Transforming growth factor ß1 genotypes in relation to TGFß1, interleukin-8, and tumor necrosis factor alpha in induced sputum and blood in cystic fibrosis.

BACKGROUND: High-producer TGFß1 genotypes are associated with severe lung disease in cystic fibrosis (CF), but studies combining IL-8, TNFα-, and TGFß1(+genotype) levels and their impact on CF lung disease are scarce. AIM: Assessing the relationship between TGF ß 1, IL-8, and TNF- α and lung disease in CF in an exacerbation-free interval. METHODS: Twenty four patients delta F508 homozygous (median age 20.5 y, Shwachman score 75, FEV1(%) 83) and 8 controls (median age 27.5 y) were examined. TGF ß 1 was assessed in serum and induced sputum (IS) by ELISA, for IL-8 and TNF- α by chemiluminescence in IS and whole blood. Genotyping was performed for TGF ß 1 C-509T and T+869C utilizing RFLP. RESULTS: TGF ß 1 in IS (CF/controls median 76.5/59.1 pg/mL, P < 0.074) was higher in CF. There was a negative correlation between TGF ß 1 in serum and lung function (LF) (FEV1 (r = -0.488, P = 0.025), MEF 25 (r = -0.425, P = 0.055), and VC (r = -0.572, P = 0.007)). Genotypes had no impact on TGF ß 1 in IS, serum, and LF. In IS TGF ß 1 correlated with IL-8 (r = 0.593, P < 0.007) and TNF- α (r = 0.536, P < 0.018) in patients colonized by bacteria with flagellin. CONCLUSION: TGF ß 1 in serum not in IS correlates with LF. In patients colonized by bacteria with flagellin, TGF ß 1 correlates with IL-8 and TNF- α in IS.

Balloon gastrostomy buttons in pediatric patients: evaluation with respect to size, lifetime in patients, and parent acceptance.

BACKGROUND AND OBJECTIVE: To evaluate the experience with "balloon" gastrostomy buttons in pediatric patients. Distributions of the shaft lengths and the longevity of the balloon tubes were examined. Parents' and caregivers' opinion about this type of tube were analysed. METHODS AND PATIENTS: Retrospective chart review (n=38) and short questionnaire (n=21) during regular follow up visits. RESULTS: The mean longevity of balloon buttons was 193 days. 90.7% shaft lengths were from 1.5 to 2.3 cm. 100% of caregivers evaluated handling of the button tube as equal or better (81%) than a conventional PEG tube. "Overall" satisfaction was equal in 5% and better in 85% of cases. CONCLUSION: Button tubes have to be replaced about 2 times a year. In pediatrics typical shaft lengths are between 1.5 and 2.3 cm. A majority of care giving persons prefers the button tube in comparison with PEG-tubes. Thus, button tubes should be recommended for long-term enteral nutrition in order to improve the patients' quality of life.

Dysphagia due to triple A syndrome: successful treatment of achalasia by balloon dilatation.

UNLABELLED: Triple A syndrome is a rare autosomal recessive inherited disorder which is characterized by alacrima, adrenal insufficiency, and achalasia. We report on a 14-year old girl with dysphagia, regurgitation, and vomiting since 5 years. At the age of five years an Addison crisis was diagnosed and cortisone substitution was initiated. In addition, the patient had episodes of conjunctivitis. Severe esophagitis and candida infection were diagnosed by esophago-gastro-duodenoscopy and treated with omeprazole and fluconazole. The esophageal barium swallow was typical for achalasia. Medical treatment of achalasia with oral nifedipine resulted only in a partial and temporal improvement. But after seven balloon dilatations dysphagia and nocturnal coughing improved clearly and a remarkable gain of weight could be seen. Direct sequencing showed a homozygous nonsense mutation in exon 11 of the AAAS gene leading to truncation at position 342 of the 546 amino acid protein. CONCLUSION: Triple A syndrome has to be considered in patients with dysphagia. In our patient, the absence of tears since birth followed by adrenal insufficiency were early signs of the triple A syndrome. Balloon dilatation of the esophago-gastric junction is an effective treatment, which can avoid surgical interventions.

[Human Metapneumovirus in hospitalized children - a review]. / Das humane Metapneumovirus als Erreger von Atemwegsinfektionen bei hospitalisierten Kindern - eine Ubersicht.

