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S Neumann

Publications and source records attributed to S Neumann.

At least 19 recordsLinked to original sources
PubMed2006

An aromatic environment in the vicinity of serine 281 is a structural requirement for thyrotropin receptor function.

The majority of constitutively activating human TSH receptor (hTSHR) mutations are located in the transmembrane helices as well as in the extracellular (ECLs) and intracellular loops. S(281) is one of two positions in the ectodomain in which activating hTSHR mutations have been identified in vivo (S(281)T, I, and N). To investigate the functional properties of this key residue in more detail, S(281) was replaced by each of the other 19 amino acids. Many substitutions led to constitutive receptor activation, suggesting that S(281) plays a pivotal role in maintaining the receptor in its inactive state. Strikingly, all substitutions with aromatic residues (S(281)W, F, Y, and H) show expression similar to that of wild-type hTSHR and are tolerated at this position because they maintain basal activity or express only slight constitutive activity. Three-dimensional modeling of the hTSHR suggested that S(281) and surrounding residues are in close proximity to ECL1. To investigate the possible importance of an aromatic environment between the ectodomain in the vicinity of S(281) and ECL1, aromatic residues Y(279), Y(476), H(478), Y(481), Y(482), and H(484) were replaced by alanine. Functional characterization showed impaired cell surface expression and signaling for Y(279)A and Y(481)A, in contrast to the other alanine mutants. However, substitutions of Y(279) and Y(481) with other aromatic residues exhibited surface expression and signaling comparable to wild-type hTSHR. Our results suggest that Y(279) in the extracellular domain and probably Y(481) in the ECL1 also are involved in an aromatic environment around S(281) in the hTSHR, which is important for functional receptor conformation and intramolecular receptor signaling.

Animals↗
PubMed2005

Use of an endoscopic suturing device (the "ESD") to treat patients with gastroesophageal reflux disease, after unsuccessful EndoCinch endoluminal gastroplication: another failure.

BACKGROUND: Endoluminal gastroplication, using the EndoCinch procedure, has emerged as a potential endoscopic antireflux therapy. Although initial results have been promising, the long-term durability of the treatment is uncertain due to suture loss. A new endoscopic suturing device, the "ESD," has been developed that promises excellent visibility and endoscopic control. The aim of this study was to evaluate prospectively the feasibility and efficacy of the ESD method after EndoCinch failure. METHODS: The study involved 20 patients with gastroesophageal reflux disease (GERD), who had been initially treated with an EndoCinch procedure, but had relapsed after a median of 7.5 months, with lost or dysfunctional sutures and with reflux symptoms that required proton pump inhibitor (PPI) treatment. Using the ESD, at least three plications were created at the gastroesophageal junction. Patients underwent endoscopy, 24-hour pH monitoring and esophageal manometry before treatment and 6 months afterwards. In addition, reflux symptoms as well as quality-of-life scores were assessed (using the SF-6 and GERD-HRQL scales). RESULTS: The ESD procedure (median procedure time 45 min) was performed successfully in all patients without major complications. After 6 months only one patient (5 %) still had all sutures in situ, while no remaining sutures could be detected in 3/20 (15 %). No significant changes in reflux esophagitis; 24-hour pH monitoring results (median pH < 4/24 h9.9 % vs. 12.3 %; P = 0.60); manometry findings (median lower esophageal sphincter pressure 7.2 mm Hg vs. 9.9 mm Hg; P = 0.22); PPI use; or reflux esophagitis could be detected after 6 months. While reflux symptoms improved (heartburn severity score 30 vs. 48, P < 0,05), no changes in quality-of-life scores were detected. CONCLUSIONS: Endoluminal gastroplication using the ESD is an easy and safe, but unfortunately ineffective procedure for endoscopic GERD treatment. Endoluminal gastroplication techniques clearly need refinements before these therapies can evolve as a treatment option for GERD patients.

Adult↗
PubMed2005

Long term failure of endoscopic gastroplication (EndoCinch).

