MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sézary syndrome.

Sézary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma and its pathogenesis is still unknown. Diagnosis/prognosis may strongly ameliorate the management of SS individuals. Here, we profiled the expression of 470 microRNAs (miRNAs) in a cohort of 22 SS patients, and we identified 45 miRNAs differentially expressed between SS and controls. Using predictive analysis, a list of 19 miRNAs, including miR-21, miR-214, miR-486, miR-18a, miR-342, miR-31 and let-7 members were also found. Moreover, we defined a signature of 14 miRNAs including again miR-21, potentially able to discriminate patients with unfavorable and favorable outcome. We validated our data for miR-21, miR-214 and miR-486 by qRT-PCR, including an additional set of array-independent SS cases. In addition, we also provide an in vitro evidence for a contribution of miR-214, miR-486 and miR-21 to apoptotic resistance of CTCL cell line.

Glucose metabolism in cardiovascular surgery.

During the past few years, it has become evident that metabolic control is a major determinant of postoperative outcomes, not only for diabetic patients but for all patients undergoing surgery.In cardiac and vascular surgery, myocardial ischemia is a common challenge and the management of hyperglycemia should be part of the strategy aimed at optimizing cardiac protection during these types of surgery, since performed in high risk patients. Little informations are available on the relation between glucose substrate and the type of anesthesia and few studies have been performed on glucose metabolism in the perioperative risk assessment as well as on intraoperative and post surgical management of hyperglycemia in patients submitted to cardiac and vascular surgery. Evidence exists that even slight increased in glycemia are detrimental for patients (diabetic and non) elective for cardiac and vascular surgery, though the precise details of the timing of insulin therapy, the desired target serum glucose level, and the duration of therapy are so far to be completely elucidated. Anesthestiologists can therefore affect outcome by simply preserving a normal blood glucose concentration initiating in the operating room. The challenge to optimize glucose control should begin during preoperative evaluation.

Kinetic of procalcitonin in patients with cardiogenic shock following acute myocardial infarction: preliminary data.

INTRODUCTION: Procalcitonin concentrations are considered as a component of the inflammatory response and as an acute-phase marker, after shock or tissue injury (i.e. burn, trauma, surgery) or infections and sepsis. No data are so far available on the dynamics of procalcitonin levels in patients with cardiogenic shock following ST-elevation myocardial infarction, with no clinical or laboratory sign of infection. METHODS: We evaluated procalcitonin values every day during intensive cardiac care staying in ten cardiogenic shock patients admitted to our intensive cardiac care unit. NT-pro Brain Natriuretic Peptide, C Reactive Protein and APACHE II score were also assessed. RESULTS: Six patients survived, whereas 4 patients died. A progressive reduction in procalcitonin values was observed in cardiogenic shock patients who survived, whereas the lack of changes in procalcitonin concentrations was documented in cardiogenic shock patients who died (survivors: slope = -3.76; dead: slope = -0.81, p=0.004). Furthermore, higher values of glycemia, NT-pro Brain Natriuretic Peptide and C Reactive Protein (as well as higher APACHE II scores) were detectable in dead patients in respect to survivors. CONCLUSIONS: In our preliminary study we observed that in patients with cardiogenic shock and no sign of infections a reduction of procalcitonin levels was detectable only in survivors. Moreover, higher values of NT- Brain Natriuretic Peptide, a marked systemic inflammation (higher values of C Reactive Protein) and higher severity score (as depicted by APACHE II) are associated with an ominous prognosis in cardiogenic shock patients.

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen-telogen transition and affects stem-cell marker CD34 expression.