The human Metapneumovirus (HMPV) has been discovered by von den Hoogen et al. in 2001 and seems to play an important role as etiologic agent in childhood respiratory tract infections in particular involving infants after the 6th month of life and toddlers. Duly considering the hitherto published studies and retrospective analysis of two HMPV seasons (2002-2004) at our institution this review focuses on children, who had to be hospitalized due to HMPV infection. The analysis confirmed, that among those patients there is a high proportion of children with pre-existing risk factors for a complicated clinical course, a high proportion of children with bronchiolitis or pneumonia and a relevant proportion of children with HMPV related apnoeas, most prevalent in the prematurely born. Although the first HMPV infection takes place somewhat later in infancy, the data do not show that HMPV infection is in general milder than RSV infection in hospitalized children. Clinical symptoms and radiological signs do not permit tentative conclusions on the causative agent. This underlines the necessity of specific diagnostic efforts (in case of HMPV with PCR). HMPV may cause lobar or segmental pneumonias difficult to distinguish from bacterial lower respiratory tract infection. Children admitted to the hospital with an acute exacerbation of asthma bronchiale or cystic fibrosis should not only be tested for RSV but also for HMPV. Prospective studies investigating specific therapeutic interventions or describing the impact and prevention of nosocomial HMPV in fection are awaited for. There has been one report of a meningoencephalitis possibly related to HMPV. Thus, liquor samples in such cases should be tested for HMPV too.

[Protein-loosing enteropathy: report of four cases and review of etiology, diagnostic work-up and treatment]. / Enteraler Eiweisserlust: Pathophysiologie, Ursachen, Diagnostik und Therapie mit Fallbeispielen.

The protein-loosing enteropathy (PLE) may result from a broad variety of underlying diseases. These conditions are of systemic nature or locally affecting the gastrointestinal tract. Major symptoms are oedema due to low plasma protein levels. Gastrointestinal symptoms are not necessarily present. The diagnosis is confirmed by the finding of increased faecal concentrations of Alpha-1-Antitrypsin (> 320 mg/L). In the majority of cases, in which underlying diseases are present, the etiology is obvious. In unclear cases the differentiation into inflammatory or circulatory disturbances or alterations of the architecture of the basal membrane is helpful. An economic, staged approach is presented. To localize the site of protein loss imaging is required (abdominal ultrasound, CT-scan, endoscopy and Technetium-Scan). If a circumscribed intestinal source of protein loss is suspected which may be amenable to surgery, intraoperative enteroscopy should be considered. If causal treatment is impossible; intravenous replacement of albumin and immunoglobulines in intervals from 1 to 4 weeks will be necessary. The prognosis in patients with isolated PLE is good. Otherwise it depends on the underlying disease.

Induction of T lymphocyte apoptosis by sulphasalazine in patients with Crohn's disease.

BACKGROUND: Lamina propria T lymphocytes (LPL) of the intestinal mucosa are chronically activated in Crohn's disease (CD). Defective apoptosis of activated LPL was proposed as a key pathogenic mechanism. In fact, increased expression of antiapoptotic molecules was observed in CD LPL. In the present work, we aimed to analyse the effects and underlying molecular mechanisms of 5-amino salicylic acid (5-ASA) and derivatives on apoptosis of LPL and peripheral blood lymphocytes (PBL) in patients with CD compared with ulcerative colitis (UC) and in non-inflammatory controls. METHODS: PBL and LPL were isolated by Ficoll-Hypopaque gradient centrifugation and the EGTA-collagenase method, respectively. PBL/LPL were stimulated with FasL, 5-ASA, sulphapyridine, and sulphasalazine for 24/48 hours and apoptosis was quantified by flow cytometry (annexin V- propidium iodide method) and immunofluorescence. The molecular mechanisms of drug induced apoptosis were analysed in wild-type and FADD-/- Jurkat T cells using western blots and caspase assays. RESULTS: While PBL displayed a normal apoptosis pattern after Fas stimulation in patients with active CD, LPL from inflammatory areas were highly resistant. Comparable resistance to apoptosis was observed in LPL of UC patients. In contrast with 5-ASA, which did not induce apoptosis in lymphocytes, sulphasalazine proved to be a potent proapoptotic agent. Sulphasalazine induced T lymphocyte apoptosis was independent of the Fas pathway but associated with marked downregulation of antiapoptotic bcl-xl and bcl2, activation of the mitochondrial apoptosis signalling pathway, and subsequent activation of caspase-9 and caspase-3. CONCLUSION: The beneficial effect of sulphasalazine in treating inflammatory bowel disease is at least in part attributable to its proapoptotic effects on LPL which allows potent downregulation of lymphocyte activation.

[Nutrition of children and adolescents. Results of the DONALD Study]. / Kinderernährung in Deutschland. Ergebnisse der DONALD-Studie.