INTRODUCTION: Endoluminal gastroplication (EndoCinch; Bard) has been introduced as an endoscopic treatment option in gastro-oesophageal reflux disease (GORD) patients with promising short term results. However, little is known about the long term efficacy of endoscopic suturing. The aim of this study was to evaluate prospectively the long term outcome after EndoCinch. PATIENTS AND METHODS: A total of 70 patients treated with EndoCinch at a single referral centre were studied prospectively. All patients were interviewed using a standardised questionnaire regarding their symptoms and medication prior to and 18 months after EndoCinch. In addition, follow up included endoscopy, 24 hour pH monitoring, and oesophageal manometry. RESULTS: The procedure was well tolerated without major short or long term complications. Eighteen months after EndoCinch, 56/70 patients (80%) were considered treatment failures as their heartburn symptoms did not improve or proton pump inhibitor medication exceeded 50% of the initial dose. Endoscopy showed all sutures in situ in 12/70 (17%) patients while no remaining sutures could be detected in 18/70 (26%). In 54 and 50 patients examined, respectively, no significant changes in 24 hour pH monitoring (median pH <4/24 hours, 9.1% v 8.5%; p = 0.82) or lower oesophageal sphincter (LOS) pressure (7.7 v 10.3 mm Hg; p = 0.051) were observed while median LOS length slightly increased (3.0 to 3.2 cm; p<0.05). CONCLUSION: Endoscopic gastroplication (EndoCinch) is a safe and minimally invasive endoscopic treatment for GORD with reasonable short term results. In contrast, long term outcome is disappointing, probably due to suture loss in the majority of patients. Therefore, technical improvements to ensure suture durability are mandatory before endoscopic suturing can evolve as a therapeutic option for GORD treatment.

Adult↗
PubMed2005

[Serum creatine kinase activity in dogs and cats with metabolic diseases].

Elevated Creatine kinase-activitiy (CK) indicates disturbances of the muscle cell integrity. In addition to primary muscle disease, like trauma, inflammation or dystrophy, diseases of other organs can lead to secondary muscle involvement, which will be indicated by increased serum activities of the CK. The mechanisms of muscle cell disturbance are still unknown. An elevated protein catabolism in the muscle cell is suspected. In the present study we investigated, if dogs and cats with metabolic diseases have increased CK-activity in the serum. From 34 dogs and cats in a group with different metabolic diseases without metabolic acidosis 19% of the dogs and 50% of the cats had increased CK-activity in the serum. From 33 dogs and cats with different metabolic diseases connected with metabolic acidosis 86% of the dogs and 95% of the cats had simultaneously increased CK-activity in the serum. In comparison to healthy dogs and cats animals with metabolic diseases have significant and in cases of metabolic di-seases with metabolic acidosis cats have high significant elevation (dogs significant) of CK-activity in the serum. There was no significant correlation between the groups of patients. In conclusion we think that our results show that metabolic diseases often induce secondary myopathy, measured by CK-activity in the serum, but metabolic acidosis has no direct influence on elevated CK activity in dogs and cats.

Acidosis↗
PubMed2004

[Pancreatico-pleural fistula in chronic pancreatitis with necrosis of the pancreatic tail].

HISTORY AND CLINICAL FINDINGS: A 68-year-old male was admitted to the hospital with progressive dyspnea and thoracic pain radiating to the shoulder, back and upper abdomen. The patients medical history included hypertension, diabetes and chronic pancreatitis with splenic vein thrombosis. INVESTIGATIONS: Laboratory findings showed no signs of myocardial infarction, but pronounced inflammation. The ECG was normal. Chest X-ray revealed a massive left-side pleural effusion with partial lung atelectasis. An abdominal CT-scan showed no signs of acute pancreatitis. Puncture of the pleural effusion revealed elevated amylase and lipase. ERCP showed pancreatic duct stenosis, partial necrosis of the pancreatic body and peripancreatic necrosis with a pancreatico-pleural fistula. TREATMENT AND CLINICAL COURSE: After ballon-dilatation of the constricted pancreatic duct, a plastic stent and a nasopancreatic drain were inserted into the necrosis and into the fistula. Drainage and antibiotic therapy led to regression of the necrosis within 3 weeks. With external pleural drainage and octreotide therapy almost complete regression of the pleural effusion and closure of the pancreatico-pleural fistula could be achieved within 3 weeks. CONCLUSION: Complications of chronic pancreatitis such as necrosis and fistulas are rare, but important differential diagnoses in patients with chronic pancreatitis and chest pain. A combination of transpapillary or transgastral endoscopic drainage procedures and pleural drainage, sometimes with additional octreotide therapy is the treatment of choice.

