Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients

Systemic mastocytosis (SM) is characterized by proliferation of mast cells in various organs, which may release a wide variety of mediators, thereby explaining the broad clinical spectrum of disease manifestations. The potentially life-threatening systemic symptoms and tumoral proliferation are poorly controlled despite the use of several cytotoxic chemotherapies and/or symptomatic treatments. Twenty consecutive adult SM patients with histologically confirmed bone marrow (BM) involvement received interferon-alpha subcutaneously (1-5 million units/m2/d, with progressive dose intensification over the first month of treatment) and were evaluated after 6 months of therapy. Seven of them had previously received symptomatic treatments, including steroids, which were ineffective. Among the 13 patients treated for at least 6 months, seven partial and six minor responses, mainly concerning vascular congestion and skin lesions, were obtained, while BM infiltration remained unchanged in 12 patients. The significant reduction of mast-cell mediator levels after 6 months of treatment was not predictive of clinical remission. The rate of depression was unexpectedly high (seven patients; 35%). Two patients died soon after starting therapy (one myocardial infarction, one septic shock). Six months of interferon-alpha may relieve vascular congestion in adults with SM, probably by inhibiting mast-cell degranulation.     

Mesenteric and renal vascular effects of diadenosine polyphosphates (APnA)

Diadenosine polyphosphates (APnA) are endogenous dinucleoside molecules consisting of two adenosine moieties linked via their 5'-ribose positions by a variable number of phosphate groups. APnA have been shown to be present in different cell types and to be released from platelets as well as co-released with catecholamines and ATP from bovine adrenal medulla. Candidate metabolites of APnA are ATP, ADP, AMP and adenosine. Vascular effects induced by APnA and their metabolites in several models have been reported to be mediated by A1- and A2-adenosine receptors as well as P2-purinoceptors. APnA have been demonstrated to differentially affect regional perfusion, to influence cardiac output and blood pressure as well as the reactivity of isolated blood vessels and vascular beds. Vascular effects of APnA vary with the number of phosphate groups linking the adenosine molecules. This review outlines the effects of APnA on mesenteric and renal circulation. The effects of the antagonists varying with the type of vascular bed and the heterogeneous and dynamic vascular effects of diadenosine polyphosphates indicate a regionally different distribution of P2X and of P2Y purinoceptors in resistance arteries from different vascular beds. Although APnA have vasoconstrictor effects on the local level, it was repeatedly confirmed that systemically applied APnA induce hypotensive effects. The vasoconstrictor effects of APnA in isolated vessels are most prominent under resting tone conditions. In vivo, the vasculature exhibits a vasotone which makes dilatory effects more likely. Information on effects of APnA in vivo is still limited despite the fact that these compounds already have been used in man.     

Is angiotensin II a proliferative factor of cardiac fibroblasts?

Angiotensin II has been implicated as an important factor in cardiac remodeling, particularly in the development of pathological left ventricular hypertrophy. It is generally assumed that angiotensin II is able to alter the phenotype of cardiac myocytes and fibroblasts, and several experiments have suggested that this peptide can particularly affect the proliferation of cardiac fibroblasts. However, a review of the published results indicates that there is no evidence that angiotensin II can directly trigger mitogenesis through activation of the cyclin-dependent pathway. The observed proliferative effect might well be caused by stimulation of the synthesis of growth or inflammatory substances like platelet-derived growth factor and cytokines, by integrin activation due to secreted extracellular matrix proteins, or by a combination of these mechanisms. Angiotensin II thus appears to differentiate cardiac fibroblasts into a growth substance-secreting phenotype.     

Smooth muscle dysfunction in resistance arteries of the staggerer mouse, a mutant of the nuclear receptor RORalpha

Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor superfamily. The mouse mutant staggerer (sg/sg) carries a deletion within the RORalpha gene. RORalpha plays a major role in cellular differentiation during development and growth. In the present study, we found a lower mean arterial blood pressure in sg/sg than in +/+ mice (80.1+/-1.2 and 87.0+/-0.9 mm Hg, respectively; P<0.0002) and a smaller increase in blood pressure after in vivo injections of phenylephrine. To elucidate the mechanisms responsible for this phenotype, we investigated the vascular reactivity of large vessels (aorta and carotid arteries) and small resistance mesenteric arteries in response to mechanical forces or vasoactive agents. Arteries from sg/sg and +/+ mice were studied in vitro in arteriographs. Vascular responses of large vessels to all stimuli were similar in both groups. However, we found a markedly altered vascular function in mesenteric arteries from sg/sg mice. Flow-induced dilation, pressure-induced myogenic tone, responses to endothelium-dependent or -independent vasodilators, and responses to vasoconstrictors were significantly reduced in sg/sg compared with +/+ mice. We also determined by Western blot analysis the expression of smooth muscle (SM)-myosin, calponin, and heavy (h)-caldesmon, in large and small arteries of sg/sg and +/+ mice, and found a marked decrease in the expression of these contractile proteins in mesenteric arteries of sg/sg mice. Our findings provide the first evidence that functional RORalpha is required for normal contractile phenotype of smooth muscle cells (SMCs) in small resistance arteries and suggest that RORalpha might be involved in the differentiation of SMCs in mesenteric arteries.     

Polarized expression of cystic fibrosis transmembrane conductance regulator and associated epithelial proteins during the regeneration of human airway surface epithelium in three-dimensional culture

We have previously shown that, in normal human airway tissue, localization of the cystic fibrosis transmembrane conductance regulator (CFTR) can be affected by epithelial maturation, polarity, and differentiation and that CFTR trafficking and apical localization depend on the integrity of the airway epithelium. In this study, we addressed the question of whether the three-dimensional (3-D) organization of adult human airway epithelial cells in suspension culture under rotation, leading to spheroid-like structures, could mimic the in vivo phenomenon of differentiation and polarization. The kinetics of the differentiation, polarity, and formation of the CFTR-ZO-1-ezrin complex was analyzed by transmission, scanning, and immunofluorescence microscopy. Functional activity of the airway surface epithelium was assessed by monitoring the degree of cAMP-stimulated chloride efflux from cultured cells. Our results show that after the initial step of dedifferentiation, characterized by a loss of ciliated cells and disappearance of epithelial subapical CFTR-ezrin-ZO-1 complex, the isolated cells formed 3-D spheroid structures within 24 hours. After 15 days, progressive ciliogenesis was observed and secretory cells could be identified. After 35 days of 3-D culture, ZO-1, CFTR, ezrin, and CD59 were apically or subapically located, and well-differentiated secretory and ciliated cells were identified. CFTR functionality was assessed by analyzing the Cl(-) secretion after amiloride and forskolin perfusion. After 35 days of culture of spheroids in suspension, a significant increase in Cl(-) efflux was observed in well-differentiated ciliated cells.     

Effect of age and cold exposure on morphofunctional characteristics of skeletal muscle in neonatal pigs

Muscular changes accompanying and/or promoting the rapid postnatal improvement of the thermogenic efficiency of shivering were investigated in piglets. Animals were obtained at birth or killed after 5 days at thermoneutrality (34-30 degrees C) or in the cold (24-15 degrees C), to stimulate intense shivering thermogenesis. Fast-twitch-glycolytic (longissimus lumborum) and slow-twitch-oxidative (rhomboid) muscles were prepared for electron microscopic examination and chemical measurements. Muscle-specific changes in energy stores and metabolism were observed after birth, including the switch from glycogen to lipids and variation of the lactate/pyruvate ratio corresponding to the progressive acquisition of the metabolic type of the mature muscles. There was major age-related and/or cold-induced development of the structures involved in excitation-contraction coupling (triadic profiles, +80% in the cold), oxidative metabolism (number of lipid droplets, +81% with age in the cold; number of mitochondria, +29% with age or cold; surface of mitochondrial inner membranes, +18% with age and +32% in the cold) and contraction potential (myofibril volume, +62% with age). In contrast, neither age nor cold affected capillary volume density and capillary-to-fibre ratio. The observed changes reflect the immaturity and remarkable plasticity of piglet skeletal muscle and are likely to underlie its enhanced capacity for shivering thermogenesis after birth.     

