Propofol-induced acute pancreatitis.

WHAT IS KNOWN AND OBJECTIVE: Drug-induced acute pancreatitis comprises only 0.5%-2% of all cases of acute pancreatitis. Propofol is a potentially dangerous drug that can cause acute pancreatitis, but this complication is extremely rare. CASE SUMMARY: A 57-year-old patient developed acute pancreatitis after a planned thyroidectomy. As the common causes of acute pancreatitis were excluded, we believe that the pancreatitis was drug-induced, in this case by a single dose of propofol administered to the patient during the surgery. WHAT IS NEW AND CONCLUSION: We present a rare case of propofol-induced acute necrotising pancreatitis, which is to the best of our knowledge the first fatal case reported in an adult patient.

DIABETIC KETOACIDOSIS WITH AN ACUTE ABDOMEN AS A FIRST MANIFESTATION OF TYPE 1 DIABETES MELLITUS.

CONTEXT: Diabetic pseudoperitonitis is a very rare complication of the type 1 diabetes mellitus and it is associated with a severe ketoacidosis. The exact pathogenesis of the status is still unclear, the typical presentation is an acute abdomen by the patient. To confirm the diagnosis, it is necessary to make examinations, which exclude other possible reason of an acute abdomen by the patient (laboratory tests, abdominal ultrasound or a CT scan). CASE PRESENTATION: A 46-years old man was admitted to the hospital wih a history of a 10 days epigastric pain. Laboratory tests, abdominal ultrasound, CT scan and upper endoscopy were performed, the reason of the pain remained unclear. Because of the peritoneal signs at the first day of the hospitalisation an acute surgery was indicated, without any pathology at the laparoscopy. A severe metabolic acidosis was recognized only after the surgery, the initial hypoglycaemia rose up after giving a total parenteral nutrition to the patient. The increase of the glycaemia, the severe metabolic acidosis with glycosuria and ketonuria, and the elevation of the glycated haemoglobin brought us to the diagnosis of the new onset of the diabetes. CONCLUSION: Diabetic pseudoperitonitis with the picture of an acute abdomen can occur as a first manifestation of the diabetes. Thinking of this rare complication and recognising it can avoid unnecessary acute surgery by the patient.

Safety and on-treatment efficacy of telaprevir: the early access programme for patients with advanced hepatitis C.

BACKGROUND AND AIM: Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1). METHODS: 1782 patients with HCV-1 and bridging fibrosis or compensated cirrhosis were prospectively recruited from 16 countries worldwide, and treated with 12 weeks of TVR plus PEG-IFN/RBV, followed by 12 or 36 weeks of PEG-IFN and RBV (PR) alone dependent on virological response to treatment and previous response type. RESULTS: 1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1-4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis). CONCLUSIONS: In compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.

Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9.

In the human paired box-containing (PAX) gene family, only two members, PAX-3 and PAX-6, which are associated with Waardenburg's syndrome and aniridia, respectively have been mapped to human chromosomes. We have now isolated cosmids for six additional human PAX genes (PAX-1,-2,-5,-7,-8,-9) and a polymerase chain reaction fragment for PAX-4. PAX-9 is a novel family member which is closely related in its paired domain to PAX-1. The chromosomal location of all cloned PAX genes was determined by analysis of somatic cell hybrids and (except PAX-4) by fluorescence in situ hybridization to metaphase chromosomes. PAX-1 and PAX-7 map to chromosomal regions containing previously assigned disease loci.

Anemia as a predictor of response to antiviral therapy in chronic hepatitis C.