Aged↗
PubMed2004

[26-year-old patient with ulcerative colitis and anemia].

A 26-year-old patient was admitted to the hospital because of severe anemia and exacerbation of ulcerative colitis. Laboratory tests revealed a hemolytic anemia and elevated parameters of acute phase reaction. Ten months ago an autoimmune hemolytic anemia was diagnosed. Three months before admission splenectomy was performed due to ongoing hemolytic exacerbations despite treatment with corticosteroids. Anemia is a common problem of inflammatory bowel disease. The association of autoimmune hemolytic anemia and ulcerative colitis presented in this case report is a rare complication of ulcerative colitis. The autoimmune hemolytic anemia is often refractory to corticosteroids. Immunosuppressive treatment with azathioprine induced a sustained remission in our patient, thereby a total colectomy could be avoided.

Adult↗
PubMed2004

Endoluminal gastroplication: what are the predictors of outcome?

BACKGROUND: Endoluminal gastroplication (EndoCinch) has emerged as an endoscopic anti-reflux therapy, but predictive factors for symptom relief have not been established. The aim of this study was to evaluate the major determinants to predict outcome in patients treated with EndoCinch. METHODS: A total of 53 consecutive patients, treated with EndoCinch at a single center were included in this prospective study. Inclusion criteria were symptoms of chronic heartburn, dependency on proton-pump inhibitors, documented pathological esophageal acid exposure, and a hiatal hernia smaller than 3 cm in length. All patients underwent endoscopy, 24-h pH monitoring, esophageal manometry, barium esophagram, and a detailed questionnaire regarding their symptoms before treatment. Patients were stratified into a responder and a non-responder group using a questionnaire at 3-month follow-up. A multivariate analysis was performed. RESULTS: The success rate was 64% (34/53 patients). Three variables weresignificantly predictive for successful endoscopic anti-reflux treatment at the multivariate level: presence of typical symptoms (P=0.01), complete symptom relief with acid suppressive therapy (P=0.01), and normal lower esophageal sphincter pressure (P = 0.04). Not predictive of outcome were age, body mass index, esophagitis, other manometric findings, hiatal hernia size, or pathological level of pH <4/24 h. Barium esophagram did not add any additional predictive information. CONCLUSIONS: Since no single factor can predict outcome after EndoCinch, a careful patient selection is mandatory to maximize the success rate. The ideal candidate for EndoCinch is a gastroesophageal (GERD) patient with a normal lower esophageal sphincter pressure, whose typical symptoms completely resolved with acid suppressive therapy.

Adult↗
PubMed2004

Number size distribution, mass concentration, and particle composition of PM1, PM2.5, and PM10 in bag filling areas of carbon black production.

Number size characteristics and PM10 mass concentrations of particles emitted during the packaging of various kinds of carbon blacks were measured continuously in the bag filling areas of three carbon black plants and concurrently at ambient comparison sites. PM10, PM2.5, and PM1 dust fractions were also determined in the bag filling areas. The filter samples were then analyzed for elemental and organic carbon. Comparisons of the measured number size distributions and mass concentrations during bag filling activities with those measured parallel at the ambient site and with those determined during nonworking periods in the work area enabled the characterization of emitted particles. PM10 mass concentrations were consistently elevated (up to a factor of 20 compared to ambient concentrations) during working periods in the bag filling area. Detailed analysis revealed that the carbon black particles released by bag filling activities had a size distribution starting at approximately 400 nm aerodynamic diameter (dae) with modes around 1 microm dae and > 8 microm dae. Ultrafine particles (< 100 nm dae), detected in the bag filling areas, were most likely attributed to noncarbon black sources such as forklift and gas heater emissions.