Overexpression of the TCL1 gene family plays a role in the onset of T-cell leukemias in mice and in humans. The Tcl1 gene is tightly regulated during early embryogenesis in which it participates in embryonic stem (ES)-cells proliferation and during lymphoid differentiation. Here, we provide evidences that Tcl1 is also important in mouse hair follicle (HF) and skin homeostasis. We found that Tcl1(-/-) adult mice exhibit hair loss, leading to alopecia with extensive skin lesions. By analysing Tcl1 expression in the wild-type (wt) skin through different stages of hair differentiation, we observe high levels in the secondary hair germ (HG) cells and hair bulges, during early anagen and catagen-telogen transition phases. The loss of Tcl1 does not result in apparent skin morphological defects during embryonic development and at birth, but its absence causes a reduction of proliferation in anagen HFs. Importantly, we show the that absence of Tcl1 induces a significant loss of the stem-cell marker CD34 (but not alpha6-integrin) expression in the bulge cells, which is necessary to maintain stem-cell characteristics. Therefore, our findings indicate that Tcl1 gene(s) might have important roles in hair formation, by its involvement in cycling and self-renewal of transient amplifying (TA) and stem-cell (SC) populations.

Adiponectin and the cardiovascular system: from risk to disease.

Adiponectin is known to play a role in fatty acid and glucose metabolism through a change in insulin sensitivity and activation of fuel oxidation by AMP-activated protein kinase. Adiponectin can be considered an important factor able to modulate the adipovascular axis which, through genomic and environmental influences, affects the cardiovascular risk milieu, from the pre-metabolic syndrome-- through the metabolic syndrome--to the overt atherosclerotic process and its clinical manifestations. Hypoadiponectinaemia can be viewed as an early sign of a complex cardiovascular risk factor predisposing to the atherosclerosis process as well as a contributing factor accelerating the progress of the atherosclerotic plaque. In addition, adiponectin per se holds a protective role thanks to its anti-inflammatory and antiatherogenic properties. The early identification of patients "at cardiovascular risk" means in the current practice to search for indexes of metabolic derangements and pro-inflammatory status (adiponectin) from adolescence and childhood.

Effects of low-dose adrenomedullin on cardiac function and systemic haemodynamics in man.

The cardiovascular effects of low-dose adrenomedullin (ADM, 1, 2 and 3 pmol kg-1 min-1 for 30 min each) were evaluated in six healthy subjects in a placebo controlled, cross-over study by determining cardiac volumes, systolic and diastolic function (echocardiography) and systemic haemodynamics before, during and after ADM or placebo. High-resolution ultrasound was used to evaluate changes in carotid artery distension. ADM caused a +85% increment in its plasma levels and significantly increased plasma cyclic adenyl monophosphate (cAMP). Compared with placebo, ADM induced significant decrements in left ventricular (LV) systolic diameter and systemic vascular resistance, and increments in LV posterior wall thickening, ejection fraction and cardiac index. Right and left atrial emptying fraction and carotid artery distention increased. LV diastolic function, heart rate, and plasma renin activity did not change, whereas packed cell volume increased. These results indicate that ADM influences cardiovascular function and systemic haemodynamics at physiological plasma levels in man mainly because of its vasodilating activity, leading to reduced afterload.

Cardiovascular effects of parathyroid hormone: a study in healthy subjects and normotensive patients with mild primary hyperparathyroidism.

The aim of the study was to evaluate: 1) the cardiovascular function and the autonomic drive to the heart in patients affected by primary hyperparathyroidism (pHPT) with no evidence of renal and cardiovascular complications; 2) the cardiovascular effects of acute administration of PTH in normal subjects. In 14 patients affected by mild asymptomatic pHPT echocardiographic assessment of cardiovascular function and of the mechanic properties of the brachial and carotid artery, heart rate variability and the dispersion of QT interval were performed before and 6 months after successful surgery. Twenty age- and sex-matched healthy subjects were included in the study. Five healthy volunteers underwent a single blind, placebo-controlled, random order, cross-over study with infusion of PTH (hPTH 1-34, 200 U in saline over 5 min) or placebo. Echocardiographic assessment of cardiovascular function, heart rate variability, and QT interval were performed between 20 and 25 min after the start of the infusion and repeated after 15 min of tilting at 60 degrees. In pHPT patients the echocardiographic parameters were normal; left ventricular isovolumetric relaxation time was always in the normal range, but significantly shorter than in control subjects, suggesting an increased sympathetic stimulation. Arterial diameters and thickness, blood pressure, and QT interval were not significantly different with respect to normal subjects and were unchanged 6 months after surgery. pHPT patients lacked the circadian rhythm of the low frequency to high frequency ratio, suggesting an increased sympathetic drive to the heart at nighttime. In normal subjects there were no significant differences in basal echocardiographic measurements during PTH infusion with respect to placebo and in the hemodynamic response to tilt. These results suggest that cardiovascular function is substantially normal in normotensive pHPT patients with mild hypercalcemia. A modulation of the adrenergic control of circulation seems to be associated with hypercalcemia and/or chronic PTH excess, but its biological relevance needs further investigations.