BACKGROUND: The standard therapy for chronic HCV infection is the administration of pegylated interferons in combination with ribavirin. Anemia is a dose-dependent side-effect of ribavirin administration. The degree of anemia could be indicative of the individual exposure to ribavirin. AIMS: 1) To evaluate the correlation of HGB level decreases at specified time-points with a sustained virological response during the antiviral treatment. 2) To compare these parameters with the virological predictors for responses. METHODS: A retrospective analysis of cohort, which comprised 164 patients treated with standard therapy at a tertiary center in Prague, Czech Republic. RESULTS: We identified several predictive factors for a sustained virological response in females: baseline HGB level ≤140 g/l (p=0.025), maximum drop from baseline >40 g (p=0.039), and a HGB drop in week 4 >30 g (p=0.044). There was only one predictor identified for males: reaching the lowest HGB level after week 19 (p=0.021). The strongest positive predictor of response was a rapid virological response. A low viral load (<600 000 IU/ml) at baseline was not associated with a sustained response in either gender. CONCLUSIONS: The parameters of HGB decrease during antiviral treatment are better correlated with a sustained response in females. None of these response predicting parameters was as significant as that of rapid virological response as that of rapid virological response (Tab. 4, Fig. 1, Ref. 15).

[Treatment of chronic hepatitis C virus infection at the beginning of a new era]. / Lécba chronické infekce virem hepatitidy C na zacátku nové éry.

After 2010 the therapy of chronic HCV infection entered a completely new era -  the era that is marked with the gradual introduction of the so-called directly acting antivirals into treatment schemes of this serious disease. The term directly acting antivirals (DAA) covers low-molecular substances that inhibit viral nonstructural proteins -  enzymes involved in the HCV replication cycle. At present, the first 2 representatives of DAA, Boceprevir and Telaprevir, have been approved for chronic HCV infection indication. The synoptic article pays the greatest attention to these 2 representatives, along with mentioning some other substances that are under later phases of clinical development and are likely to be approved in the near future.

[Hepatic cein catheterisation -  selected assessment aspects]. / Katetrizace jaterních zil -  vybrané aspekty hodnocení

INTRODUCTION: Hepatic vein catheterisation and portal hypertension assessment using the value of portal hepatic gradient (HVPG) is currently a method of choice. METHODOLOGY: In our paper we shall compare HVPG with the so called direct gradient -  using the difference in pressure in the portal vein and free hepatic vein in 5 groups of patients with liver cirrhosis. RESULTS: Hepatic vein catheterisation is reliable for assessing the portal hypertension in the group of patients with liver cirrhosis of ethylic etiology. In patients with liver cirrhosis resulting from hepatitis B, Wilsons disease or primary biliary cirrhosis, a statistically significant difference between HVPG and the direct gradient has been found. In patients with liver cirrhosis resulting from hepatitis C the obtained values differed but without statistical significance. CONCLUSION: In catheterisation of hepatic veins the HVPG value in liver cirrhosis with a presinusoidal component may be reduced, which has to be primarily taken into account when assessing the relationship to some critical values of the portal hepatic gradient.

[Wilson's disease]. / Wilsonova choroba.

Wilson's disease is an inherited disorder leading to accumulation of copper in tissues, mainly in the liver and brain. Genetic defect is in the gene coding ATPase type P (ATP7B). The inheritance is autosomal recessive. Up to now, more then 500 mutations causing Wilson's disease were described. The most frequent mutation in Central Europe is mutation H1069Q. The manifestation of Wilson's disease is usually hepatic or neurologic. Hepatic form is manifested by acute or chronic hepatitis, steatosis or cirrhosis. Neurologic involvement is manifested usually after 20 year of age by motor disturbances (tremor, disturbed speech, problems with writing), which could progress into severe extrapyramidal syndrome with tremor, rigidity, dysartria, dysfagia and muscle contracture. Diagnosis is based on clinical and laboratory examinations (neurologic symptoms, liver disease, low serum ceruloplasmin levels, elevated free copper concentration in serum, high urine copper excretion, and presence of Kayser-Fleischer rings). Confirmation of diagnosis is done by hepatic copper concentration in liver biopsy or by genetic examination. Untreated disease leads to the death of a patient. Treatment is based on chelating agents decreasing the copper content by excretion into urine (D-penicillamine, trientine) or on agents preventing absorption of copper from food (zinc, ammonium-tetrahiomolybdene). Patients with asymptomatic Wilson's disease have to be treated as well. In Czech Republic either penicillamine or zinc are used. Liver transplantation is indicated in patients with fulminant liver failure or decompensated cirrhosis. Screening in families of affected patients (all siblings) is obvious.