Air Pollution, Indoor↗
PubMed2003

No association between the angiotensin-converting-enzyme gene insertion/deletion polymorphism and the occurrence of macroangiopathy in patients with diabetes mellitus type 2.

Previous studies have reported an association between the ACE-I/D-polymorphism and coronary heart disease (CHD) in patients with diabetes mellitus. However, ACE inhibitor treatment, which could have compensated for negative effects of the D/D form of the ACE gene polymorphism, was not considered in the studies. We investigated the influence of the ACE-I/D polymorphism and the ACE inhibitor treatment in patients with diabetes mellitus on the occurrence of CHD by multiple-regression analysis. Distribution of the ACE gene I/D-polymorphism was investigated in 691 patients with diabetes mellitus prospectively characterised for the presence/absence of coronary heart disease. The distribution of DD; ID; II genotypes was 105 vs. 202 vs. 102 (25.7 % vs. 49.4 % vs. 24.9) in the CHD + group and 55 vs. 160 vs. 67 (19.5 % vs. 56.7 % vs. 23.8 %) in the CHD - group, respectively (p = 0.1). A multiple logistic regression analysis introducing the typical risk factors for CHD (age, gender, smoking, BMI > 26 kg/m 2, LDL elevation, HbA1c > 7 %) could not identify the ACE gene I/D-polymorphism as an independent risk factor for CHD (p = 0.87). Our data therefore suggest that the ACE gene I/D polymorphism is not associated with the occurrence of diabetic macroangiopathy in patients with or without treatment of ACE inhibitors.

Adult↗
PubMed2002

Gene cloning, overexpression and biochemical characterization of the peptide amidase from Stenotrophomonas maltophilia.

The peptide amidase (Pam) from the gram-negative bacterium Stenotrophomonas maltophilia catalyzes predominantly the hydrolysis of the C-terminal amide bond in peptide amides. Its gene ( pam) was isolated by Southern hybridization using a DNA probe derived from the known N-terminal amino acid sequence. Pam is a member of the amidase signature family and was identified as a periplasmic protein by an N-terminal signal peptide found in the gene. The processed protein consists of 503 amino acids with a molecular mass of 53.5 kDa. The recombinant enzyme with a C-terminal His(6) tag has a monomeric structure and its isoelectric point is 6.3. The dipeptide amide L-Ala- L-Phe-NH(2) is hydrolyzed in the absence of cofactors to L-Ala- L-Phe-OH and ammonia with V(max)=194 U/mg and K(m) <0.5 mM. The natural function of Pam remains unclear. Chymostatin ( K(i)<0.3 microM) and Pefabloc SC ( K(i) not determined) were identified as inhibitors. When the gene was expressed in Escherichia coli on a 12-l scale, the specific activity in the crude extract was 60 U/mg, compared to 0.24 U/mg in S. maltophilia. In the expression system, Pam made up about 31% of the total soluble cell protein. From 75 g wet cells, 2.1 g of >95% pure enzyme was obtained, which corresponds to a total activity of 416,000 units.

Amidohydrolases↗
PubMed2002

Adrenocorticotrope deficiency with clinical evidence for late onset in combined pituitary hormone deficiency caused by a homozygous 301-302delAG mutation of the PROP1 gene.

