[Autoimmune pancreatitis and IgG-positive sclerosing cholangitis]. / Autoimunitní pankreatitida a IgG pozitivní sklerotizující cholangitida.

Sclerosing cholangitis is a heterogenous disease. Sclerosing cholangitis with an unknown cause is abbreviated PSC. PSC affects extra- as well as intra-hepatic bile ducts and since this is a permanently progressing fibrous condition, it leads to liver cirrhosis. The disease is often associated with a development of cholangocarcinoma and idiopathic intestinal inflammation. Causal therapy does not exist; liver transplantation is indicated. IgG4 cholangitis differs from PSC in a number of features. This form is, unlike PSC, linked to autoimmune pancreatitis (AIP) as well as other IgG4 sclerosing diseases. Anatomically, distal region of ductus choledochus is most frequently involved. Icterus is, unlike in PSC, a frequent symptom of AIP. There also is a distinctive histological picture--significant lymphoplasmatic infiltration of the bile duct wall with abundance of IgG4 has been described, lymphoplasmatic infiltration with fibrosis in the periportal area and the presence of obliterating phlebitis is also typical. However, intact biliary epithelium is a typical feature. IgG4 can be diagnosed even without concurrent presence of AIP. IgG4 sclerosing cholangitis is a condition sensitive to steroid therapy. At present, there is no doubt that IgG4 sclerosing cholangitis is a completely different condition to primary sclerosing cholangitis. From the clinical perspective, these diseases should be differentiated in every clinician's mind as (a) AIP is treated with corticosteroids and not with an unnecessary surgery, (b) IgG4 sclerosing cholangitis is mostly successfully treated with corticosteroids and the disease is not, unlike PSC, a risk factor for the development of cholangiocarcinoma.

[Incidence of pancreatic carcinoma in persons with chronic pancreatitis]. / Incidence pankreatického karcinomu u osob s chronickou pankreatitidou.

INTRODUCTION: Pancreatic carcinoma is one of the diseases which mostly fail to be diagnosed on a timely basis, and there is no way to effectively screen patients for pancreatic carcinoma either. An option for the diagnosis of the "early glandular carcinoma" therefore resides in identification and systematic screening of patients with risk of pancreatic carcinoma. METHOD: We monitored 223 patients with chronic pancreatitis on a systematic basis from 1992 to 2005. During this 14-year period, we monitored the number of cigarettes smoked per year in addition to standard parametres measured by biochemical methods, endosonography, CT and ERCP exams, and assigned the alcoholic form of chronic pancreatitis to patients consuming more than 80g of alcohol per day on a systematic basis for more than 5 years in the case of men, and 50 g of alcohol per day in the case of women, and classed the patients according the TIGARO classification. RESULTS: Alcoholic etiology was proven in 73.1% of the examined patients, chronic obstructive form of pancreatitis was diagnosed in 21.5% of patients, and only 5.4% of patients were classified into the idiopathic pancreatitis group. Pancreatic carcinoma in the region of chronic pancreatitis was found in 13 patients (5.8%); stomach carcinoma was diagnosed in 3 patients with chronic pancreatitis, and oesophageal carcinoma in 1 patient of the total of patients monitored. Malignant pancreatic disease was diagnosed primarily in patients with alcoholic pancreatitis (4.5%). During the period of 14 years, 11 patients died, 8 of the deaths being associated with pancreatic carcinoma. CONCLUSION: Both pancreatic and extrapancreatic carcinoma in gastrointestinal location is a serious complication of protracted chronic, non-hereditary pancreatitis. Systematic identification and treatment of patients with chronic pancreatitis is therefore necessary for timely diagnosis ofgastrointestinal and pancreatic malignancies.

Epidemiology of canine urolithiasis in the Czech Republic from 1997 to 2002.

OBJECTIVES: To compare data on the epidemiology of canine urolithiasis in the Czech Republic with that from other countries. METHODS: The records from the Centre for Mineralogical Analysis from 1997 to 2002 were reviewed. The data were obtained from mineralogical analysis of 1366 canine uroliths obtained from patients in the Czech Republic. These included 396 females and 629 males. RESULTS: Sixty-eight breeds plus crossbreeds were identified. Eight breeds plus the crossbreeds accounted for 71.3 per cent of all cases. Males were affected more frequently than females (61.4 per cent versus 38.6 per cent). Struvites significantly predominated in females, while in males calcium oxalates, brushites and cystines were the most common stones. Most of the uroliths (48.9 per cent) were 5 mm or less in dimension. By 2001, struvite was the most frequent (38.5 to 44.1 per cent) urolith, followed by calcium oxalate (26.5 to 32.0 per cent). In 2002, calcium oxalate became the most frequent calculus, followed by struvite, mixed calculi and others. CLINICAL SIGNIFICANCE: Comparison of these results with studies by other authors showed that for most of the monitored parameters there was agreement with respect to the proportions of different breeds within the populations of dogs in different geographical areas.

