ТRANSPLANTATION OF AUTOLOGOUS CELLS IN COMPLEX OF TREATMENT OF COMPLICATED ARTERIAL FORM IN THE THORACIC OUTLET SYNDROME.

Impact of the autologous cells transplantation in complex of treatment of complicated arterial form of thoracic outlet syndrome was estimated. In accordance to the proce' dure proposed 18 patients were operated on, in 16 patients a standard decompressive and reconstructive operative interventions were performed. The proposed procedure application have promoted improvement of the patients' treatment results due to opti' mization of microcirculation and angiogenesis.

[THE TREATMENT OF PATIENTS FOR ULCERATIVE-NECROTIC DEFECTS IN CHRONIC ISCHEMIA OF THE LOWER EXTREMITY TISSUES, USING BIOTECHNOLOGICAL METHODS].

The results of treatment of 53 patients, suffering "unreconstructable" affection of the lower extremities (LE) arteries and ulcerative-necrotic defects in their distal parts tissues, were analyzed. In 33 patients (the main group) the allotted mononuclear cells fraction, the bone marrow and the plasm, enhanced by thrombocytes, were applied, using multiple injections along a perimeter and into the bottom of the ulcerative-trophic defect in combination with autotransplantation of the bone marrow aspirate into the ischemized tissues--the shin muscles; in 20 patients (the comparison group)--the autotransplantation of the bone marrow aspirate was accomplished into the ischemized tissues--the shin and the foot muscles. In terms up to 3 mo postoperatively a clinical improvement in the main group was noted in 25 (75.7%) patients, the bearing function of the LE was preserved in 90.9%; and in the comparison group--accordingly, in 8 (40%) and 70%. In 36 mo in the main group the bearing function of the LE was preserved in 75.7% patients, and in the comparison group--in 50%. Application of the biotechnological methods proposed in patients, suffering ulcerative-necrotic defects in chronic ischemia of the LE tissues, have promoted the angiogenesis processes activation, the tissues reparation and regeneration, the wounds healing, and the disease clinical course optimization.

[Realizing systematic cavity margins in conservative breast cancer surgery]. / Intérêt de la réalisation de recoupes systématiques dans la chirurgie conservatrice du cancer du sein.

The quality of surgical margins in lumpectomy are strong criteria to define risk of locoregional recurrence when conservative treatment is undertaken. Intraoperatively, the limits of adequate resection are sometimes difficult to define. This is why some teams propose the realization of systematic cavity margins during the excision of lumpectomy during the same operation. We expose the potential benefits of this type of practice using data from the literature.

The biochemical complexity of the endocannabinoid system with some remarks on stress and related disorders: a minireview.

Nowadays, the endocannabinoid-regulated processes are in the focus of interest, among others, for the treatment of stress-related disorders. In this minireview, we attempt to give some possible explanations for the conflicting results of the cannabinoidergic regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis and related disorders, drawing attention to the complexity of the endocannabinoid system. The endocannabinoid system is a part of an intricate network of lipid pathways and consists of the cannabinoid receptors, their endogenous ligands, and the enzymes catalyzing their formation and degradation. The stress research is focused almost exclusively on the anandamide and 2-arachidonyl glycerol, and the cannabinoid 1 receptor. However, physiological, pathological, and pharmacological perturbations of the interconnected lipid pathways have a profound effect on the regulation of the endocannabinoid signaling system. For example, diet may substantially influence the lipid composition of the body. Recent studies have indicated that beside cannabinoid 1 receptor, the endocannabinoids may act on the cannabinoid 2, peroxisome proliferator-activated, and transient receptor potential of vanilloid type-1 receptors, too. All of these receptors are implicated in the development of stress-related disorders. However, it has to be mentioned that degradation of the endocannabinoids may result in the production of active compounds as well. Since endocannabinoids have a widespread distribution in the body, they may influence a phenomenon at several points. Different effects (stimulatory or inhibitory) at different levels of endocannabinoids (e.g. hypothalamus, hypophysis, adrenal gland in the case of HPA axis) may explain some of their unequivocal results.

Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan(®): validation in chronic hepatitis C.

A novel controlled attenuation parameter (CAP) has been developed for Fibroscan(®) to assess liver steatosis, simultaneously with liver stiffness measurement (LSM). We assessed CAP diagnostic accuracy in a large cohort of patients with chronic hepatitis C (CHC) virus. A total of 615 patients with CHC, who underwent both Fibroscan(®) and liver biopsy, were analysed. Fibrosis was graded using METAVIR score. Steatosis was categorized by visual assessment as S(0) : steatosis in <10% of hepatocytes, S(1) : 11-33%, S(2) : 34-66% and S(3) : 67-100%. Performances of CAP and liver stiffness were determined using receiver operating characteristic (ROC) curve analysis and cross-validated using the bootstrap method. The Obuchowski measure was used to assess overall accuracy of CAP and to differentiate between steatosis grades. In multivariate analysis, CAP was related to steatosis (P < 10(-15) ) independently of fibrosis stage (which was related to LSM). The areas under ROC curves using CAP to detect steatosis were 0.80 (95% CI, 0.75-0.84) for S ≥ S(1) , 0.86 (0.81-0.92) for S ≥ S(2) and 0.88 (0.73-1) S = S(3) . CAP exhibited a good ability to differentiate steatosis grades (Obuchowski measure = 0.92). Performance of LSM for fibrosis assessment confirmed results from previous studies. CAP is a novel tool to assess the degree of steatosis and both fibrosis and steatosis can be evaluated noninvasively during the same procedure using Fibroscan(®) , in patients with CHC.

[Application of autologous aspirates as well as multipotent stromal cells of the bone marrow and adipose tissue in vascular surgery].

Basing on experiments, performed on laboratory animals, and on the literature data, there was proved stimulating influence of transplantation of stromal cells, residing in adipose tissue, in a kind of stromal-adiposal fraction towards angiogenesis and reparative processes in tissues in ischemic conditions. There was elaborated and introduced the tactics of treatment in patients, suffering chronic ischemia of the lower extremities tissues, using combined methods of surgical treatment, including the bone marrow aspirate (BMA) autotransplantation into the ischemized tissues, the rotation ostheotrepanation, reconstructive and endovascular interventions on proximal segment of the extremity. The efficacy and potential of application of the BMA and adipose tissue was proved in the treatment of patients, suffering ischemia of the upper extremities tissues, caused by thromboobliterating affection of peripheral vascular bed.

[Alternative method of surgical treatment for aortic arteritis in non-repairable forms of vessels damage].

The purpose of the work--the choice of optimal treatment tactics of patients at the extremity tissue ischemia due to nonspecific aortoarteritis (NA). In the surgical treatment of patients with NA, particularly with concomitant peripheral lesions, and to a greater degree of terminal arterial bed, significantly limited the possibility of direct revascularization. Conservative treatment and subthoracal sympathectomy are ineffective. Autotransplantation of mesenchymal stem cells (MSCs), adipose tissue or bone marrow in ischemic tissue in the form of aspirates or selected from these aspirates cell cultures allowed to correct hemodynamic disorders by stimulating angiogenesis and development of collateral circulation.

Congenital absence of vasopressin and age-dependent changes in ACTH and corticosterone stress responses in rats.

The hypothalamic components of the hypothalamo-pituitary-adrenal axis (HPA) are corticotropin-releasing hormone (CRH) and vasopressin. To test the hypothesis that HPA regulation changes with age, we compared ether and bacterial lipopolysaccharide (LPS) injection induced stress reactions in adult and 10-day-old Brattleboro rats, which naturally lack vasopressin owing to mutation of the gene (di/di). The LPS stimulus was used also with V(1b) receptor antagonist pretreatment (SSR149415). In adult di/di or V(1b) pretreated rats, we observed normal pituitary and adrenocortical secretory responses, while in all 10-day-old rats stress-induced serum corticosterone increases were marked, but adrenocorticotropin (ACTH) increases were significantly smaller. Compared to control pups the adenohypophysis of the 10-day-old di/di rats responded normally to CRH, but their adrenal glands were hyper-responsive to ACTH, while in adults there was greater secretion at both levels with no difference between the genotypes. The serum transcortin level was higher in adults than pups, with the di/di pups having higher transcortin levels than controls. Hence, using the same stressors in adults and pups with both a genetic model and pharmacological pretreatment, we have shown that the role of vasopressin in ACTH regulation is more important during the neonatal period than in adulthood. Blunted hypophysial sensitivity to CRH and similar adrenal gland sensitivity to ACTH in the pups compared to adults suggest that hypothalamic factors could be responsible for the neonatal stress hyporesponsive period.