[Efficacy of combination treatment with pegylated interferon plus ribavirin in patients chronically infected with HCV]. / Ucinnost terapie pegylovaným interferonem a ribavirinem u pacientu s chronickou HCV infekcí.

THE AIM OF THE STUDY: To evaluate the efficacy of combined antiviral treatment with pegylated interferon alpha plus ribavirin in patients with chronic HCV infection who have not yet been treated with antivirals (treatment-naive patients). To compare the treatment effect in patients with low (< 600,000 IU/ml) and high (> or = 600,000 IU/ml) initial viremia. METHODS AND TREATMENT REGIME: Treatment-naive patients with chronic HCV infection treated with the combination therapy of pegylated interferon-alpha2a plus ribavirin. Treatment response was evaluated at weeks 12, 24 and 48 when treatment was ongoing and at weeks 12, 24 and 48 after the treatment was finished. Commercially available sets from various manufacturers were used for serum and molecular genetic diagnostics of HCV infection. PATIENT SAMPLE: Antiviral treatment was initiated in 175 patients between 2001 and 2007. The complete data sets suitable for statistical analysis were available for 143 patients. End of treatment response and sustained viral response analyses were conducted separately for HCV genotype 1 (n = 124) and genotype 2 + 3 (n = 7). RESULTS: In the genotype 1 group, 76% of patients achieved end of treatment response and 59% of patients achieved sustained viral response. Both types of response were observed in 100% of the genotype 2 and 3 infected patients. When a correlation between initial viremia and sustained viral response was analysed, no statistically significant difference was observed between patients with low (< 600,000 IU/ml) and high (> or = 600,000 IU/ml) initial viremia. CONCLUSION: The results observed in the present study are generally slightly better than comparable results from large registration studies. In contrary to the published literature, the threshold of 600,000 IU/ml for initial viremia did not correlate statistically significantly with SVR.

The role of BSAP (Pax-5) in B-cell development.

The hierarchy of transcriptional control in B-cell development has recently been analyzed by targeted gene inactivation in the mouse. In this manner, the paired box containing gene Pax-5, encoding the B cell specific transcription factor BSAP, has been shown to play a key role in early B lymphopoiesis. Other experimental strategies have implicated BSAP in the control of cell proliferation, isotype switching and transcription of the immunoglobulin heavy-chain gene at late stages of B-cell differentiation.

[Incidence of hiatal hernias in the current endoscopic praxis]. / Výskyt hiátové hernie v bezné endoskopické praxi.

BACKGROUND: Hiatal hernia represents penetration of the oral part of stomach together with the distal part of oesophagus via oesophageal hiatus into the thoracic cavity. On the basis of endoscopic examination hiatal hernia is defined as circular pull out of the gastric mucosa longer then 2 cm from the diaphragm to Z line, measured at the end of examination during removing the endoscope. Hiatal hernia is usually an acquired state which can worsen oesophagitis by holding refluxate and thus by prolonging the duration of purgation. METHODS AND RESULTS: Endoscopic and radiological studies show that 50 to 94 % of patients with gastroesophageal reflux disease have an axial hiatal hernia while in control persons the incidence fluctuates between 13 % and 59 %. Hiatal hernia is a frequent finding during upper gastrointestinal endoscopy. Hernia can contribute to the development of reflux into the proximal oesophagus. A cohort of one thousand patients (18 to 94 years) who underwent upper gastrointestinal endoscopy was analysed retrospectively. Endoscopy was performed between January and June 2005 at the Endoscopic center of the 4th Medical Department of the University Hospital in Prague. CONCLUSIONS: Presented study has shown that in patients who underwent endoscopy, hiatal hernia occurs in 16.6%, more frequently in men (53.6%). The most common type is an axial hiatal hernia with incidence of 94.58%. In 50% of patients with hiatal hernia the reflux oesophagitis of various degrees was diagnosed.