Combined pituitary hormone deficiency (CPHD) can be caused by mutation of the pituitary transcription factors POU1F1 or PROP1. More recently mutations in the HESX1, the LHX3 and LHX4 transcription factor genes have also been described as a cause in patients with CPHD. In most patients the disorder is characterized by an impaired production of GH, TSH, PRL and gonadotropins. In some cases of CPHD adrenocorticotropin deficiency is also present. We report the progressive CPHD and its molecular etiology in a woman with CPHD presenting with first symptoms of ACTH/cortisol deficiency at the age of 48 years. The 49 year old patient's initial symptoms were growth retardation at the age of 2 years and symptoms of hypothyroidism at the age of 5 years. The patient never entered puberty spontaneously. No familial history of delayed puberty, growth retardation or other symptoms of CPHD were present. At the age of 48 years the patient presented with the first symptoms of hypocortisolism such as recurring hypoglycaemias and hyponatriaemia with coma. Cortisol, ACTH, TSH, fT3, fT4 and GH as well as LH, FSH and PRL were measured in basal conditions. GH, cortisol and ACTH were also measured in response to an Insulin Tolerance Test. Molecular analysis was performed by PCR amplification and sequencing of exon 1-3 of the PROP1 gene. The patient had insufficiencies of TSH, LH, FSH and GH. PRL was normal. Serum cortisol was low and basal ACTH was normal. However, there were no responses of cortisol, ACTH and GH to hypoglycaemia. Magnetic resonance imaging showed a hypoplastic anterior pituitary lobe. Direct sequencing revealed a homozygous 2 base-pair deletion 301-302delAG in exon 2 of the PROP1 gene. This case suggests that in patients with CPHD ACTH producing cells may be involved at a rather late age.

Adrenocorticotropic Hormone↗
PubMed2001

Tumor necrosis factor alpha is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes.

Resistin has recently been implicated as an adipocytokine leading to insulin resistance and, therefore, potentially linking obesity and diabetes. To further characterize the regulation of this fat-secreted protein by insulin sensitivity-modulating hormones, 3T3-L1 adipocytes were treated with tumor necrosis factor (TNF) alpha, angiotensin (AT) 2, as well as growth hormone (GH), and resistin gene expression and protein secretion were determined by quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. Interestingly, both, resistin mRNA expression and protein secretion, were inhibited by 70-90% after TNFalpha-treatment whereas AT2 and GH did not have any effect. The inhibitory effect of TNFalpha was time- and dose-dependent with significant inhibition occurring as early as 4 h after effector addition and at concentrations as low as 1 ng/ml TNFalpha. Pharmacological inhibition of protein kinase A (PKA), p44/42, and p38 mitogen-activated protein (MAP) kinase did not reverse the inhibitory effect of TNFalpha suggesting that neither of these signaling molecules is involved in suppression of resistin gene expression by TNFalpha. Furthermore, suppression of resistin mRNA levels could be completely reversed to control levels by withdrawal of TNFalpha for 24 h. Taken together, these results suggest that TNFalpha is a pivotal negative regulator of resistin gene expression. This may have important implications for the pathogenesis of insulin resistance and its link to obesity.

3T3 Cells↗
PubMed2001

Adiponectin gene expression is inhibited by beta-adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes.

Recently, it has been shown that the fat-derived factor adiponectin is downregulated in insulin resistance and obesity and that replenishment of this adipocytokine reverses insulin resistance in mice. Growing evidence, on the other hand, suggests that raised levels of catecholamines due to increased activity of the sympathetic nervous system are an integral part in the development of insulin resistance. To clarify whether catecholamines might exert their insulin resistance-inducing effects at least partly via downregulation of adiponectin gene expression, 3T3-L1 adipocytes were treated with isoproterenol, and adiponectin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. In fact, isoproterenol treatment reduced the level of adiponectin mRNA by about 75% in a dose-dependent fashion with significant inhibition detectable at concentrations as low as 10 nM isoproterenol. Furthermore, the inhibitory effect of isoproterenol was almost completely reversed by pretreatment of 3T3-L1 cells with the beta-adrenergic antagonist propranolol and the protein kinase A (PKA) inhibitor H-89. Moreover, the effects of isoproterenol could be mimicked by stimulation of stimulatory guanine nucleotide-binding (G(S))-proteins with cholera toxin and adenylyl cyclase with forskolin. Thus, our results suggest that adiponectin gene expression is severely suppressed by beta-adrenergic agents via activation of a G(S)-protein-PKA-dependent pathway. The data support a possible role of adiponectin in catecholamine-induced insulin resistance.

3T3 Cells↗
PubMed2001

Thyrotropin receptor mutations as a tool to understand thyrotropin receptor action.