In this paper, the actual diet of children and adolescents is characterized by food group intake. Age-dependent dietary patterns and long-term dietary trends are described and commented on against the background of the optimized mixed diet, a preventive total diet concept for German children and adolescents. Dietary intake data come from 3-day dietary records obtained in the DONALD Study (Dortmund Nutritional and Anthropometrical Longitudinally Designed Study), an ongoing mixed longitudinal cohort study conducted at the Research Institute of Child Nutrition since 1985. The actual diet of the observed children and adolescents differed to some extent from the optimized mixed diet. For example, the intake of vegetables was lower and the intake of meat/sausage and confectionary was higher than recommended. The three rules for food selection of the optimized mixed diet (consume plant foods and beverages liberally, animal foods moderately, and high-fat, high-sugar foods occasionally) show a practical way to improve unfavorable dietary habits of children and adolescents without fundamental changes of food intake patterns and taste properties of the actual diet. The partly favorable and partly unfavorable dietary trends observed in the DONALD Study should continue to be critically considered.

Serum lipid analysis confirms the diagnosis of X-linked dominant chondrodysplasia punctata - Conradi-Hünermann-Happle syndrome.

We present the morphological and biochemical findings in a twelve month old girl with chondrodysplasia punctata X2 - Conradi-Hünermann-Happle syndrome. This disease is characterized by limb length discrepancies, growth retardation, ichthyosis, cataracts, and punctate calcification. The diagnosis could finally be confirmed by increased concentrations of cholesterol precursors as recently found in the plasma and tissues of affected patients.

Antibiotic-associated diarrhea: therapeutic aspects and practical guidelines--an interdisciplinary approach to a common problem.

Antibiotic-associated diarrhea (AAD) is a common complication of antibiotic treatment, most often seen in non-hospitalised patients. In principle, such diarrhea can be triggered by any antibiotic. An interdisciplinary working group discussed the different aspects of AAD in view of its gastroenterological, microbiological, paediatric, general medical and pharmaceutical implications, also in consideration of the position of patients and health insurance funds. This paper implies therapeutic aspects and practical guidelines to raise awareness of these problems also in routine situations and to enable the persons and institutions involved on the various levels of the health-care system (patients, pharmacists, family doctors, specialists and hospitals) to handle the problem of AAD more easily in a standardised way as far as diagnostics, therapy and prevention are concerned.

Antibiotic-associated diarrhea: incidence, risk factors of antibiotics and patients, pathophysiology and differential diagnosis--an interdisciplinary approach to a common problem.

Antibiotic-associated diarrhea (AAD) is a common complication of antibiotic treatment, most often seen in non-hospitalised patients. In principle, such diarrhea can be triggered by any antibiotic. An interdisciplinary working group discussed the different aspects of AAD in view of its gastroenterological, microbiological, paediatric, general medical and pharmaceutical implications, also in consideration of the position of patients and health insurance funds. The incidence, risk factors of antibiotics and patients, the pathophysiology of the various types of AAD and the differential diagnosis are reviewed.

Butyrate induced Caco-2 cell apoptosis is mediated via the mitochondrial pathway.

BACKGROUND: During the process of tumorigenesis most colon cancer cells acquire resistance to apoptosis. The short chain fatty acid butyrate is well established as an antitumour agent which selectively induces apoptosis in colon cancer cells but not in normal intestinal epithelial cells. AIMS: To analyse the signalling pathway of butyrate induced apoptosis. METHODS: Using Caco-2 cells we focused on the bcl family of proteins, mitochondrial pathway, and caspase signalling cascade involved in butyrate induced apoptosis. Techniques employed included western blots, immunofluorescence, as well as experiments with peptide inhibitors of specific caspases. RESULTS: Butyrate induced a clear shift of the mitochondrial bcl rheostat towards a proapoptotic constellation, as demonstrated by upregulation of proapoptotic bak accompanied by reduced antiapoptotic bcl-x(L) levels. This was associated with translocation of cytochrome-c from the mitochondria to the cytosol, resulting in activation of the caspase cascade via caspase-9. Key executioner enzymes were caspases-3 and -1. No effect of butyrate on regulatory proteins of the inhibitor of apoptosis family was observed. CONCLUSIONS: Butyrate induced Caco-2 cell apoptosis via the mitochondrial pathway. Upregulation of bak and translocation of cytochrome-c were upstream of the caspase cascade. Subsequently, this cascade was activated via the formation of an apoptosome.

Lipopolysaccharide modulation of normal enterocyte turnover by toll-like receptors is mediated by endogenously produced tumour necrosis factor alpha.

