Homozygous KIDINS220 loss-of-function variants in fetuses with cerebral ventriculomegaly and limb contractures.

Heterozygous mutations in KIDINS220 were recently suggested a cause of spastic paraplegia, intellectual disability, nystagmus and obesity. All patients carried terminal nonsense de novo mutations that seemed to escape nonsense-mediated mRNA decay. The mechanism for pathogenicity is yet unexplained, as it seems that heterozygous loss-of-function variants of KIDINS220 are generally well tolerated. We present a consanguineous couple who experienced four pregnancy terminations due to repeated findings in the fetuses comprising enlarged cerebral ventricles and limb contractures. Exome sequencing in two of the aborted fetuses revealed a shared homozygous frameshift variant in exon 24 in KIDINS220. Sanger sequencing of the variant in available family members showed complete segregation with the affection status, resulting in a LOD score of 2.5 under an autozygous inheritance model. mRNA studies revealed destruction of the original splice site, resulting in an out-of-frame transcript and introduction of a premature termination codon in exon 25. Premature termination codons in this position are likely to cause activation of nonsense-mediated mRNA decay and result in complete absence of KIDINS220 protein in individuals homozygous for the variant. The phenotype of the presented fetuses overlaps with findings in functional studies of knockout Kidins220 mice embryos that are non-viable with enlarged cerebral ventricles. The human fetuses also exhibit several similarities to the milder phenotype described in patients with heterozygous KIDINS220 mutations. We hence propose that the identified homozygous loss-of-function variant in KIDINS220 causes the phenotype in the presented fetuses, and that this represents a hitherto undescribed severe autosomal recessive neurodevelopmental disorder.

[Malnutrition in gastroenterological diseases]. / Malnutrition: häufiges Problem bei Erkrankungen des Magen-Darm-Trakts. Ernährungstherapien verbessern Prognose und Lebensqualität.

Significant weight loss, a body mass index of less than 18.5, hypoalbuminemia, and a deficiency in specific nutrients are major criteria. Depending on the underlying diagnosis, maldigestion, malabsorption, catabolism, dysphagia, anorexia and intestinal obstruction are possible causes of malnutrition. In the majority of cases, malnutrition is associated with a poorer prognosis, a reduced general health status, and poorer quality of life. This means that in addition to treatment of the underlying disease, specific nutritional support, preferably by the enteral route, with the aim of providing an adequate supply of nutrients and improving the patient's general nutritional status is of importance.

[Basics of nutrition in cirrhosis of the liver]. / Richtige Ernährung bei Leberzirrhose. Eiweissrestriktion ist meist fehl am Platz.

Liver cirrhosis is associated with complex metabolic disorders, and regularly leads to a catabolic state. Catabolism, malassimilation, but also loss of protein and, frequently, malnutrition, are the main reasons underlying reduced the nutritional status frequently encountered in these patients. This promotes such complications as ascites, diabetes mellitus, encephalopathy, infections and the hepatorenal syndrome. Dietary therapy individually tailored to the course of the disease provides the often increased energy requirement, while also serving to prevent and treat complications.

Neutrophil antibodies (pANCA) in chronic liver disease and inflammatory bowel disease: do they react with different antigens?

OBJECTIVE: A high frequency of perinuclear neutrophil antibodies (pANCA) has been described in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We evaluated the presence of pANCA in chronic liver disease and compared the immunoglobulin G (IgG) subclasses of pANCA in inflammatory bowel disease with chronic liver disease. Since the antigen reacting with pANCA could not be determined, the antigenic role of various neutrophil antigens was evaluated. SUBJECTS AND METHODS: Detection of pANCA and their IgG subclass was performed by immunofluorescence. One hundred and forty patients with chronic liver disease, 96 patients with inflammatory bowel disease and 40 healthy controls were tested for pANCA. pANCA positive and negative sera were evaluated for their reactivity with different neutrophil antigens in an enzyme-linked immunosorbent assay (ELISA) system. RESULTS: pANCA were found in 8 of 23 patients (35%) with autoimmune hepatitis, in 6 of 21 patients (28%) with primary biliary cirrhosis (PBC), in 18 of 25 patients (72%) with PSC, in 3 of 48 patients (6%) with viral hepatitis, in 30 of 48 patients (62%) with UC, and in 2 of 48 patients (4%) with Crohn's disease. All 20 patients with alcoholic liver disease and 40 healthy controls were negative for pANCA. In contrast to the patients with UC who had 83% IgG1 and only 13% IgG3 antibodies, patients with PSC and PBC had an overexpression of IgG3 antibodies (PSC: 50% IgG3; PBC: 67% IgG3). A proportion of pANCA positive sera recognized lactoferrin, myeloperoxidase, cathepsin G, laminarase and alpha 1-antitrypsin. CONCLUSION: pANCA is not present only in patients with UC but in autoimmune liver diseases such as PSC, autoimmune hepatitis and PBC. Considering the IgG subclass of pANCA, the antibody response of patients with UC is different from patients with liver disease. No unique pANCA specific antigen could be detected, so heterogeneity of pANCA has to be considered.