A large number of mutations have been identified in the thyrotropin (TSH) receptor (TSHR) gene causing human diseases. Toxic thyroid nodules are frequently associated with somatic constitutively activating TSHR mutations. Autosomal dominant non-autoimmune hyperthyroidism is caused by activating TSHR germline mutations. Inactivating germline mutations cause TSH unresponsiveness. Discovery of the different TSHR mutations in various regions of the receptor molecule has led to the identification of important domains for intramolecular TSHR signal transduction. However, despite the functional characterization of the naturally occurring mutations the precise molecular mechanisms of receptor activation including the processes of hormone binding, intramolecular signaling between the different TSHR domains and of G protein coupling are not completely understood. This review discusses the importance of the various receptor domains for TSHR activation identified on the basis of the naturally occurring gain or loss of function mutations and in vitro investigations performed with site-directed mutagenesis, synthetic peptides, or antibodies. Several in vitro studies have provided new insights into structure-function relationships by site-directed mutagenesis in combination with molecular modeling. These in vitro investigations have often been guided by naturally occurring mutations and have provided new insights into intramolecular changes during receptor activation. This has led to progress in understanding the mechanism of TSHR activation.

Animals↗
PubMed2001

Isoproterenol inhibits resistin gene expression through a G(S)-protein-coupled pathway in 3T3-L1 adipocytes.

Resistin was recently identified as a hormone secreted by adipocytes which leads to insulin resistance in vivo and in vitro and might therefore be an important link between obesity and diabetes. To clarify the regulation of resistin gene expression, 3T3-L1 adipocytes were treated with various agents known to modulate insulin sensitivity, and resistin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, isoproterenol treatment reduced the level of resistin mRNA to 20% of non-treated control cells. This effect was dose-dependent with significant inhibition occurring at concentrations as low as 10 nM isoproterenol. Moreover, pretreatment of adipocytes with the beta-adrenergic antagonist propranolol almost completely reversed the inhibitory effect of isoproterenol, whereas addition of the alpha-adrenergic antagonist phentolamine did not have any effect. Furthermore, the effect of isoproterenol could be mimicked by activation of G(S)-proteins and adenylyl cyclase. Thus, both cholera toxin and forskolin decreased resistin mRNA expression in a dose-dependent fashion by up to 90% of control levels. Taken together, these results suggest that resistin gene expression is regulated by a protein kinase A-dependent pathway in 3T3-L1 adipocytes.

3T3 Cells↗
PubMed2001

A small dose of droperidol decreases postoperative nausea and vomiting in adults but cannot improve an already excellent patient satisfaction.

BACKGROUND: We evaluated whether or not 1) a routine prophylaxis with 20 microg x kg(-1) body weight of droperidol would efficiently prevent postoperative nausea and vomiting (PONV) after elective surgery in adults and 2) an efficient prophylaxis would improve patient satisfaction. METHODS: With approval of the local ethics committe and after having obtained informed written consent, 1334 patients in a randomised, single-blinded fashion either received droperidol (group 1, n=665) or saline intravenously (group 2, n=669) 20 min before the end of a standard O2/N2O/fentanyl/isoflurane anaesthesia of at least 30 min duration. END POINTS: incidence of PONV during the first 24 h; individual episodes of nausea or vomiting, overall patient satisfaction with the procedure. RESULTS: Compared to saline, intravenous injection of droperidol substantially and significantly reduced the incidence of PONV from 30% to 20% (P<0.0001). Women suffered three times more frequently from PONV (10.5% vs. 30%, P<0.0001). Droperidol significantly reduced the incidence of PONV from 35.4% to 24.4% in women (relative risk reduction: 31%, P=0.0002), but not in men (13.1% vs. 8.2%, relative risk reduction: 37%, P=0.159)--without impact on overall patient satisfaction (98.8% vs. 97.1%, P=0.439). Distribution of surgical procedures, sex, age, height, weight and anaesthetic duration were not different between groups. To prevent one woman from suffering PONV, nine had to be treated prophylactically at an individual drug cost (German prices) of about Euro0.80 per woman. CONCLUSION: Routine PONV prophylaxis with 20 microg x kg(-1) body weight of droperidol is cost-efficient and appropriate in women but not in men.

Adult↗