Photoaffinity labelling of the mitochondrial uncoupling protein by [3H]azido fatty acid affects the anion channel.

Brown adipose tissue (BAT) mitochondria were incubated with the azido derivative of fatty acid (hexadecanoic) containing four tritium atoms, [3H]AzHA, and among all mitochondrial proteins only a few proteins were photolabelled after irradiation with UV. It suggests the existence of specific fatty acid binding sites on mitochondrial proteins. It was also possible to label with [3H]AzHA the isolated uncoupling protein (UcP) of BAT mitochondria with a low stoichiometry--lower than one AzHA per dimeric UcP. These results together with the observed competition (i.e. prevention of photolabelling) of various UcP anionic substrates with [3H]AzHA and its dodecanoic acid analogue, suggest the existence of the specific fatty acid binding site on UcP identical with the anion channel or anion translocating site.

Existence of uncoupling protein-2 antigen in isolated mitochondria from various tissues.

Antibodies against Escherichia coli-expressed uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) were raised by operating the blotted proteins into the spleen of minipigs. The antisera reacted more intensively with the recombinant UCP2 and UCP3 than with uncoupling protein-1 (UCP1) isolated from brown adipose tissue. Moreover, anti-UCP2 and cross-reacting anti-UCP3 antibodies identified the presence of the UCP2/3 antigen in isolated mitochondria from rat heart, rat kidney, rat brain, rabbit epididymal white adipose tissue, hamster brown adipose tissue, and rabbit skeletal muscle. It has been concluded that UCP2 is expressed in these tissues (UCP3 in skeletal muscle); however their existence in mitochondria had not previously been demonstrated.

Sensitivity to ischaemic ATP breakdown in different models of cardiac hypertrophy in rats.

OBJECTIVE: To evaluate the sensitivity to ischaemia of rat hearts made hypertrophic by pressure overload [two-kidney, one clip (2-K,1C) rats], volume overload (aortocaval arteriovenous shunt), minoxidil or isoproterenol. METHODS: Ischaemia was induced in the isolated perfused hearts by a stepwise lowering of the perfusion pressure; at each step the coronary effluent was assessed for the products of ATP breakdown. RESULTS: Hypertension increased cardiac weight by 35 and 56% after 2.5 and 12 weeks, respectively. Volume overload increased heart weight by 25 and 55% after 1 and 12 weeks, respectively. Minoxidil (for 5 weeks) or isoproterenol (for 1 week) increased cardiac weight by 22 and 16%, respectively. The hearts from 2-K,1C rats started to release ATP catabolites in the coronary effluent at a substantially higher perfusion pressure, and with significantly higher maximal levels, than the control hearts. In contrast, in volume overload cardiac ATP breakdown was similar to that in the controls, and isoproterenol administration caused significantly lower levels of ATP breakdown. At identical flow rates, normalized per gram dry tissue, the purine concentration in the coronary effluent was similar in all of the models of cardiac hypertrophy studied and in the respective controls, and was even lower in the long-term volume-overloaded and isoproterenol-induced hypertrophic hearts. CONCLUSIONS: We conclude that hearts from hypertensive rats are more sensitive to ischaemic ATP breakdown during lowering of perfusion pressure than hearts from volume-overloaded or control rats. This is independent of the duration of the hypertrophic process, and can be explained by a lower coronary flow per gram heart tissue at a given perfusion pressure. This conclusion is strengthened by the observation that hypertrophic hearts from volume-overloaded rats had similar amounts of cardiac hypertrophy to the hearts from the hypertensive rats, without a change in flow, coronary vascular resistance or ischaemic sensitivity, whereas the hearts from isoproterenol-treated rats had lower ischaemic sensitivity and coronary vascular resistance.

Cardiovascular effects of social stress in borderline hypertensive rats.

