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H Schäfer

Publications and source records attributed to H Schäfer.

At least 19 recordsLinked to original sources
PubMed2007

No evidence for preferential transmission of common valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor gene (BDNF) in ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable common neurodevelopmental disorder with onset in childhood. A coding SNP (rs6265, Val66Met) of the brain-derived neurotrophic factor gene (BDNF) has recently been associated with ADHD. More specifically, paternal over-transmission of the common Val66 allele to affected children had been observed. We aimed to confirm these findings in a large, sufficiently powered, and well characterized German ADHD family sample. The Val66Met polymorphism of BDNF was genotyped in 294 families comprising one or more affected sibs (468 children). Contrary to previous reports, we did not observe over-transmission of the common Val66 allele, from either parent to affected children. We did not find support for an involvement of the Val66 allele of the Val66Met polymorphism of BDNF in the pathogenesis of ADHD in our sample.

Attention Deficit Disorder with Hyperactivity↗
PubMed2006

Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample.

Alterations in the serotonergic pathway have been implicated in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate seven genetic variants in three genes (serotonin transporter (5-HTT), serotonin receptor 1B (5-HTR1B) and serotonin receptor 2A (5-HTR2A)), which have previously been shown to be associated with ADHD. The polymorphisms under investigation were the 5-HTTLPR, the VNTR in intron 2 and the 3'UTR SNP in 5-HTT, the 5-HTR1B variations 861G>C and 102T>C, and the 5-HTR2A variations His452Tyr and 1438G>A. We genotyped these variants in a sample of 102 families with 229 children with ADHD according to DSM-IV criteria. Among the affected children, 69% fulfilled criteria for the combined type, 27% for the predominantly inattentive type, and 4% for the predominantly hyperactive-impulsive type. Associations were tested by the pedigree transmission disequilibrium test (PDT). All investigated polymorphisms in serotonergic candidate genes showed no association to ADHD in our sample. Earlier studies of these polymorphisms had also shown inconsistent results, with some studies reporting significant associations and others demonstrating no association. This discordance between studies may reflect variation in patient ascertainment criteria, genetic heterogeneity, too low statistical power for the expected effects or false positive results in the initial reports. We cannot rule out the possibility that other variations in the investigated genes contribute to the etiology of ADHD.

Adult↗
PubMed2006

Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid tumor progression, high metastatic potential and profound chemoresistance. We recently reported that induction of a chemoresistant phenotype in the PDAC cell line PT45-P1 by long-term chemotherapy involves an increased interleukin 1 beta (IL1beta)-dependent secretion of nitric oxide (NO) accounting for efficient caspase inhibition. In the present study, we elucidated the involvement of L1CAM, an adhesion molecule previously found in other malignancies, in this NO-dependent chemoresistance. Chemoresistant PT45-P1res cells, but not chemosensitive parental PT45-P1 cells, express high levels of L1CAM in an ILbeta-dependent fashion. PT45-P1res cells subjected to short interfering RNA (siRNA)-mediated L1CAM knock-down exhibited reduced inducible nitric oxide synthase expression and NO secretion, as well as a significant increase of anti-cancer drug-induced caspase activation, an effect reversed by the NO donor S-nitroso-N-acetyl-D,L-penicillamine. Conversely, overexpression of L1CAM in PT45-P1 cells conferred anti-apoptotic protection to anti-cancer drug treatment. Interestingly, L1CAM ectodomain shedding, in example, by ADAM10, as reported for other L1CAM-related activities, seemed to be dispensable for anti-apoptotic protection by L1CAM. Neither the shedded L1CAM ectodomain was detected in chemoresistant L1CAM-expressing PT45-P1 cells nor did the administration of various metalloproteinase inhibitors affect L1CAM-dependent chemoresistance. Immunohistochemical analysis revealed L1CAM expression in 80% of pancreatic cancer specimens, supporting a potential role of L1CAM in the malignancy of this tumor. These findings substantiate our understanding of the molecular mechanisms leading to chemoresistance in PDAC cells and indicate the importance of L1CAM in this scenario.

Adenocarcinoma↗
PubMed2006

Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1beta and NO lead to inactivation of caspases.