[The upper extremities revascularization in patients with brachial artery thrombosis due to its chronic damaging by crutches: new approaches to the treatment].

An optimal tactics of treatment of patients, suffering the upper extremities (UE) ischemia, caused by arterial thrombosis, occurred due to subclavian artery damage in those patients, who apply crutches for a long period of time, was elaborated. In modern medicine in patients with the UE arterial bed thrombosis with affection of its peripheral, and more in terminal, portion the possibilities of direct revascularization performance are significantly restricted, especially in patients, suffering from constant mechanical injury of armpit and its vascular content, caused by crutches. Application of the method, consisting of automyelotransplantation of the bone marrow aspirate, have permitted to regulate the disorders of microhemodynamics, using stimulation of angiogenesis and development of a collateral blood flow.

Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats.

RATIONALE: Since the discovery of endogenous cannabinoid signaling, the number of studies exploring its role in health and disease has increased exponentially. Fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid anandamide, has emerged as a promising target for anxiety-related disorders. FAAH inhibitors (e.g., URB597) increase brain levels of anandamide and induce anxiolytic-like effects in rodents. Recent findings, however, questioned the efficacy of URB597 as an anxiolytic. OBJECTIVES: We tested here the hypothesis that conflicting findings are due to variations in the stressfulness of experimental conditions employed in various studies. RESULTS: We found that URB597 (0.1-0.3 mg/kg) did not produce anxiolytic effects when the aversiveness of testing procedures was minimized by handling rats daily before experimentation, by habituating them to the experimental room, or by employing low illumination during testing. In contrast, URB597 had robust anxiolytic effects when the aversiveness of the testing environment was increased by eliminating habituation to the experimental room or by employing bright lighting conditions. Unlike URB597, the benzodiazepine chlordiazepoxide (5 mg/kg) had anxiolytic effects under all testing conditions. The anxiolytic effects of URB597 were abolished by the cannabinoid CB1-receptor antagonist AM251, showing that they were mediated by CB1 receptors. Close inspection of experimental conditions employed in earlier reports suggests that conflicting findings with URB597 can be explained by different testing conditions, such as those manipulated in the present study. CONCLUSIONS: Our findings show that FAAH inhibition does not affect anxiety under mildly stressful circumstances but protects against the anxiogenic effects of aversive stimuli.

Blood, adipose tissue and brain levels of the cannabinoid ligands WIN-55,212 and SR-141716A after their intraperitoneal injection in mice: compound-specific and area-specific distribution within the brain.

Cannabinoid ligands have wide ranging neural and behavioral effects; therefore, they are of substantial therapeutic interest. The levels of cannabinoids are tightly controlled in brain infusion and in vitro methodologies, although the studied dose-ranges are extremely wide (e.g. 0.4-470 nmol in brain infusion studies). The brain levels reached after systemic administration are virtually unknown. To investigate this issue, we injected intraperitoneally (3)H-labeled WIN-55,212 and SR141716A (0.3, 1 and 3 mg/kg) and estimated their accumulation in the blood, adipose tissue and brain. Accumulation was dose-dependent. The largest amounts were found in the adipose tissue, while the levels seen in the blood and brain were approximately similar. The accumulation of SR141716A was markedly more pronounced than that of WIN-55,212 in all three tissues. The brain distribution of WIN-55,212 showed large regional differences. Such differences were significant but much smaller with SR141716A. The largest brain levels noticed after intraperitoneal injections did not exceed 2.5 nmol/g. This is larger than the brain level of the endocannabinoid anandamide but smaller than that of 2-arachidonoyl glycerol. Yet, the CB1 receptor affinity of WIN-55,212 and SR-141716A is two orders of magnitude larger than that of 2-arachidonoyl glycerol, suggesting that the exogenously administered compounds were functionally more active. Our findings also suggest that brain infusion and in vitro techniques employing considerably larger doses than 2.5 nmol should be dealt with caution. It appears that measuring brain levels after systemic injections increases our understanding of cannabinoid effects, and provides important clues for the comparison of results obtained with different methodologies.