[Diagnosis and treatment of chronic hepatitis B. Recommendations of the Czech Hepatology Society of the J. E. Purkinje Medical Society and the Society of Infectious Medicine of the J.E. Purkinje Medical Society]. / Diagnostika a lécba chronické hepatitidy B.

Chronic hepatitis B is one of the world's most common infectious diseases. In the Czech Republic it has a prevalence of 0.56%. Antiviral therapy for chronic hepatitis B demonstrably increases quality of life and where indication criteria are met and standard therapeutic procedures are followed, it is clearly cheaper than treatment for the complications of advanced cirrhosis of the liver or hepatocellular carcinoma. At the time of issuing of this recommendation, 4 medicines were classified for the treatment of chronic hepatitis B in the Czech Republic--pegylated interferon (IFN) alpha-2a, conventional IFN alpha, lamivudine (LAM) and adefovir dipivoxil (ADV). In a number of other developed states, entecavir (ETV) and telbivudine (LdT) have also been approved for treatment. The most effective treatment available at present is pegylated IFN alpha-2a, which should be the medication of first choice for initial treatment of hepatitis B, HBeAg positive and negative forms, provided that there are no contraindications for IFN alpha treatment. Conventional (standard, classical) IFN alpha can also be used, though clinical studies have shown it to be less effective than pegylated IFN alpha-2a. The main advantage of interferon compared to other commercially available medications is its relatively shorter and more clearly defined treatment period, the high probability of permanent suppression of virus replication and seroconversion of HBeAg/anti-HBe (in HBeAg positive forms of the illness) and the non-creation of mutant strains of HBV resistant to IFN in the course of treatment. If there are contraindications for IFN alpha (pegylated or conventional) or it is ineffective or poorly tolerated, ADV, ETV, LAM or LdT can be used. LAM and LdT treatments are often accompanied by the appearance of mutant strains of HBV, that are resistant to lamivudine or LdT and therefore they are not preferred.

Posttranscriptional regulation of FOXO expression: microRNAs and beyond.

Forkhead box, class O (FOXO) transcription factors are major regulators of diverse cellular processes, including fuel metabolism, oxidative stress response and redox signalling, cell cycle progression and apoptosis. Their activities are controlled by multiple posttranslational modifications and nuclear-cytoplasmic shuttling. Recently, post-transcriptional regulation of FOXO synthesis has emerged as a new regulatory level of their functions. Accumulating evidence suggests that this post-transcriptional mode of regulation of FOXO activity operates in response to stressful stimuli, including oxidative stress. Here, we give a brief overview on post-transcriptional regulation of FOXO synthesis by microRNAs (miRNAs) and by RNA-binding regulatory proteins, human antigen R (HuR) and quaking (QKI). Aberrant post-transcriptional regulation of FOXOs is frequently connected with various disease states. We therefore discuss characteristic examples of FOXO regulation at the post-transcriptional level under various physiological and pathophysiological conditions, including oxidative stress and cancer. The picture emerging from this summary points to a diversity of interactions between miRNAs/miRNA-induced silencing complexes and RNA-binding regulatory proteins. Better insight into these complexities of post-transcriptional regulatory interactions will add to our understanding of the mechanisms of pathological processes and the role of FOXO proteins. LINKED ARTICLES: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.

Generation of completely embryonic stem cell-derived mutant mice using tetraploid blastocyst injection.

Embryonic stem (ES) cells provide a unique tool for producing specifically designed mutations in mice. Here, we describe an alternative approach toward the generation of mice which are derived completely from ES cells (ES mice), as judged by glucose phosphate isomerase (GPI) analysis, without prior passage through the germline. By injecting wild-type and mutant ES cells into tetraploid blastocysts, viable and fertile ES mice were generated, suggesting that totipotency of ES cells was not affected by long-term culture and experimental manipulation in vitro. When ES cell clones harboring a lacZ reporter gene introduced by either targeted insertion or a gene-trap approach were used, the expression pattern of the lacZ gene in ES fetuses was identical to that of fetuses that were derived from breeding of chimeric mice. Thus, this technique can be considered as a useful and rapid approach to produce fetuses and mice directly from ES cells carrying predetermined genetic changes and offers many applications for studies in molecular genetics and developmental biology.

