal obesity. It is estimated that 47 million Americans have metabolic syndrome. A variety of therapies may help reduce the incidence and risk, including diet, weight loss, physical exercise, glycemic control, and pharmacological treatments. Nursing care is focused on developing an individualized plan of care that includes family members and providing education, psychosocial support, close monitoring, and continued follow-up to ensure adherence and success in achieving patient outcomes.

[Severity of anemia and operative morbidity and mortality. Report on 3 clinical cases in Jehovah's Witnesses and review of the literature]. / Morbi-mortalità operatoria relativa alla severità dell'anemia acuta. Presentazione di 3 casi clinici complicati in pazienti Testimoni di Geova e revisione della letteratura.

It has been reported that patients who refuse blood transfusions, such as Jehovah's witnesses, can undergo major surgery. In a review of the literature, however, we critically examined the severity of anaemia in relation to operative mortality and morbidity rates. We report three cases of Jehovah's witnesses who underwent major surgery and presented complication during the postoperative period. Case 1: a 50-year-old man with oesophageal achalasia who underwent Heller's myotomy and Nissen's fundoplication. The postoperative period was complicated by massive haemorrhage and the patient was reoperated on postoperative day 1. After four years, he underwent total oesophagectomy because of severe chronic oesophagitis. On postoperative day 13 the patient suffered anteroseptal myocardial ischaemia, which was treated with medical therapy. Case 2: a 40-year-old man, admitted for ulcerative rectocolitis, who underwent total colectomy. On postoperative day 1 he presented massive haemorrhage and shock. He was reoperated and the postoperative period was complicated by myocardial ischaemia, renal failure and an enterocutaneous fistula. Case 3: a 65-year-old woman with ulcerative rectocolitis who underwent total colectomy and a temporary ileostomy. She suffered venous thrombosis of the lower limbs and pulmonary oedema. The patient died 14 months after surgery as a result of massive haemolysis by cryoagglutinins and cardiac arrest.

Rosuvastatin reduces intima-media thickness in hypercholesterolemic subjects with asymptomatic carotid artery disease: the Asymptomatic Carotid Atherosclerotic Disease in Manfredonia (ACADIM) Study.

BACKGROUND: An increase in carotid intima-media thickness (CIMT) represents an early phase of the atherosclerotic process. The aim of this study was to evaluate whether a reduction in CIMT could be seen with only 16 weeks of treatment with rosuvastatin (10 mg/day). METHODS/RESULTS: Sixty-six participants of the ACADIM Study with hypercholesterolemia and carotid atherosclerosis at baseline carotid ultrasound investigation (CUI) were examined, with repeat CUI after 16 weeks of treatment. Demographic and lifestyle data were collected, as well as physical examination and fasting venous blood samples. Total cholesterol, low density lipoprotein cholesterol (LDL-C) and triglycerides decreased significantly (p < 0.0001), while high density lipoprotein cholesterol (HDL-C) increased significantly (p < 0.0001) during the intervention. The mean decrease in IMT of the right and left common carotid arteries (CCAs) was 0.35 and 0.38 mm, respectively (p < 0.05 for each). Age and lipid profile parameters were significant predictors of change in CIMT in linear regression analyses after adjustment for established atherosclerosis risk factors. CONCLUSIONS: Treatment with rosuvastatin in adults with evidence of subclinical atherosclerosis significantly reduced the CIMT of both CCAs, as well as improving lipid and lipoprotein levels.

Early detection of psychosis: finding those at clinical high risk.

AIM: In early detection work, recruiting individuals who meet the prodromal criteria is difficult. The aim of this paper was to describe the development of a research clinic for individuals who appear to be at risk of developing a psychosis and the process for educating the community and obtaining referrals. METHODS: The outcome of all referrals to the clinic over a 4-year period was examined. RESULTS: Following an ongoing education campaign that was over inclusive in order to aid recruitment, approximately 27% of all referrals met the criteria for being at clinical high risk of psychosis. CONCLUSIONS: We are seeing only a small proportion of those in the community who eventually go on to develop a psychotic illness. This raises two important issues, namely how to remedy the situation, and second, the impact of this on current research in terms of sampling bias and generalizability of research findings.

The role of the antioxidant vitamin supplementation in the prevention of cardiovascular diseases.

Industrial and technological revolutions have resulted in dramatic shifts in the diseases that are responsible for illness and death. In particular, cardiovascular disease (CVD) has emerged as the dominant chronic disease in many parts of the world. Diet, tobacco smoking, physical inactivity, obesity, lipid levels, hypertension and diabetes mellitus have contributed to their wide diffusion. Oxidative damage and the production of free radicals in the endothelium are two of the main factors involved in the pathogenesis of the atherosclerotic process that causes CVD. One of the more important results of basic research on dietetic regimes has shown that people who consume large amounts of fruits and vegetables have a lower incidence of CVD, stroke and tumours, but the specific mechanisms of these foods (which have an apparently protective effect) are still not completely clear. Possible reasons could include a greater consumption of fruit and vegetables, and an increased consumption of dietetic fibres. Recently, it been proposed that micronourishments with an antioxidant activity could be responsible for the reduction of chronic diseases. Research supplies a hypothetical mechanism by which antioxidant substances may be reducing the risk of atherosclerosis through the inhibition of oxidative damage. Appropriate nutritional practices are of central importance in managing risk and treatment of CVD; in fact, many current guidelines for a healthy general population contain nutritional recommendations to reduce the risk of these diseases. A large number of descriptive and case-control studies suggests that the consumption of many antioxidant vitamins (A, C and E) reduces the risk of CVD. Such data raises the following problem of whether supplementation of vitamins A, C and E emerges as being useful in the primary prevention of CVD. Many important studies involving a great number of participants have not confirmed this hypothesis and the results are often contradictory. This review examines the studies published in the literature that document the effect of supplementation with antioxidant vitamins (A, C and E) in the primary and secondary prevention of CVD due to an atherosclerosis process.

The effects of 99mTc-HMPAO-labelled leucocyte scan on human karyotype.

Technetium-99m hexamethylpropylene amine oxime (HMPAO) white blood cell scan (WBCS) requires separation and labelling of mixed leucocytes, which include particularly radiosensitive cells, lymphocytes. Lymphocytes labelled during the mixed leucocyte labelling procedure could represent a problem for patients owing to the possible induction of chromosomal aberrations. Lymphocytes labelled in mixed leucocyte preparations are probably killed by the high-dose radiation. Nevertheless, it has been reported that some of these lymphocytes can proliferate after in vitro stimulation. If these cells were to reproduce themselves in vivo, onset of, or increase over time in, chromosomal aberrations could occur on peripheral blood lymphocytes. The present study was performed on 21 patients who underwent WBCS for suspected infection/inflammation. Blood samples of these patients were submitted to cytogenetic study, comprising karyotype determination, evaluation of sister chromatid exchanges (SCE) and evaluation of induced chromosomal breakages or rearrangement rate (B/R). This study was performed 2 h before and 7 days and 6 months after the WBCS. The results demonstrated no statistically significant differences between SCE and B/R values before and after WBCS. No cause-effect relationship appeared to exist between WBCS and the onset of chromosomal aberrations in peripheral blood lymphocytes, at least during the first 6 months post WBCS and within the limits of this study's approach. The high-dose radiation administered to lymphocytes was almost certainly sufficient to kill these cells.