Analysis of the effect of neuropeptides and cannabinoids in gastric mucosal defense initiated centrally in the rat.

Increasing number of evidence suggest that gastric mucosal protection can be induced also centrally. Several neuropeptides, such as TRH, amylin, adrenomedullin, enkephalin, beta-endorphin, nociceptin, nocistatin, ghrelin or orexin given centrally induce gastroprotection and the dorsal vagal complex and vagal nerve may play prominent role in this centrally initiated effect. Since also cannabinoid receptors are present in the dorsal vagal complex, we aimed to study whether activation of central cannabinoid receptors result in gastric mucosal defense and whether there is an interaction between cannabinoids and endogenous opioids. Gastric mucosal damage was induced by 100% ethanol in rats. The cannabinoids were given intravenously (i.v.) or intracerebroventricularly (i.c.v.), while the antagonists were given i.c.v or intracisternally (i.c.). Gastric lesions were evaluated macroscopically 60 min later. Anandamide, methanandamide and WIN55,212-2 reduced ethanol-induced mucosal lesions after both peripheral (0.28-5.6 micromol/kg, 0.7-5.6 micromol/kg and 0.05-0.2 mumol/kg i.v., respectively) and central (2.9-115 nmol/rat, 0.27-70 nmol/rat and 1.9-38 nmol/rat i.c.v., respectively) administration. The gastroprotective effect of anandamide and methanandamide given i.c.v. or i.v.was reversed by the CB(1) receptor antagonist SR141716A (2.16 nmol i.c.v.). Naloxone (27.5 nmol i.c.v.) also antagonized the effect of i.c.v. or i.v. injected anandamide and WIN55,212-2, but less affected that of methanandamide. The gastroprotective effect of anandamide was diminished also by endomorphin-2 antiserum. In conclusion it was first demonstrated that activation of central CB(1) receptors results in gastroprotective effect. The effect is mediated at least partly by endogenous opioids.

The analgesic effect of pamidronate is not caused by the elevation of beta endorphin level in Paget's disease--a controlled pilot study.

INTRODUCTION: Although an analgesic effect is an essential component of the mode of action of bisphosphonates, its physiological mechanisms are still unclear. Beta-endorphin release plays an important role in the analgesic effect of both calcitonin and raloxifene. As patients with Paget's disease receive large doses of bisphosphonates within relatively short time periods, we examined whether repeated pamidronate infusion therapy would cause measurable change in beta-endorphin levels MATERIALS & METHODS: Visual analog scale (VAS) scores of pain intensity, beta-endorphin levels, and alkaline phosphatase activity of 11 patients with Paget's disease (7 with the mono- and 4 with the polyostotic form) were determined at baseline, as well as after 3 and 6 infusions (on Days 6 and 12 of treatment, respectively). Eleven untreated patients with Paget's disease (7 with the mono- and 4 with the polyostotic form) served as controls. RESULTS: It was established that in the course of pamidronate infusion therapy BE levels remained constant, whereas the values in serum alkaline phosphatase and pain intensity scores were significantly reduced. CONCLUSIONS: Although high-dose pamidronate therapy does mitigate pain substantially (as demonstrated by the reduction of VAS scores), its analgesic action is probably unrelated to the enhancement of beta-endorphin release.

The role of endogenous cannabinoids in the hypothalamo-pituitary-adrenal axis regulation: in vivo and in vitro studies in CB1 receptor knockout mice.