Pax2/5 and Pax6 subdivide the early neural tube into three domains.

The nested expression patterns of the paired-box containing transcription factors Pax2/5 and Pax6 demarcate the midbrain and forebrain primordium at the neural plate stage. We demonstrate that, in Pax2/5 deficient mice, the mesencephalon/metencephalon primordium is completely missing, resulting in a fusion of the forebrain to the hindbrain. Morphologically, in the alar plate the deletion is characterized by the substitution of the tectum (dorsal midbrain) and cerebellum (dorsal metencephalon) by the caudal diencephalon and in the basal plate by the replacement of the midbrain tegmentum by the ventral metencephalon (pons). Molecularly, the loss of the tectum is demonstrated by an expanded expression of Pax6, (the molecular determinant of posterior commissure), and a rostral shift of the territory of expression of Gbx2 and Otp (markers for the pons), towards the caudal diencephalon. Our results suggest that an intact territory of expression of Pax2/5 in the neural plate, nested between the rostral and caudal territories of expression of Pax6, is necessary for defining the midbrain vesicle.

[Hepatitis C viral infection at the beginning of twenty-first century]. / Infekce virem hepatitidy C na pocátku 21. století.

The article reviews basic information on the epidemiology, origin, diagnostics and therapy of hepatitis C viral infection. Virus of the hepatitis C was identified in 1989. The most frequent transmission pathway till 1992 was the reception of blood derivatives, after that year, when transfusion centres started to use detection sets to prove anti-HCV antibodies, the incidence of post-transfusion hepatitis C dropped almost to zero. The most common route of transmission at present is the intravenous toxicomany, and significant participation represents the medical care. The basic serological marker of HCV infection is the presence of anti-HCV antibodies. Those antibodies signify markers of the human contact with the virus; they need not automatically mean the encounter of infection. More often it is contrariwise--because the C viral hepatitis develops the chronic stadium up in 85%, the anti-HVC positivity signifies usually the active form of infection. To prove the active form of infection it is necessary to identify viral nucleic acids in the serum of the examined patient. The standard therapy of the chronic form of the C viral hepatitis is at present a combination of pegylated interpherons alpha and ribavirin. Such form of therapy can result the permanent elimination of the virus in about 60% of cases. In the C viral hepatitis neither the specific pre-exposition nor post-exposition prophylaxis is available. The only prevention of the transmission of infection is the avoidance of any risk factor of transmission, namely in the medical care.

[Long-term pharmacological treatment of portal hypertension]. / Dlouhodobá farmakologická lécba portální hypertenze.

Portal hypertension is an unavoidable complication of liver cirrhosis, which usually limits the survival (bleeding from esophageal varices, ascites). Increase in portal pressure is not only due to mechanical obstruction of portal circulation, but there is also a dynamic component (endothelial dysfunction of hepatic microcirculation) and increased blood flow through the splanchnic circulation. For the long-term treatment of portal hypertension two groups of medicaments are available at present: non-selective betablockers (vasoconstriction in splanchnic bed) and nitrates (lowering of intrahepatic resistance). Long-term treatment is necessary in these situations: Primary prophylaxis of bleeding from esophageal varices (in patients, who never bled, but with "risk" varices)--non-selective betablockers; secondary prophylaxis (in patients after variceal bleeding)--non-selective betablockers (possibly with nitrates) or endoscopic treatment. It is clearly documented, that this treatment lowers the risk of the first or repeated bleeding from varices and hence lowers the mortality and morbidity due to this complication in patients with liver cirrhosis. Another serious complication of liver cirrhosis is the spontaneous bacterial peritonitis. All patients after that infection have to receive prophylactic treatment with antibiotics. This treatment should be long life, till the disappearance of ascites or till the liver transplantation.