24-hour heart rate variability in patients with vasovagal syncope.

Since alterations in the autonomic nervous system are thought to play a major role in the pathogenesis of vasovagal syncope, we characterized the chronic autonomic profile of 44 patients with syncope and 20 healthy subjects by means of heart rate variability using 24-hour Holter recordings (time- and frequency-domain indexes), and evaluated whether the different types of responses to tilting (vasodepressive versus cardioinhibitory) could be associated with different cardiac autonomic patterns. Twenty-three patients exhibited a positive response to tilting, which was vasodepressive in 11 patients and cardioinhibitory in 12 patients. All vasodepressive patients had a standard deviation of the averages of NN (SDANN) intervals in all 5-minute segments lower than 100 ms. Patients with vasodepressive syncope also had significantly lower values of RMSSD (the 24-hour square root of the mean of the sum of the squares of differences between adjacent normal RR intervals) than those with cardioinhibitory response, and lacked the day-night rhythm of the low frequency/high frequency ratio. However, only SDANN values correctly identified patients with vasodepressive response to tilting. We conclude that (1) the population of patients with vasovagal syncope is heterogeneous, (2) patients with vasodepressive syncope have a peculiar chronic autonomic profile as assessed by 24-hour heart rate variability analysis, and (3) the evaluation of the autonomic profile in 24-hour Holter recordings could be of value in the diagnosis of patients with syncope.

Regulation of TCL1 expression in B- and T-cell lymphomas and reactive lymphoid tissues.

Chromosomal rearrangements observed in T-cell prolymphocytic leukemia involve the translocation of one T-cell receptor gene to either chromosome 14q32 or Xq28, deregulating the expression of cellular protooncogenes of unknown function, such as TCL1 or its homologue, MTCP1. In the human hematopoietic system, TCL1 expression is predominantly observed in developing B lymphocytes, whereas its overexpression in T cells causes mature T-cell proliferation in transgenic mice. In this study, using a newly generated monoclonal antibody against recombinant TCL1 protein, we extended our analysis mainly by immunohistochemistry and also by fluorescence-activated cell sorting and Western blot to a large tumor lymphoma data bank including 194 cases of lymphoproliferative disorders of B- and T-cell origin as well as reactive lymphoid tissues. The results obtained show that in reactive lymphoid tissues, TCL1 is strongly expressed by a subset of mantle zone B lymphocytes and is expressed to a lesser extent by follicle center cells and by scattered interfollicular small lymphocytes. In B-cell neoplasia, TCL1 was expressed in the majority of the cases, including lymphoblastic lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma (60%), and primary cutaneous B cell lymphoma (55%). TCL1 expression was observed in both the cytoplasmic and nuclear compartments, as confirmed by Western blot analysis. Conversely, TCL1 was not expressed in Hodgkin/Reed-Sternberg cells, multiple myelomas, marginal zone B-cell lymphomas, CD30+ anaplastic large cell lymphoma, lymphoblastic T-cell lymphoma, peripheral T-cell lymphoma, and mycosis fungoides. These data indicate that TCL1 is expressed in more differentiated B cells, under both reactive and neoplastic conditions, from antigen committed B cells and in germinal center B cells and is down-regulated in the latest stage of B-cell differentiation.