Pancreatic cancer exhibits profound chemoresistance resulting either from pre-existing (intrinsic) mechanisms, or from anticancer drug treatment itself (acquired chemoresistance). To identify molecular alterations leading to acquired chemoresistance, the chemosensitive pancreatic carcinoma cell line PT45-P1 was exposed to low-dose treatment with etoposide for 6 weeks. Afterwards, these cells (PT45-P1res) were much more resistant to high-dose treatment with anticancer drugs than parental cells. Among several differentially expressed genes in PT45-P1res cells, IL-1beta was most significantly upregulated, a finding in line with our previous observation that IL-1beta accounts for intrinsic chemoresistance of pancreatic carcinoma cells. Elevated IL-1beta expression in PT45-P1res cells was confirmed by real-time PCR and ELISA, and treatment with the IL-1 receptor antagonist restored drug-induced apoptosis. The increased IL-1beta secretion was accompanied by an elevated formation of nitric oxide (NO) and a NO-dependent inhibition of the etoposide-induced caspase-3/-7/-8/-9 activity. Caspase activation was restored either by the iNOS inhibitor 1400W, the reducing agent dithiothreitol or the IL-1 receptor antagonist, resulting in greater sensitivity towards anticancer drug treatment. Conversely, IL-1beta or the NO-donor SNAP decreased caspase activation and apoptosis in etoposide-treated PT45-P1 cells. These data confirm IL-1beta and NO as determinants of chemoresistance in pancreatic cancer, and indicate that the intrinsic and acquired chemoresistance rely to some extent on common molecular targets beneficial for improved therapeutical strategies.

Antineoplastic Agents↗
PubMed2006

Tracheal allograft transplantation in rats: the role of different immunosuppressants on preservation of respiratory epithelium.

BACKGROUND: Bronchiolitis obliterans is the most significant complication adversely affecting the survival of lung allograft recipients. Injury and loss of epithelium are associated with obliteration of the airway lumen. The aim of this study was to examine the effects of various immunosuppressants on airway epithelium. METHODS: Tracheae from Brown Norway donors were heterotopically transplanted into the greater omentum of Lewis (allografts) or Brown Norway (isografts) animals. Recipients were treated for 28 days with FK778 (20 mg/kg), tacrolimus (4 mg/kg), or sirolimus (2 mg/kg). Tracheal segments were evaluated for the degree of luminal occlusion as well as the type and percent of luminal epithelial cell coverage. RESULTS: All agents inhibited peritracheal infiltration and luminal obliteration. Tacrolimus- more than sirolimus-treated recipients showed partial preservation of the luminal epithelial coverage, whereas animals that received FK778 showed no respiratory epithelium. The epithelial loss was accompanied by the appearance of fibrous tissue, which replaced the mucosa. CONCLUSIONS: Tacrolimus as well as sirolimus effectively prevented the development of obliterative airway disease whereas tacrolimus and, to a lesser degree, sirolimus preserved epithelial cells as a source of protective cytokines. With FK778 significant airway obliteration was suppressed despite complete epithelial loss. Thus, FK778-treated animals displayed an epithelial-independent inhibitory effect on myofibroblast proliferation.

Animals↗
PubMed2006

Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with -7/del7q and 11 with normal karyotype) with 23 CD34+ preparations from healthy bone marrow donors. SKI, a nuclear oncogene, was highly up regulated. In a second set of 183 AML patients analyzed with real-time PCR, the highest expression level of SKI in AML with -7/del7q could be confirmed. As previously described, Ski associates with the retinoic acid receptor (RAR) complex and can repress transcription. We wanted to investigate the interference of Ski with RARalpha signaling in AML. Ski was co-immunoprecipitated and colocalized with RARalpha. We also found that overexpression of wild-type Ski inhibited the prodifferentiating effects of retinoic acid in U937 leukemia cells. Mutant Ski, lacking the N-CoR binding, was no more capable of repressing RARalpha signaling. The inhibition by wild-type Ski could partially be reverted by the histone deacetylase blocking agent valproic acid. In conclusion, Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARalpha signaling.

Acute Disease↗
PubMed2006

A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs.

Three groups have previously performed genome scans in attention-deficit/hyperactivity disorder (ADHD); linkage to chromosome 5p13 was detected in all of the respective studies. In the current study, we performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17 cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39 cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in our sample the DAT1 VNTR did not show association with ADHD. We additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent.

Adolescent↗
PubMed2006

[Combined laparoscopic/endoscopic treatment of gastric stroma tumors].