[Hereditary nonpolyposis colorectal carcinoma (HNPCC). Current review of etiology, clinical aspects, diagnosis and therapy]. / Hereditäres Non-Polyposis kolorektales Karzinom (HNPCC). Aktuelle Ubersicht zur Atiologie, Klinik, Diagnostik und Therapie.

ETIOLOGY: The hereditary non-polyposis colorectal carcinoma (HNPCC) is the most common monogenic colon cancer syndrome. It is characterized by autosomal dominant inherited cancers of the colon, rectum, and the endometrium. Less frequently, cancer of the upper gastrointestinal tract, the hepatobiliary system and the urogenital tract may occur. Typical characteristics are an early onset, usually before the age of 50, manifestation of colorectal cancer proximal of the splenic flexure, and often poorly differentiated carcinomas. GENETICS: Recently, germline mutations in several DNA mismatch repair genes have been identified as the molecular basis of HNPCC, resulting in deficient DNA repair and genetic instability, indicated by microsatellite instability in tumor specimens. DIAGNOSIS: New insights into pathogenesis, clinical features, and diagnosis of HNPCC have improved the identification of HNPCC patients and persons at risk. Diagnosis of HNPCC is primarily based on family history and is complemented by molecular findings. After detection of the underlying germline mutation in families with HNPCC, screening procedures can be restricted to mutation carriers. TREATMENT: Recommendations for therapy and prevention are in part controversial and are under investigation in several studies.

[Selenoproteins in bone, gastrointestinal tract and thyroid gland of the human]. / Selenoproteine im Knochen, Gastrointestinaltrakt und in der Schilddrüse des Menschen.

BASIS: Selenium is an essential trace element, which is incorporated as selenocysteine (secys) into specific proteins in a regulated fashion. In the presence of a hairpin loop structure within the 3' untranslated region of the mRNA the opal stop codon UGA is coding for selenocysteine. Selenoprotein functions are dependent on secys incorporation. Members of the family of deiodinases as well as the family of glutathione peroxidases, selenoprotein P and thioredoxin reductase are selenoproteins. DISCUSSION: Bone, the intestine and the thyroid rely on antioxidant systems against potential cell and DNA damage through endogenous and environmental peroxides and reactive oxygen species (ROS) potentially promoting inflammation and tumorigenesis. Optimized cell defense through antioxidant selenoproteins requires optimal selenium supplementation of the organism. We have analyzed the expression of selenoproteins in these tissues, thus providing molecular tools to further elucidate optimal selenium supply on a cellular level. CONCLUSION: Clinical intervention studies that focus on the development of disease must confirm the relevance of optimized selenium supply for the pathogenesis, prevention and therapy of metabolic bone disease as well as chronic (autoimmune) inflammation and tumorigenesis in the thyroid and intestine.

[Therapy of liver cirrhosis. Managing complications with fingertip control]. / Therapie der Leberzirrhose. Komplikationen managen mit Fingerspitzengefühl.

Chronic liver diseases often lead to cirrhosis of that organ. As this progresses, hepatic function decreases, and the risk of life-threatening complications increases. Common complications are variceal bleeding, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome and hepatocellular carcinoma. The only therapeutic option that offers a chance of a cure is transplantation which, however, owing to strict selection criteria and the limited number of donor organs, can be applied only in a minority of patients. For most of the cases, the therapeutic strategy comprises treatment of the underlying disease, prevention and symptomatic treatment of typical complications.