Exogenous cannabinoids affect multiple hormonal systems including the hypothalamo-pituitary-adrenocortical (HPA) axis. These data suggest that endogenous cannabinoids are also involved in the HPA control; however, the mechanisms underlying this control are poorly understood. We assessed the role of endogenous cannabinoids in the regulation of the HPA-axis by studying CB1 receptor knockout (KO) and wild type (WT) mice. Basal and novelty stress-induced plasma levels of adrenocorticotropin (ACTH) and corticosterone were higher in CB1-KO than in WT mice. We investigated the involvement of the pituitary in the hormonal effects of CB1 gene disruption by studying the in vitro release of ACTH from anterior pituitary fragments using a perifusion system. Both the basal and corticotropin releasing hormone (CRH)-induced ACTH secretion were similar in CB1-KO and WT mice. The synthetic glucocorticoid, dexamethasone suppressed the CRH-induced ACTH secretion in both genotypes; thus, the negative feedback of ACTH secretion was not affected by CB1 gene disruption. The cannabinoid agonist, WIN 55,212-2 had no effects on basal and CRH-stimulated ACTH secretion by anterior pituitary slices. In our hands, the disruption of the CB1 gene lead to HPA axis hyperactivity, but the pituitary seems not to be involved in this effect. Our data are consistent with the assumption that endogenous cannabinoids inhibit the HPA-axis via centrally located CB1 receptors, however the understanding of the exact underlying mechanism needs further investigation.

No significant change of plasma beta-endorphin levels of psoriasis patients after synchronous balneophototherapy.

BACKGROUND/PURPOSE: Previous studies suggested that beta-endorphin has a pathogenic role in psoriasis: its increased plasma concentration may play a role in the neuroimmunological processes in the pathomechanism of the disease, and plasma beta-endorphin levels should reflect the changes in the patients' skin status. The purpose of this study was to investigate the changes of peripheral blood beta-endorphin levels in psoriatic patients in conjunction with changes in their skin symptoms after synchronous balneophototherapy. METHODS: With synchronous balneophototherapy, 12 patients with extended skin symptoms of psoriasis were treated. The therapy followed the Regensburg protocol, consisting of a basic course of 35 sessions. Patients' skin status was characterized by evaluating the Psoriasis Area and Severity Index score before and after the therapy course. Blood samples were taken before treatment, and 1 day after the last session, with symptom-free skin. Plasma beta-endorphin levels were measured by a specific radioimmunoassay developed by the authors. RESULTS: There was no significant change in plasma levels of beta-endorphin after clinical clearance of psoriatic skin symptoms. CONCLUSION: In this non-randomized, uncontrolled study no significant difference could be detected between plasma beta-endorphin levels before and after a basic course of synchronous balneophototherapy in patients with psoriasis. Although beta-endorphin has many neuroimmunological effects, the changes of its plasma level do not consistently reflect the skin status. Inflammation in psoriatic skin lesions is probably not mediated directly by circulating beta-endorphin.

Context-dependent effects of CB1 cannabinoid gene disruption on anxiety-like and social behaviour in mice.

Contrasting data were reported regarding the effects of cannabinoids on anxiety and social behaviour in both animals and humans. The cognitive effects of cannabinoids and their interactions with the HPA-axis raise the possibility that cannabinoid effects are context but not behaviour specific. To assess this hypothesis, we submitted CB1 receptor knock-out (CB1-KO) and wild-type (WT) mice to tests, which involved similar behaviours, but the behavioural context was different. The elevated plus-maze test was performed under less and more anxiogenic conditions, i.e. under low and high light, respectively. We also compared the social behaviour of the two genotypes in the resident/intruder and social interaction tests. Both tests represent a social challenge and induce similar behaviours, but involve different contexts. The behaviour of CB1-KO and WT mice was similar under low light, but CB1 gene disruption increased anxiety-like behaviour under the high light condition. CB1 gene disruption promoted aggressive behaviour in the home-cage, whereas it inhibited social behaviour in the unfamiliar cage. Thus, the anxiogenic-like effect was restricted to the more stressful unfamiliar environment. These data suggest that the effects of CB1 gene disruption were context and not behaviour specific. Novelty stress resulted in higher ACTH levels in CB1-KOs than in WTs, which suggests that context dependency occurred in conjunction with an altered HPA axis function. The present data at least partly explain contrasting effects of cannabinoids in different contexts as well as in different species and strains that show differential stress responses and coping strategies.