OBJECTIVE: To test the hypothesis that chronic exposure to psychosocial stress, alone or in combination with elevated levels of dietary salt, leads to hypertension and cardiac pathology in a susceptible strain of rats. DESIGN AND METHODS: In four experiments, borderline hypertensive rats, maintained on normal or high-salt diets, were exposed to 14-16 weeks aggregation in a colony housing or in larger breeder cages. Pulsatile blood pressure was measured once a week in unrestrained male rats by pressure telemetry. Direct carotid pressures of the aggregated rats and of control rats were measured before they were killed; at necropsy cardiac and adrenal weights and ventricular design were determined. RESULTS: Despite continuous fighting, their weekly measured blood pressures remained stable; no differences in final carotid pressures between experimental and control rats were found. Rats from three aggregations showed significant increases in left and right ventricular and adrenal weights. CONCLUSION: No hypertension developed in any aggregation, although most of the rats showed signs of perceived stress (significantly reduced weight gain, enlarged adrenals and a large number of body wounds). Cardiac hypertrophy did ensue, possibly reflecting increased physical activity or intermittent increases in sympathetic activity, or both.

The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data.

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events.

Monotherapy versus combination therapy as first line treatment of uncomplicated arterial hypertension.

Mild to moderate hypertension still remains poorly controlled. This relates to multiple factors including low antihypertensive efficacy of single drug therapies reluctance of primary care physicians to modify/titrate initially chosen therapy to obtain target blood pressure, and poor compliance with medication. Several guidelines for the treatment of high blood pressure now include combination therapy with low doses of 2 drugs as one of the strategies for the initial management of mild/moderate arterial hypertension. Evidence discussed in this article points to superior control of blood pressure by combinations of low doses of 2 drugs as compared with monotherapy in regular doses. This superior effectiveness of combined therapy relates to a better antihypertensive efficacy and higher response rates in the low range of doses as the result of complementary mechanisms of antihypertensive effects, better tolerance as a result of a lower rate of adverse effects in the low dose range, improved compliance from better tolerance and simple drug regimen, and lower cost. Whether increased use of fixed low dose combination therapies would translate to better control of arterial hypertension in the population and thereby further reduction of cardiovascular/cerebrovascular morbidity and mortality caused by hypertension remains to be assessed.

Relevance of 24 H blood pressure profile and sympathetic activity for outcome on short- versus long-acting 1,4-dihydropyridines.

Short-acting formulations of nifedipine-like 1,4-dihydropyridines cause clearly less regression of left ventricular hypertrophy (LVH) than anticipated from their antihypertensive effect. Moreover, these compounds increase the risk of cardiac death and myocardial reinfarction in patients with coronary artery disease (CAD) not on concomitant beta-blocker therapy. Increased sympathetic activity is one of the non-pressure-related risk factors for LVH and atherosclerosis in hypertensives. In addition, increased sympathetic tone may precipitate clinical events in subclinical or stable CAD. Intermittent increases in sympathetic activity persist during chronic treatment with those 1,4-dihydropyridines that have a poor peak/trough ratio with a rapid fall of BP and deactivation of the arterial baroreflex. On the other hand, these intermittent increases in sympathetic activity do not occur for formulations and compounds with a gradual and sustained antihypertensive effect over the dosing interval. Such long-acting 1,4-dihydropyridines cause regression of LVH as anticipated from their antihypertensive effect, and are similar to angiotensin converting enzyme inhibitors. In contrast to short-acting 1,4-dihydropyridines, long-acting 1,4-dihydropyridines appear not to be detrimental for patients with stable CAD. However, the evidence is still missing for patients with unstable CAD. Neither is there evidence that they will reduce cardiovascular morbidity and mortality in patients with CAD when used for the chronic treatment of hypertension.

Amplification and overexpression of HER-2/neu in invasive ductal carcinomas of the pancreas and pancreatic intraepithelial neoplasms and the relationship to the expression of p21(WAF1/CIP1).

Overexpression of HER-2/neu was described in pancreatic intraepithelial neoplasia (PanIN) and in invasive ductal adenocarcinoma of pancreas in a variable proportion of cases. The effects of HER-2/neu overexpression on mitogenic signalling and cell cycle progression were studied in breast luminal epithelial cells and mitogen activated protein kinase-dependent induction of p21(WAF1/CIP1) was found to be necessary for G1 phase progression. Overexpression of p21(WAF1/CIP1) was described as an early event in the development of PanIN by Biankin et al. (2001) and this finding was supported by our previous study that, moreover, did not confirm the possible role of activating K-ras mutations in the induction of p21(WAF1/CIP1) overexpression. Relationship between p21(WAF1/CIP1) expression and HER-2/neu status in PanIN lesions and ductal adenocarcinoma of the pancreas was investigated in our study. Expression levels of p21(WAF1/CIP1) and HER-2/neu were examined imunohistochemically and the amplification of HER-2/neu gene was evaluated by fluorescence in situ hybridisation in HER-2/neu overexpressing adenocarcinomas. Fourty nine pancreatic resection specimens from patients with invasive adenocarcinoma were included into the study. A large spectrum of PanIN lesions adjacent to the structures of infiltrating adenocarcinoma was also examined. The possible role of HER-2/neu in an induction of p21(WAF1/CIP1) overexpression was not confirmed and p21(WAF1/CIP1) overexpression seems to be HER-2/neu independent in pancreatic ductal adenocarcinoma according to our results. Increasing levels of HER-2/neu expression were demonstrated in pancreatic intraepithelial neoplasia and in 18.75% of pancreatic adenocarcinoma. The only 2 from 9 HER-2/neu overexpressing adenocarcinomas showed the amplification of HER-2/neu gene. Based on these results, the overexpression of HER-2/neu in pancreatic adenocarcinoma seems to be a result of increased transcription rather than gene amplification. Therefore HER-2/neu represents a good target for therapy of pancreatic adenocarcinoma only in isolated cases.

