Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotypedBCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset. (Blood. 2012;119(19):4467-4475) IntroductionThe analysis of the Ig genes in chronic lymphocytic leukemia (CLL) has contributed significantly toward deciphering the molecular pathogenesis of the disease. Studies from the 1990s provided the first indications for a possible role of Ag(s) in selecting the CLL progenitor cells, through the discovery of a biased Ig heavy variable (IGHV) gene repertoire, different from that of normal B cells, as well as distinctive Ag-binding sites among unrelated cases. [1][2][3][4][5] By the late 1990s, it emerged that the mutational status of the rearranged IGHV genes directly correlated with patient survival. In particular, patients with unmutated IGHV genes were found to follow a more aggressive clinical course and have significantly shorter survival than patients carrying mutated IGHV genes. 6,7 Yet, there were exceptions to this rule: cases using the IGHV3-21 gene, although mostly expressing mutated Ig, had a survival similar to that of unmutated cases. 8 Intriguingly, approximately half of the IGHV3-21 cases were found to display restricted and, in some instances, essentially identical variable heavy complementarity determining region 3 (VH CDR3) sequences and identical light chains, strongly suggesting recognition of a common antigenic determinant. 9 Soon thereafter, the study of Ig sequences in CLL by groups in both Europe and the United States led to the identification of several other subsets of cases carrying highly similar BCR Igs among both mutated and unmutated cases (stereotyped BCR). [10][11][12][13][14] The identification of stereotypy among unrelated and geographically distant cases was widely accepted as evidence for the Submitted November 26, 2011; accepte...

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Insulin resistance and other risk factors for atherosclerosis, such as hypertension and hypercholesterolemia, promote endothelial dysfunction and lead to development of metabolic syndrome which constitutes an introduction to cardiovascular disease. The insulin resistance and endothelial dysfunction cross talk between each other by numerous metabolic pathways. Hence, targeting one of these pathologies with pleiotropic treatment exerts beneficial effect on another one. Combined and expletive treatment of hypertension, lipid disorders, and insulin resistance with nonpharmacological interventions and conventional pharmacotherapy may inhibit the transformation of metabolic disturbances to fully developed cardiovascular disease. This paper summarises the common therapeutic targets for insulin resistance, endothelial dysfunction, and vascular inflammatory reaction at molecular level and analyses the potential pleiotropic effects of drugs used currently in management of cardiovascular disease, metabolic syndrome, and diabetes.

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Hypertension is a major risk factor for cardiovascular disease, which is a serious health problem in the highly industrialized countries. In more than 95% of the cases, the etiology of hypertension remains unknown. a key role in the etiology of hypertension is played by endothelial dysfunction and the inflammatory reaction in the vascular wall, in which the low molecular weight proteins -so-called chemokines -are involved. The chemokines involved in the pathogenesis of hypertension include monocyte chemoattractant protein-1, MCP-1, CCL2, interferon--inducible protein (IP-10; CXCL10), interleukin-8 (IL-8; CXCL8), RaNTeS (CCL5), fractalkine (CX3CL1) and their receptors CCR2, CCR5, CXCR1, CXCR2, CXCR3 and CX3CR1. The mechanisms involving chemokines and their receptors in the pathogenesis of hypertension are complex and not fully understood. They include the impact of the migration of macrophages and monocytes to the vascular wall, endothelial dysfunction, effects on nitric oxide and endothelin-1 and smooth muscle cell proliferation. Chemokines are also involved in the pathogenesis of complications of hypertension, such as atherosclerosis, myocardial and renal fibrosis. Hypertension is one of the most important risk factors for cardiovascular diseases. In Poland, cardiovascular diseases pose a major medical, economic and social problem. The prevalence of hypertension in Poland reaches 32% of the adult population, but only one in three Poles suffering from hypertension is aware of the disease [1]. In more than 95% of the cases, the etiology of essential hypertension remains unknown. a significant role in the pathogenesis of hypertension is played by genetic factors regulating the transport of ions and water, renal hemodynamics and the function of numerous hormones such as aldosterone, catecholamines, renin, vasopressin and endothelin-1 (eT-1). The level of blood pressure depends on the interplay of numerous systems and factors such as the renin-angiotensin-aldosterone system (RaaS), the sympathetic nervous system, natriuretic peptides and the vascular endothelium. blood pressure level is also affected by factors such as sodium intake, low physical activity, stress and obesity. In recent years, attention has been paid to the participation of inflammatory factors in the etiology of hypertension leading to endothelial dysfunction, which in turn plays a key role in the pathogenesis of hypertension. Low molecular weight proteins of the cytokine family which have the ability to stimulate and control leukocyte migration -so-called chemokines -participate in the inflammatory reaction involving the vascular wall. These proteins have the ability to bind to receptors associated with 7-transdomain G proteins; however, most chemokines bind to more than one receptor, and the receptors are capable of binding more than one * dorian Nowacki's doctoral scholarship is co-financed by the european Union as part of the european Social fund.

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Mean values of all force-velocity parameters and walk distance were significantly higher in the control group than in the peripheral arterial disease group. In the PAD group, in both men and women, the value of the agonist/antagonist ratio of both lower limbs are lower in men and women comparing to the control group. A rehabilitation program for patients with intermittent claudication must consider exercises improving strength, exercise capacity, and endurance in patients with PAD.

Malignant B lymphocytes from chronic lymphocytic leukemia (CLL) patients maintain the capacity to respond to CD40 ligation, among other microenvironmental stimuli. In this study, we show that (i) leukemic CLL cells stimulated with the soluble form of CD40L in vitro show differential responses in terms of upregulation of surface markers (CD95 and CD80) and induction of chemokines (CCL22 and CCL17) expression/secretion, and that (ii) these changes are mirrored by a distinct activation of intracellular signalling pathways including increase in IKKalpha/beta phosphorylation and upregulation of antiapoptotic proteins (BCL-2 and MCL-1). CLL patients can then be segregated into two distinct functional subsets. We defined the responsive subset of cases CD40L dependent, considering the capacity to respond as a sign of persistent need of this stimulation for the leukemic expansion. Conversely, we named the unresponsive cases CD40L independent, considering them less dependent on this microenvironmental signal, presumably because of a higher autonomous proliferative and survival potential. Importantly, we report that (iii) the two functional subsets show an opposite clinical outcome, with CD40L-independent cases having a shorter time to progression. This indicates that the functional differences observed in vitro may reflect a different leukemic potential in vivo likely responsible for a distinct clinical course.