The clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is variable, and novel biologic parameters need to be added to the clinical staging systems to predict an indolent or aggressive outcome. We investigated the 70-kDa zetaassociated protein (ZAP-70), CD38, soluble CD23 (sCD23), and cytogenetics in 289 patients with B-CLL. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70 ؉ (P < .001), in CD38 ؉ (P < .001) and in sCD23 ؉ patients (P < .001 and P ؍ .013, respectively). ZAP-70 ؉ CD38 ؉ or ZAP-70 ؉ patients with an unmutated IgV H status showed both a shorter PFS (P < .001) and OS (P < .001 and P < .001, respectively) as compared with ZAP-70 ؊ /CD38 ؊ or ZAP-70 ؊ patients with mutated IgV H genes. Discordant patients showed an intermediate outcome. Note, ZAP-70 ؉ patients even if CD38 ؊ or mutated showed a shorter PFS, whereas ZAP-70 ؊ patients even if CD38 ؉ or unmutated had a longer PFS. Furthermore, ZAP-70 positivity was associated with a shorter PFS both within normal karyotype (P < .001) and within the poor-risk cytogenetic subset (P ؍ .02).
Anandamide (arachidonoylethanolamide, AnNH) is shown to activate human platelets, a process which was not inhibited by acetylsalicylic acid (aspirin). Unlike AnNH, hydroperoxides generated thereof by lipoxygenase activity, and the congener (13-hydroxy)linoleoylethanolamide, were unable to activate platelets, though they counteracted AnNH-mediated stimulation. On the other hand, palmitoylethanolamide neither activated human platelets nor blocked the AnNH effects. AnNH inactivation by human platelets was afforded by a high-affinity transporter, which was activated by nitric oxide-donors up to 225% of the control. The internalized AnNH could thus be hydrolyzed by a fatty acid amide hydrolase (FAAH), characterized here for the first time.z 1999 Federation of European Biochemical Societies.
The endocannabinoid 2-arachidonoylglycerol (2-D 4 AchGro) activates human platelets in platelet-rich plasma at physiological concentrations. The activation was inhibited by selective antagonists of CB 1 and CB 2 cannabinoid receptors, but not by acetylsalicylic acid. Human platelets can metabolize 2-D 4 Ach-Gro by internalization through a high affinity transporter (K m 300^30 nm, V max 10^1 pmol´min 21´m g protein 21 ), followed by hydrolysis by a fatty acid amide hydrolase (K m 8^1 mm, V max 400^50 pmol´min 21´m g protein 21 ). The anandamide transport inhibitor AM404, and anandamide itself, were ineffective on 2-D 4 Ach-Gro uptake by platelets, whereas anandamide competitively inhibited 2-D 4 Ach-Gro hydrolysis (inhibition constant 10^1 mm). Platelet activation by 2-D 4 Ach-Gro was paralleled by an increase of intracellular calcium and inositol-1,4,5-trisphosphate, and by a decrease of cyclic AMP. Moreover, treatment of preloaded platelet-rich plasma with 2-D 4 Ach-Gro induced an approximately threefold increase in [ 3 H]2-D 4 Ach-Gro release, according to a CB receptor-dependent mechanism. On the other hand, ADP and collagen counteracted the activation of platelets by 2-D 4 Ach-Gro, whereas 5-hydroxytryptamine (serotonin) enhanced and extended its effects. Remarkably, ADP and collagen also reduced [ 3 H]2-D 4 AchGro release from 2-D 4 Ach-Gro-activated platelets, whereas 5-hydroxytryptamine further increased it. These findings suggest a so far unnoticed interplay between the peripheral endocannabinoid system and physiological platelet agonists.
To assess the role of platelets and lymphocyterelated immunological mechanisms in livedo vasculopathy (LV) and cutaneous small vessel vasculitis (CSVV). Livedo vasculopathy is thought to be related to the thrombotic occlusion of small and medium-sized dermal vessels. Cutaneous small vessel vasculitis comprises a heterogeneous group of disorders in which the main pathogenetic events could be modulated by circulating cytokines.Design: Case series study of 2 groups of patients affected respectively with LV and CSVV. Setting: A large clinical and research institute for the study and treatment of cutaneous diseases. Patients: Consecutive patients with clinically and histologically proved idiopathic LV (n = 8) and CSVV (n = 20) were studied and compared with healthy donors (n = 20). Patients with potentially correlated systemic diseases were excluded. Main Outcome Measures: Surface expression of platelet P-selectin and circulating level of interleukin (IL) 1, tumor necrosis factor ␣ (TNF-␣), IL-8, IL-2, and soluble IL-2 receptor.Results: The IL-2 and soluble IL-2 receptor levels were significantly higher in serum samples from patients with
The primary purpose of these practical guidelines related to Kawasaki disease (KD) is to contribute to prompt diagnosis and appropriate treatment on the basis of different specialists’ contributions in the field. A set of 40 recommendations is provided, divided in two parts: the first describes the definition of KD, its epidemiology, etiopathogenetic hints, presentation, clinical course and general management, including treatment of the acute phase, through specific 23 recommendations.Their application is aimed at improving the rate of treatment with intravenous immunoglobulin and the overall potential development of coronary artery abnormalities in KD. Guidelines, however, should not be considered a norm that limits treatment options of pediatricians and practitioners, as treatment modalities other than those recommended may be required as a result of peculiar medical circumstances, patient’s condition, and disease severity or complications.