Effect of chronic treatment with bovine recombinant growth hormone on cardiac dysfunction and lesion progression in UM-X7.1 cardiomyopathic hamsters

In view of the potentially beneficial effect of GH on ventricular function of humans suffering from idiopathic dilated cardiomyopathy, we undertook a study to evaluate the optimal time to initiate treatment with GH and its duration in UM-X7.1 cardiomyopathic hamsters (CMH). GH (1 mg/kg.d) therapy was initiated either in the early or late (30 and 160 d old, respectively) phases of the disease and continued until death at 240 d of age. Age- and sex-matched Golden Syrian hamsters (GSH) were used as controls. Basal IGF-1 levels in serum were reduced by nearly half in CMH compared with GSH but were increased within a physiological range in male hamsters. In contrast, female hamsters presented elevated basal serum IGF-1 levels that were not further elevated by GH administration, as reported in experimental models and humans. Accordingly, the present study will focus on the effects of GH therapy on cardiac performance in male hamsters. GH did not improve ventricular function when starting at a late stage of the disease compared with CMH controls. Maximum rate of left ventricular pressure development decreased by approximately 64% in CMH treated early with recombinant bovine GH. Ventricular dysfunction was associated with morphologic indices of hypertrophy, ventricular dilatation, and extensive fibrosis. Mortality was strikingly increased in GH-treated CMH for 210 d (four males and eight females), as opposed to four females (and no male) in the vehicle-treated group. These results suggest that chronic treatment with recombinant bovine GH in CMH, starting at an early stage of lesion development, is associated with a reduced cardiac performance at the terminal stage of the disease.     

Features of radio wave tissue dissection in surgical practice

Results of experimental and clinical investigations of using radioknife "Surgitron" for dissection and coagulation of tissues were compared. In 145 experiments the possibility to dissect different tissues (skin, muscles, fascia) and parenchymatous organs of the abdominal cavity was studied. The specific course of reparative processes was analyzed at different periods after operation. In clinical conditions the radioknife was used for operative interventions on 520 patients: in 91 cases the device was used for dissection and coagulation of hollow organs and in 73 cases--of parenchymatous organs of the abdominal cavity, in 356 patients radioknife was used for plastic operations. The radioknife "Surgitron" was established to be very good for dissection of tissues. The coagulating effect was weak. The zone of undesirable lateral necrosis was negligible, and often it was absent that makes favorable conditions for the reparative processes. On the basis of clinical and experimental investigations it was established that using radioknife "Surgitron" is indicated and expedient in plastic and esthetic surgery because it is in this field where the positive properties of radiowave action can have maximal realization taking into account the requirements of the means and quality of dissection of tissues.     

Aristolochic acid nephropathy and the peritoneum: Functional, structural, and molecular studies

BACKGROUND: Aristolochic acid nephropathy (AAN) is a rapidly progressive interstitial nephropathy linked to the exposure to aristolochic acid (AA) and characterized by extensive fibrosis and urothelial atypia. Although the fibrotic process has been documented in extrarenal tissues, the involvement of the peritoneum, as well as the efficacy of peritoneal dialysis in AAN patients, remain uncertain. METHODS: The structure of the peritoneal membrane and the expression of basic fibroblast growth factor (bFGF), collagen type III, endothelial nitric oxide synthase (eNOS), and aquaporin-1 (AQP1) were investigated in peritoneal biopsies from an index AAN patient, four other AAN patients, four regular peritoneal dialysis patients, and two controls. Similar methods were used to investigate a rabbit model of AAN after intraperitoneal exposure to high-dose AA. AA-DNA adducts were screened by 32P-postlabeling analysis. RESULTS: The AAN patients had renal failure, renal fibrosis, and urothelial atypia. The peritoneum of AAN patients had a normal structure, lacked cellular atypia, and, in comparison with regular peritoneal dialysis patients and controls, did not show abnormal regulation of fibrotic and endothelial markers. Furthermore, specific AA-DNA adducts were not identified in the peritoneum of AAN patients. In contrast, AA-DNA adducts were detected in peritoneal and kidney tissues of all exposed rabbits, and one of them developed a malignant mesothelioma. CONCLUSION: These data demonstrate the lack of fibrotic and vascular alterations and the absence of cellular atypia in the peritoneum from AAN patients. Thus, peritoneal dialysis should not be discouraged in these patients. Nevertheless, studies in a rabbit model of high-dose AA exposure may suggest a potential risk of peritoneal malignancy.