[Acid reflux on the esophagus. What helps in acute reflux esophagitis, how to prevent a recurrence?]. / Säureattentate auf die Speiseröhre. Was hilft bei akuter Refluxösophagitis, wie verhindern Sie Rezidive?

Gastro-esophageal reflux disease--one of the most common diagnoses in gastroenterology--is characterized by its symptoms or mucosal lesions caused by the non-physiological exposure of the esophagus to gastric juice. For its acute treatment, proton pump inhibitors are distinctly superior to histamine 2 receptor antagonists, and are the treatment of choice. Since relapse is common, long-term treatment is often necessary. Although PPI are the most effective substances over the long-term too, cisapride and/or histamine receptor antagonists may suffice to prevent relapse. In severe and complicated cases, however, the long-term use of proton pump inhibitors is mandatory. While, in such cases, laparoscopic antireflux surgery offers an alternative, neither long-term data nor controlled studies comparing this approach with long-term medical treatment have been carried out. A major complication of reflux disease is Barrett's metaplasia with its associated risk for adenocarcinoma development. Barrett's epithelium can be eradicated by endoscopic thermal ablation combined with acid suppression. However, as endoscopic therapy bears risks and data on long-term efficacy are still lacking, the significance of thermal ablation has further to be evaluated in specialized centers.

Cyclic AMP-dependent inotropic effects are differentially regulated by muscarinic G(i)-dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle.

BACKGROUND AND PURPOSE: ß-Adrenoceptor (ß-AR)-mediated inotropic effects are attenuated and G(i) proteins are up-regulated in heart failure (HF). Muscarinic receptors constitutively inhibit cAMP formation in normal rat cardiomyocytes. We determined whether constitutive activity of muscarinic receptors to inhibit adenylyl cyclase (AC) increases in HF and if so, whether it modifies the reduced ß-AR- or emergent 5-HT4-mediated cAMP-dependent inotropic effects. EXPERIMENTAL APPROACH: Contractility and AC activity were measured and related to each other in rat ventricle with post-infarction HF and sham-operated (Sham) controls with or without blockade of muscarinic receptors by atropine and inactivation of G(i) protein by pertussis toxin (PTX). KEY RESULTS: Isoprenaline-mediated inotropic effects were attenuated and basal, isoprenaline- and forskolin-stimulated AC activity was reduced in HF compared with Sham. Atropine or PTX pretreatment increased forskolin-stimulated AC activity in HF hearts. ß-AR-stimulated AC and maximal inotropic response were unaffected by atropine in Sham and HF. In HF, the potency of serotonin (5-HT) to evoke an inotropic response was increased in the presence of atropine with no change in the maximal inotropic response. Interestingly, PTX pretreatment reduced the potency of 5-HT to evoke inotropic responses while increasing the maximal inotropic response. CONCLUSIONS AND IMPLICATIONS: Although muscarinic constitutive inhibition of AC is increased in HF, it does not contribute to the reduced ß-AR-mediated inotropic effects in rat ventricle in HF. The data support the hypothesis that there are differences in the functional compartmentation of 5-HT4 and ß-AR AC signalling in myocardium during HF.

5-HT4-elicited positive inotropic response is mediated by cAMP and regulated by PDE3 in failing rat and human cardiac ventricles.

BACKGROUND AND PURPOSE: The left ventricle in failing hearts becomes sensitive to 5-HT parallelled by appearance of functional G(s)-coupled 5-HT(4) receptors. Here, we have explored the regulatory functions of phosphodiesterases in the 5-HT(4) receptor-mediated functional effects in ventricular muscle from failing rat and human heart. EXPERIMENTAL APPROACH: Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats. Contractility was measured in left ventricular papillary muscles of rat, 6 weeks after surgery and in left ventricular trabeculae from explanted human hearts. cAMP was quantified by RIA. KEY RESULTS: In papillary muscles from postinfarction rat hearts, 5-HT(4) stimulation exerted positive inotropic and lusitropic effects and increased cAMP. The inotropic effect was increased by non-selective PDE inhibition (IBMX, 10 microM) and selective inhibition of PDE3 (cilostamide, 1 microM), but not of PDE2 (EHNA, 10 microM) or PDE4 (rolipram, 10 microM). Combined PDE3 and PDE4 inhibition enhanced inotropic responses beyond the effect of PDE3 inhibition alone, increased the sensitivity to 5-HT, and also revealed an inotropic response in control (sham-operated) rat ventricle. Lusitropic effects were increased only during combined PDE inhibition. In failing human ventricle, the 5-HT(4) receptor-mediated positive inotropic response was regulated by PDEs in a manner similar to that in postinfarction rat hearts. CONCLUSIONS AND IMPLICATIONS: 5-HT(4) receptor-mediated positive inotropic responses in failing rat ventricle were cAMP-dependent. PDE3 was the main PDE regulating this response and involvement of PDE4 was disclosed by concomitant inhibition of PDE3 in both postinfarction rat and failing human hearts. 5-HT, PDE3 and PDE4 may have pathophysiological functions in heart failure.