Autosomal-recessive osteopetrosis is a severe genetic disease caused by osteoclast failure. Approximately 50% of the patients harbor mutations of the ATP6i gene, encoding for the osteoclast-specific a3 subunit of V-ATPase. We found inactivating ATP6i mutations in four patients, and three of these were novel. Patients shared macrocephaly, growth retardation and optic nerve alteration, osteosclerotic and endobone patterns, and high alkaline phosphatase and parathyroid hormone levels. Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae. Scarce hematopoietic cells and abundant fibrous tissue containing TRAP-positive putative osteoclast precursors were noted. In vitro osteoclasts were a3-negative, morphologically normal, with prominent clear zones and actin rings, and TRAP activity more elevated than in control patients. The osteoclast vacuolar-type translocating ATPase (VATPase) is central to the mechanism of bone resorption. It is located in the ruffled border membrane where it releases protons underneath the resorbing lacuna, acidifying this microenvironment and permitting solubilization of the hydroxyapatite crystals.1-3 This event requires continuous release of protons because of the high-buffering capacity of phosphates, and 8 mol of H ϩ are required to solubilize 1 mol of hydroxyapatite.4 Therefore, efficient activity of the V-ATPase is mandatory for bone matrix demineralization.The V-ATPase shares similarity with the F 0 -F 1 ATPsynthase complex present in mitochondria, chloroplasts, and bacteria.5-8 It consists of a V 0 transmembrane proton channel and a V 1 ATP hydrolytic domain. The structure of the V 1 complex is well defined. It is a 570-kd peripheral protein composed of eight subunits (A to H), with three copies of the A and B subunits and single copies of the remaining subunits. The V 0 transmembrane domain contains five subunits (a, d, c, cЈ, and cЉ), with six copies of c and cЈ, and single copies of the others. c, cЈ, and cЉ subunits span the membrane and contribute to the organization of the proton channel. The a subunit is found in three isoforms, a1, a2, and a3, with the a3 being the one that is osteoclast-specific. 5,9 -11 Transcription of this subunit increases in resorption-competent osteoclasts and the protein is transferred to the ruffled border membrane during the process of cell polarization. 12,13The a subunit is a transmembrane glycoprotein possessing a large N-terminal hydrophilic domain and a C-terminal hydrophobic domain, containing multiple putative transmembrane helices. It has several buried charged residues that appear to be in a position to influence proton translocation. It also emerges to possess the binding site for the V-ATPase inhibitor bafilomycin.
We have explored MICA/B expression and its relationship with innate inflammatory infiltrate in renal cell carcinoma (RCC). The expression of MICA/B, CD16, CD56, and CD68 in 140 RCC lesions contained in a tissue microarray (TMA) was investigated by immunohistochemistry. MICA/B gene and protein expressions in Caki-1 cells were analyzed by reverse transcription-polymerase chain reaction and flow cytometry, respectively. Natural killer (NK) cells were studied by flow cytometry. All the RCC lesions (n = 140) were MICA/B-positive. MICA/B was mainly expressed in the cytoplasm of tumor cells, whereas stromal cells were negative. Renal cell carcinoma lesions showed low NK cell infiltration, although they were rich in CD16(+)CD56(-) cells, strongly resembling macrophages. CD16(+) macrophage infiltration was more frequently detectable in metastatic lesions compared with primary tumors (P = .0223) and was associated with poor RCC differentiation (P = .007). To investigate mechanisms potentially underlying the lack of NK cells infiltration into MICA/B-positive RCC lesions, we used Caki-1 RCC cells. Caki-1 expressed MICA and MICB genes. However, MICA protein was not detectable in Caki-1 cells, whereas MICB protein was detectable in their cytoplasm and on the cell membrane. Coculture of peripheral blood mononuclear cells with Caki-1, K562, HCT116, respectively, resulted in CD56(+)CD16(+) NK cells deletion without affecting CD56(+)/CD16(-) NK subset and immature NK cells generated in vitro from CD34(+) cells. Natural killer cell apoptosis seemed to be preferentially triggered by cancer cells because HLA-A0201(+) NK cells were only marginally affected by allogeneic HLA-A0201(-) peripheral blood mononuclear cells. Caki-1 cell-mediated NK cell apoptosis was reduced by an anti-beta(2)-integrin (CD18) monoclonal antibody but was NKG2D-, granule exocytosis-, and caspase-independent.
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