C-type natriuretic peptide does not affect plasma and urinary adrenomedullin in man.

To investigate whether C-type natriuretic peptide (CNP) at pathophysiological plasma levels stimulates the release of adrenomedullin (ADM) in man, six healthy subjects (three men and three women, mean age 35 +/- 3 years, range 33-40 years) received an intravenous infusion of synthetic human CNP-22 (2 pmol kg-1 min for 2 h), in a single-blind, placebo-controlled, random order, cross-over study, with measurements of the plasma levels of cyclic guanosine monophosphate (cGMP), ADM, renin and atrial natriuretic peptide (ANP), arterial pressure, heart rate, renal blood flow (para-aminohippurate clearance), glomerular filtration rate (creatinine clearance), and the urinary excretion rates of cGMP, ADM and sodium. Infusion of CNP induced increases in its own levels (from 1.17 +/- 0.11 up to 21.13 +/- 1.41 pmol l-1) without modifying the plasma levels of cGMP, ADM, renin and ANP, the urinary excretion rate of ADM and cGMP, renal haemodynamics and sodium excretion. These data indicate that circulating CNP is not involved in the regulation of ADM release, renal haemodynamics and sodium excretion in man.

Deregulated expression of TCL1 causes T cell leukemia in mice.

The TCL1 oncogene on human chromosome 14q32.1 is involved in the development of T cell leukemia in humans. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. The TCL1 oncogene is activated in these leukemias by juxtaposition to the alpha or beta locus of the T cell receptor, caused by chromosomal translocations t(14:14)(q11:q32), t(7:14)(q35:q32), or by inversions inv(14)(q11:q32). To show that transcriptional alteration of TCL1 is causally involved in the generation of T cell neoplasia we have generated transgenic mice that carry the TCL1 gene under the transcriptional control of the p56(lck) promoter element. The lck-TCL1 transgenic mice developed mature T cell leukemias after a long latency period. Younger mice presented preleukemic T cell expansions expressing TCL1, and leukemias developed only at an older age. The phenotype of the murine leukemias is CD4-CD8+, in contrast to human leukemias, which are predominantly CD4+CD8-. These studies demonstrate that transcriptional activation of the TCL1 protooncogene can cause malignant transformation of T lymphocytes, indicating the role of TCL1 in the initiation of malignant transformation in T prolymphocytic leukemias and T chronic lymphocytic leukemias.

TCL1 is overexpressed in patients affected by adult T-cell leukemias.

Among mature postthymic T-cell leukemias, adult T-cell leukemia (ATL) has characteristic clinicopathological entities. The association with the human T-cell leukemia/lymphotropic virus type I is one of the distinctive etiopathogenetic features of this disease. However, unlike other acute transforming retroviruses, the human T-cell leukemia/lymphotropic virus type I lacks an oncogene within its genome. Other human postthymic leukemias, such as T-prolymphocytic leukemias, involve mostly the CD4 cellular subset and share many similarities to ATLs (aggressive course, cutaneous involvement, CD4+, CD29+, CD45RA- phenotype, and alpha-naphthyl-acetate esterase positivity). A chromosomal rearrangement at 14q32.1, involved in translocations or inversions with either the alpha/delta locus [t(14;14)(q11;q32.1), inv14(q11;q32.1)], or the beta-chain locus of the T-cell receptor [t(7;14)(q35;q32.1)] is found. These rearrangements disregulate a gene, TCL1, located at the 14q32.1 region, that we show is physiologically expressed in CD4/CD8 double-negative thymocyte cells, but not in more differentiated CD4+ and CD8+ subpopulations. Here, using molecular and immunocytochemical analysis, we report that TCL1 is also overexpressed in 10 of 10 ATL specimens, indicating that this gene may play an important role in the pathogenesis of this disease.