Contribution of different Ca-activated K channels to the first phase of the response to TRH in clonal rat anterior pituitary cells.

AIMS: Thyrotropin-releasing hormone (TRH) induces biphasic changes in electrical activity, cytosolic free Ca(2+) level ([Ca(2+)](i)), and prolactin secretion from both clonal GH cells and native lactotrophs. The first phase of the TRH response is characterized by hyperpolarization because of activation of Ca(2+)-activated K(+) channels (K(Ca)). In the present study, the relative contribution of BK, SK, and IK channels to the first phase of the TRH response in GH(4) cells was assessed. METHODS: The expression of IK channels was confirmed by PCR with specific primers for SK4 (IK). The response to TRH was studied using the perforated patch technique and Ca(2+) microfluoromety (fura-2). The involvement of different K(Ca) channels was estimated by employing the specific channel blockers iberiotoxin (BK), apamin (SK) and clotrimazole (IK). RESULTS: Application of 100 nM iberiotoxin, 1 microM apamin, and 10 microM clotrimazole reduced the peak value of the outward K(+) current during the first phase of the TRH response by 33, 26, and 33%, respectively. Clotrimazole also shortened the duration of the outward current response by 60%, causing a reduction of total charge movement by 73%. All these toxin-induced reductions were significant (P < 0.05). A combination of all three toxins abolished the current response almost completely. CONCLUSION: All the three main types of K(Ca) channels are involved in the first phase of the TRH response, with IK as the major contributor. This is the first demonstration of a dominant role of IK compared with BK and SK channels in excitable cells.

[Chronic occult gastrointestinal hemorrhage]. / Die chronische okkulte gastrointestinale Blutung.

Iron deficiency anemia is a common symptom of chronic occult gastrointestinal bleeding. There are numerous potential sources of gastrointestinal hemorrhage, most of which can be detected with the aid of endoscopy of the upper and lower digestive tract. Diagnostic procedures for the small bowel are less sensitive and usually more invasive. On the basis of the relevance of information they provide, the various diagnostic procedures and their indication in the diagnosis of iron deficiency anemia are critically reviewed, and a systematic diagnostic strategy developed.

Hypereosinophilic syndrome resembling chronic inflammatory bowel disease with primary sclerosing cholangitis.

A patient who presented with chronic inflammation of the colon, and initially also the terminal ileum, accompanied by marked diarrhea, is described. Repeated high-dose steroid therapy was only temporarily successful, and symptoms recurred upon dose reduction. During the further course of the disease, a marked elevation of alkaline phosphatase and transaminases, as well as soft tissues swelling occurred. Clinically, the diagnosis of inflammatory bowel disease with primary sclerosing cholangitis was made. Irregularities in the walls of the common bile duct and the intrahepatic ducts seen at endoscopic retrograde cholangiopancreatography were consistent with the latter diagnosis. However, extreme eosinophilia of peripheral blood, bone marrow and bowel mucosa was present, and liver histology showed eosinophilic cholangiohepatitis. Under the diagnosis of hypereosinophilic syndrome with involvement of bowel, liver and biliary system, therapy with hydroxyurea was initiated. The patient's condition improved promptly. Eosinophil count and liver enzymes have remained normal under long-term medication with 1.0 g per day of this drug.

[Successful therapy of persistent androgen-induced cholestasis with ursodeoxycholic acid]. / Erfolgreiche Therapie einer persistierenden androgeninduzierten Cholestase mit Ursodesoxycholsäure.