Effective control of hypertension: a project of the Hungarian Society of Hypertension, baseline data.

The aim of the project is to assess the quality and improve the preventive and curative practices at the primary care level in Hungary. A total of 50 general practitionaires were selected on a voluntary basis in Budapest, Hungary, and from them, 30 were randomized to the intervention (I) group and 20 to the reference (R) group. The members in the I group have been trained for the official hypertension guideline and their everyday work is monitored. Those in the R group have only been monitored to measure the efficacy of the training. In all, 10% from the known hypertensive persons (N=10,799) and 5% of the remaining (nonhypertensive) patients (N=60,341) were selected randomly from the GP's computer files and invited for screening investigation performed by trained medical students. They measured the blood pressure of patients, assessed the cardiovascular risk status and the quality of education of patients by standardized questionnaires. In total, 4083 patients were invited, but only 39.2% attended the screening visit. The prevalence of undetected hypertension was 34.6%. This prevalence was significantly higher in the older (>60 years: 46.8%) than in the younger (<50 years: 20.8%, P<0.0001) age group and it was higher in men (41.5%) than in women (30.1%, P<0.001). The proportion of H patients on drug treatment was 85.3% and the frequency of patients under effective blood pressure control (eg<140/90 mmHg) was 27.8%. Counselling to patients for a healthier lifestyle (exercise, smoking, alcohol consumption, diet) was very rare. In conclusion, our data represent the primary care of Budapest and may not be relevant to the whole country. As a consequence of this study, education of primary care physicians and patients is a must for further improvement of hypertension care.

Neonatal monosodium glutamate treatment abolishes both delta opioid receptor-induced and alpha-2 adrenoceptor-mediated gastroprotection in the lower brainstem in rats.

Neonatal monosodium glutamate treatment reduced immunoreactive beta-endorphin content in the mediobasal hypothalamus by 50% in adult, male Wistar rats as compared to hypertonic saline-treated littermates; there was also a moderate (approx. 25%) reduction in the rostral part of the nucleus of the solitary tract. In sham-treated adults the intracisternally injected alpha-2 adenoceptor stimulant clonidine (0.47 nmol/rat) and the delta opioid receptor type agonist (D-Ala(2), D-Leu(5))-enkephalin (0.8 nmol/rat) reduced acidified ethanol-induced mucosal lesions in the stomach by 84.1 and 77.5%, respectively, whereas the same doses were completely ineffective in rats treated neonatally by monosodium glutamate. The data taken together with the results of previous studies with the same substances in rats with retroarcuate knife cuts suggest that neuronal damage in the nucleus of the solitary tract region rather than in the arcuate nucleus is responsible for the changes seen in the pharmacological responsiveness.

Oestrogen and vitamin D receptor (VDR) genotypes and the expression of ErbB-2 and EGF receptor in human rectal cancers.

Oestrogen/oestrogen receptor (ER) and vitamin D/vitamin D receptor (VDR) systems have been implicated in the pathogenesis of colorectal cancers. The expression of erbB-2 and epidermal growth factor receptor (EGFR) in colorectal cancers has been suggested to have diagnostic and prognostic significance. In our study, XbaI and PvuII polymorphisms of the ER gene and the BsmI polymorphism of the VDR gene were studied in 56 Caucasian patients with rectal cancer. The relationship between the ER and VDR genotypes and the expression of oncogenes was also investigated. The presence of the x allele of ER gene significantly correlated with the overexpression of the erbB-2 and EGFR oncogenes. Significantly increased erbB-2 expression was observed in patients with the VDR B allele. The XXbb allelic combination of the ER/VDR genes was associated with a significantly lower erbB-2 expression, whereas in the other genotypes significantly higher oncogene expression was seen. Our data raise the possibility that ER/VDR gene polymorphisms accompanied by variable oncogene expression might influence the pathogenetic processes of colorectal cancers.