BACKGROUND: Circulating levels of endotoxin (or lipopolysaccharide (LPS)) and anti-endotoxin antibodies are increased in patients with inflammatory bowel disease, supporting the hypothesis of a role for endogenous bacterial products in the pathogenesis of these disorders. AIM: The aim of this study was to analyse the direct effects of LPS on intestinal epithelial cell turnover. METHODS AND RESULTS: LPS significantly inhibited growth of the human non-transformed immature crypt cell line (HIEC), whereas IEC-6 cell proliferation was stimulated by LPS. As LPS is a physiological inducer of tumour necrosis factor alpha (TNFalpha) in various cell systems and this cytokine exerted similar anti-proliferative (HIEC) or growth stimulatory (IEC-6 cells) effects, the study thus tested the hypothesis that endogenously produced TNFalpha in response to LPS mediates this growth modulatory effect in an autoparacrine/paracrine way. Therefore, during LPS stimulation, the biological activity of TNFalpha was blocked using neutralising anti-TNFalpha antibodies, as well as inhibitory, antagonistic antibodies directed against the p55 TNF receptor, signalling the antimitotic TNFalpha effect in HIEC. Both experimental approaches completely abolished the growth modulatory effects of LPS in HIEC/IEC-6 cells. Production and secretion of TNFalpha by HIEC/IEC-6 cells in response to LPS was confirmed on mRNA and protein level by reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay. LPS signalling was independent of CD14 in HIEC, as these cells lack this receptor. However, HIEC expressed TLR4 and MD2 resulting in a fully functional signalling complex as demonstrated by RT-PCR, western blot, and immunofluorescence analyses. CONCLUSION: These results support the hypothesis that LPS induced changes of intestinal epithelial cell turnover may directly contribute to the pathogenesis of inflammatory epithelial cell lesions by endogenous TNFalpha production by enterocytes.

The susceptibility to Fas-induced apoptosis in normal enterocytes is regulated on the level of cIAP1 and 2.

Various members of the tumor necrosis factor receptor superfamily are implicated in the regulation of enterocyte apoptosis. Previously, we observed that human intestinal epithelial cells are rather unsusceptible to Fas-induced apoptosis. In the present study we analyzed these protective mechanisms in the human intestinal epithelial cell line HIEC, focusing on antiapoptotic molecules of the IAP family which block apoptosis at the level of the caspase cascade. HIEC expressed all key molecules required to trigger Fas-induced apoptosis. However, no apoptosis occurred after activation of Fas, whereas an upregulation of antiapoptotic cIAP1 and 2 was observed. Suppression of this upregulation with the proteasome inhibitor MG132 or the protein synthesis inhibitor cycloheximide highly sensitized HIEC toward Fas-induced apoptosis. Western blot analyses revealed that both inhibitors potently suppressed endogenously produced cIAP1 and 2. No effect was observed on XIAP expression. These data indicate that enterocytes are particularly protected against Fas-induced apoptosis on the level of executionary caspases.

The beta2-microglobulin/cystatin C ratio--a potential marker of post-transplant lymphoproliferative disease.

BACKGROUND: As a consequence of more intensified immunosuppression, post-transplant lymphoproliferative disease (PTLD) is increasingly observed in patients after solid-organ transplantation. Beta2-microglobulin, a low-molecular weight protein (MW 11.8 kDa), is produced by all nucleated cells as part of the HLA complex. Its serum concentration is directly correlated with prognosis in patients with lymphatic neoplasms. Like other low-molecular weight proteins, beta2-microglobulin is eliminated by glomerular filtration. This complicates its use as a tumor marker in renal insufficiency. Cystatin C, a low-molecular weight protein of 13.3 kDa, is a new marker of kidney function largely unaffected by extrarenal disease. We, therefore, sought to assess the potential of the beta2-microglobulin/cystatin C ratio (beta2M/Cys) as a marker of lymphoproliferation. PATIENTS AND METHODS: Beta2M/Cys was determined by particle-enhanced immunonephelometry in sera from 132 children with different degrees of renal insufficiency, 5 of whom had lymphoproliferative disease. Renal function was assessed using the Schwartz formula. RESULTS: Beta2M/Cys was constant between 1.2 and 2.4 mg/mg for Schwartz GFR > or = 40 ml/min x 1.73 m2. With lower GFR, beta2M/Cys rose progressively, maximum values being found in the hemodialysis patients (4.85-11.73). Healthy renal transplant recipients had beta2M/Cys comparable to controls. With acute lymphoproliferative disease, all but one patient had significantly elevated beta2M/Cys between 2.68 and 3.68 mg/mg, which returned to normal in remission (1.67-2.35 mg/mg). The sensitivity of a beta2M/Cys ratio > 2.4 mg/mg for the detection of PTLD was 80%, the specificity 100%, positive predictive value 100%, negative predictive value 90%. CONCLUSION: The beta2-microglobulin/cystatin C ratio is a promising parameter of lymphoproliferation in patients with normal or mildly impaired renal function.

Prolonged awakening and pulmonary edema after general anesthesia and naphazoline application in an infant.

IMPLICATIONS: Naphazoline intoxication by intrabronchial overdose caused prolonged unconsciousness of an 18-mo-old child after general anesthesia for tracheal rigid bronchoscopy. The leading symptoms were side effects involving the cardiovascular, pulmonary, and central nervous systems. Intensive care unit admission with the need for mechanical ventilation was necessary. Recovery was uneventful.