Mitochondrial uncoupling proteins--facts and fantasies.

Instead of a comprehensive review, we describe the basic undisputed facts and a modest contribution of our group to the fascinating area of the research on mitochondrial uncoupling proteins. After defining the terms uncoupling, leak, protein-mediated uncoupling, we discuss the assumption that due to their low abundance the novel mitochondrial uncoupling proteins (UCP2 to UCP5) can provide only a mild uncoupling, i.e. can decrease the proton motive force by several mV only. Contrary to this, the highly thermogenic role of UCP1 in brown adipose tissue is not given only by its high content (approximately 5 % of mitochondrial proteins) but also by the low ATP synthase content and high capacity respiratory chain. Fatty acid cycling mechanism as a plausible explanation for the protonophoretic function of all UCPs and some other mitochondrial carriers is described together with the experiments supporting it. The phylogenesis of all UCPs, estimated UCP2 content in several tissues, and details of UCP2 activation are described on the basis of our experiments. Functional activation of UCP2 is proposed to decrease reactive oxygen species (ROS) production. Moreover, reaction products of lipoperoxidation such as cleaved hydroperoxy-fatty acids and hydroxy-fatty acid can activate UCP2 and promote feedback down-regulation of mitochondrial ROS production.

Our approach to the surgical treatment of chronic pancreatitis.

BACKGROUND/AIMS: Optimal surgical management of the patients suffering of chronic pancreatitis still remains a controversial problem. The base for the evaluation of patients is for us the Marseille-Roma classification from 1988 with 4 fundamental types of the disease. Surgical therapy is usually indicated in patients with intractable or continuous pain, stenosis of the common bile duct and duodenal stenosis. The source of the above mentioned problems is related to the head of the pancreas and we prefer as the procedure of choice duodenum sparing resection of the pancreatic head. METHODOLOGY: Seventy patients were treated by our team in the years from 1985 to 1995 surgically and 55 of these patients underwent resection of the head of the pancreas. RESULTS: Eighteen patients were treated by hemipancreatoduodenectomy and 37 patients by the duodenum sparing resection of the pancreatic head. CONCLUSION: Left sided resection and drainage procedures appear to be much less effective from the point of view of long term follow-up.

Duodenum-sparing resection of the pancreatic head combined with pancreatogastroanastomosis in the treatment of chronic pancreatitis--surgical technique.

Chronic pancreatitis is defined as progressively developing disease which reduces exocrine parenchyma and decreasing exocrine capacity of the pancreas. The disease is commonly manifested by recurrent attacks of severe and often incapacitating upper abdominal and back pain. The goal of surgical therapy is pain relief and unblocking of the stenosis of the common bile duct and duodenum. Our method of solving this problem is a duodenum sparing resection of the pancreatic head followed by simple reconstruction of the gastrointestinal tract using pancreatogastroanastomosis. All unnecessary anastomoses are thus reduced and the risk of anastomotic leak is minimized. The substantial advantage of this operation is the removal of the pancreatic head where the source of symptoms related to chronic pancreatitis is localized.

Portal hypertension as a complication of chronic pancreatitis.

BACKGROUND/AIMS: Intractable abdominal pain, duodenal stenosis and common bile duct stenosis are considered the main reasons for surgery in cases of chronic pancreatitis. The aim of the study was to discover the influence of the disease on the portal pressure. METHODOLOGY: Blood pressure was measured in the superior mesentric vein before and after resection of the head of the pancreas in 17 patients by direct method. RESULTS: Venous pressure was lower after resection of the head of the pancreas in all 17 measured patients. CONCLUSIONS: Chronic pancreatitis increases not only left-sided portal pressure but also right-sided portal pressure.