Drug-induced cholestasis can rarely persist for a considerable time period even after withdrawal of the drug. We report the case of a 55-year-old man with progressive jaundice after oral therapy with 17-alpha-methyltestosterone. Under empiric therapy with ursodeoxycholic acid the condition resolved completely. According to this observation, we suggest a therapeutic trial with ursodeoxycholic acid in cases of prolonged androgen-induced cholestasis.

Possible mechanisms of pain perception in patients with episodic tension-type headache. A new experimental model of myofascial pain.

A new experimental human model of myofascial pain using intramuscular infusion of a combination of bradykinin, serotonin (5-hydroxytryptamine), histamine, and prostaglandin E2 was applied to patients with episodic tension-type headache (ETTH) in order to examine pain perception. Fifteen patients with ETTH and 15 healthy controls completed the randomized, balanced, double-blinded, placebo-controlled study. Pain intensity, punctate hyperalgesia and allodynia, and pain quality were recorded. The combination induced a moderate and prolonged pain in both patients (median 51 min) (P = 0.001) and controls (median 22 min) (P = 0.001). Patients reported more pain than controls both after the combination (P = 0.045) and after placebo (P < 0.001). The McGill pain score [PRI(R)] was significantly higher in patients (P = 0.002) and in controls (P = 0.001), whereas pain quality and hyperalgesia were similar after the combination compared with placebo in the two groups. Due to side-effects nine subjects did not complete the study. The increased pain response, but similar qualitative pain perception, in ETTH patients may be explained by sensitization of peripheral nociceptors even though central mechanisms may also be involved.

Computed tomography after lymphangiography in the diagnosis of intestinal lymphangiectasia with protein-losing enteropathy in Noonan's syndrome.

Noonan's syndrome is a rare congenital disorder that may be associated with abnormalities in the lymphatic drainage. In this case of a 21-year-old man CT after bipedal lymphangiography confirmed the diagnosis of intestinal lymphangiectasy causing protein-losing enteropathy in Noonan's syndrome by showing contrast-enhanced abnormal lymphatic vessels in the mesentery and the intestinal wall. Because of the benefit of diet in case of intestinal involvement, we recommend a thorough documentation of the lymphatic drainage with lymphangiography followed by CT, if clinical signs of lymphatic dysplasia, such as pleural effusions, lymphedema, or hypoproteinemia are present.

Pancreatic autoantibodies in Crohn's disease: a family study.

BACKGROUND: Pancreatic antibodies occur in about one third of patients with Crohn's disease. AIMS: To evaluate the relevance of pancreatic antibodies as a genetic marker in patients with Crohn's disease and their first degree family members and spouses. To characterise further pancreatic antibodies by assessment of IgG subclasses. METHODS: Six hundred and fifty serum samples were tested for pancreatic antibodies by immunofluorescence on sections of human pancreas. Incidence of pancreatic antibodies and their subtypes were studied on 212 serum samples from patients with Crohn's disease. In the familial study, 72 patients with Crohn's disease and 196 first degree family members and 26 patients with ulcerative colitis and 90 first degree family members were included. Ten healthy families served as controls. RESULTS: Pancreatic antibodies were found in 58 (27%) of the patients with Crohn's disease and in none of the controls. Thirty patients had pancreatic antibodies of subtype I characterised by a drop-like fluorescence in the pancreatic acini, 28 patients had subtype II with a fine speckled staining in the acinar cells. Pancreatic antibodies of subtype I were both IgG1 and IgG2 antibodies by contrast with subtype II which were mainly of IgG1 subclass. Only five of 196 first degree relatives of patients with Crohn's disease had pancreatic antibodies. Four of these people had anamnestic data compatible with inflammatory bowel disease. Further investigations showed Crohn's disease in two of these people. In families with more than one member positive for pancreatic antibodies, pancreatic antibodies were of the same subtype in all cases. CONCLUSIONS: Pancreatic antibodies are a specific marker for Crohn's disease. Two subgroups of pancreatic antibodies can be distinguished by their pattern and immunoglobulin subclasses. Pancreatic antibodies rarely occur in family members of patients with Crohn's disease. These family members may also have Crohn's disease.