Pancreatic enzyme replacement therapy: comparative effects of conventional and enteric-coated microspheric pancreatin and acid-stable fungal enzyme preparations on steatorrhoea in chronic pancreatitis.

The therapeutic effectiveness of a conventional (Pankreon-Granulat) and an acid-protected (Kreon) porcine pancreatic enzyme preparation, and an acid-stable fungal enzyme preparation (Nortase) in the treatment of severe pancreatogenic steatorrhoea was investigated. The study comprised 17 patients with chronic pancreatitis and exocrine pancreatic insufficiency with (A) or without (B) a previous Whipple's procedure (B II resection + partial duodenopancreatectomy). With all three enzyme preparations, a significant (p less than 0.05) reduction in the total faecal fat excretion/day was achieved. In therapy group A, this reduction was, on average, 58% for Kreon (100,000 U lipase/day), 67% for Pankreon-Granulat (360,000 U lipase/day) and 54% for Nortase (75,000 U lipase/day), the respective figures for therapy group B being 58%, 52% and 46% at identical dosages. Thus, in both groups, the effect produced by the conventional porcine pancreatic enzyme preparation and the acid-protected porcine or the acid-stable fungal enzyme preparation was largely equivalent, although the latter two preparations were administered at only 1/4 of the dosages of the former preparation. On the basis of the respective average reduction in total faecal fat excretion and average number of stools/day, it would appear that in patients with chronic pancreatitis and prior Whipple's procedure, Pankreon-Granulat should be administered for enzyme replacement while in patients with an intact upper gastrointestinal tract, Kreon should be administered, in the treatment of steatorrhoea in chronic pancreatitis.

Modelling tissue behaviour based on hyperelasticity theory.

The tissues are during their physiological function, e.g., in the course of growth, adolescence, and aging, subjected to a cyclic mechanical loading and to large displacements and rotations as well. A tissue free of all external tractions is in a state that minimizes its internal power. In the course of aging of the tissues, for instance in the wall of the aorta, the vein, and also in the myocardium or heart valves, the decrease of the water content and increase of the collagen content occurs; while in compact and trabecular bone the contents of both mineral substances and collagen, undergo reduction. In accordance with it, the strain energy function and the constitutive equations of living tissue based on the hyperelasticity theory using rotationless strain were studied. On the base of the proposed eigenvalue decomposition of the rotationless strain tensor and hyperelasticity the strain energy function was formulated as depending on biological time of tissue. The quantity of strain energy function per unit of the biological time, which essentially characterizes the velocity of change of mechanical response of tissue in the course of its aging, was also defined. The coefficient of tissue aging is the further diagnostic parameter, which is independent of the rotationless strain tensor and expresses the relative change of mechanical response of tissue during the biological time. The corresponding constitutive equation of tissue depending on the biological time is also determined. On the base of the regression analysis the theoretical stress-strain curves for myocardium and blood vessels were determined. The numerical results reveal that the coefficient of aging progressively increases in hardening tissues (coronary artery, vena cava inferior) whereas at the softening tissues it has a relatively slow increase at the dependence on tissue aging.

Predictor variables of clergy pedophiles.

File data on familial traits, past sexual experience as a victim, and other traits identified in the literature as leading toward pedophilia, were summarized for 10 convicted clergy pedophiles to construct a set of variables possibly useful for screening. Further research is underway to identify trauma in early life and those personality-related variables current studies indicate as relevant.

Relationship between perceived parental behaviors and the self-esteem of gifted children.

This pilot study sought to investigate parent-child interactions which influenced self-esteem in a sample of gifted children. 13 gifted children, aged 6 to 10 yr., who were enrolled in a private elementary school, were tested on the Coopersmith Self-esteem Inventory and the Parent Practices Questionnaire (PPQ). Significant correlations obtained between (1) each of four maternal PPQ variables (physical punishment, consistency of expectations, principled discipline, and support) and (2) one paternal PPQ variable (deprivation of privileges) with the total self-esteem score. Maternal variables and dimensions, more than paternal, appear to influence self-esteem in these subjects. Explanations for these findings are proposed along with recommendations for study.

Women's multiple roles and psychological well-being.

Examination of the relationships of multiple roles and internal-external locus of control with psychological well-being among 162 middle-class women aged 23 yr. and over, returning to school at a community college, showed women occupying two or three of the roles of partner, mother, and paid employee were happier than those occupying one or none. Internal locus of control was important in adding significantly to the prediction of both happiness and self-esteem, beyond that predicted by number of roles and control variables. Psychological well-being for women returning to school is positively correlated with more social roles and internal scores on locus of control.