INTRODUCTION: Surgical therapy of Gastrointestinal stroma tumor (GIST) is the treatment of choice. Local resection will be carried out if technically possible. We describe the technique of laparoscopic wedge resection combined with intraoperative gastroscopy in order to achieve complete tumor resection. METHOD: We report on 4 cases with gastrointestinal stroma tumors which were located in the gastric corpus (n = 2) and the cardia (n = 2). RESULTS: In all patients the tumor could be removed completely without any perioperative complications using laparoscopic wedge resection controlled by intraoperative endoscopy. The duration of hospitalisation after operation was 7 days (5-10). On the basis of the mean tumor size (mean 3.8 cm) and the low mitotic activity (mean 2.75/high power fields) the tumors belong to the group with low malignant potential. There is no evidence of recurrence after a mean follow up period of 23 (6-30) months. CONCLUSION: Combined laparoscopic/endoscopic wedge resection is a safe method for total resection of GIST of the stomach and should be preferred as alternative to open surgery.

Follow-Up Studies↗
PubMed2006

[Mutation in factor II and factor V gene in patients with peripheral arterial occlusive disease].

Mutations in factor-V- and factor-II-genes are correlated with an increased risk for venous thrombosis according to the literature. The significance of the mutations in factor- II- and factor-V-genes for the development of the peripheral arterial occlusive disease is not known. Therefore, we investigated the presence of these mutations in 152 patients with documented peripheral arterial occlusive disease and 318 controls without peripheral arterial occlusive disease with polymerase chain reaction (PCR). There was no association between factor-II-mutation and peripheral arterial occlusive disease. The factor-V-mutation, however, was increased in patients with peripheral arterial occlusive disease double fold (12 positive cases in 318 controls, 12 positive cases in 152 patients with peripheral arterial occlusive disease). The significance level was reached (p = 0.05) in statistical analysis but the result did not fall below the significance level as necessary to reach statistical significance (odds ratio 2.19). Nevertheless, from these data we have to discuss a biological relevance of factor-V-mutation in the pathogenesis of peripheral arterial occlusive disease.

Arterial Occlusive Diseases↗
PubMed2005

Influence of obstructive sleep apnea on heart rate turbulence.

BACKGROUND: Patients with obstructive sleep apnea (OSA) are at increased risk for cardiovascular disease. Increased sympathetic drive is considered as one of the underlying mechanisms. Both heart rate turbulence (HRT) and heart rate variability (HRV) are parameters to describe autonomic regulation. We investigated the influence of sleep-disordered breathing (SDB) on HRT and HRV in patients with OSA. METHODS: Sixty-five patients underwent overnight polysomnography for clinically suspected SDB and simultaneous Holter monitoring (11 p.m.-6 a.m.). Patients with diabetes mellitus, a history of cardiac disease, left ventricular dysfunction, periodic breathing pattern, and those on beta-blockers or theophylline were excluded. According to the apnea-hypopnea index (AHI), the patients were assigned to group A (AHI <20, n = 31) or group B (AHI > or =20, n = 34). HRV (time domain, frequency domain) and HRT (onset, slope) were then related to the severity of SDB. RESULTS: Nighttime turbulence slope (TS) correlated inversely with the AHI (r = -0.45, p = 0.01) and was significantly lower in group B (8.9 +/- 1.6 ms/R-R interval) compared with that in group A (19.8 +/- 4.0 ms/R-R interval, P = 0.01). This relationship remained stable after adjusting TS for the number of ventricular premature contractions. No significant differences in turbulence onset or parameters of nighttime HRV were observed. CONCLUSIONS: Alterations in nighttime HRT correlate with the severity of SDB, indicating abnormalities in cardiac autonomic activity in moderate-to-severe OSA even in the absence of overt cardiac disease. These changes may be associated with the subsequent development of cardiovascular disease.

Adult↗
PubMed2005

[Submucosal infiltration and local recurrence in pT1 low-risk rectal cancer treated by transanal endoscopic microsurgery].

BACKGROUND: The association between submucosal infiltration and tumor recurrence was analyzed by long-term follow-up of patients with pT1 "low risk" rectal carcinoma. PATIENTS AND METHODS: Forty patients with pT1 rectal cancer of the upper and middle rectum were treated by transanal endoscopic microsurgery. All carcinomas fulfilled the low-risk criteria, and were completely resected. No further treatment was carried out. Follow-up data were available for all 40 patients, with a median follow-up of 5.4 years. RESULTS: Two patients (5.0%) developed local tumor recurrence after 14 and 18 months, respectively, and had curative rectal resection after neoadjuvant radiochemotherapy. In the histology of the initial specimens, both patients had deep submucosal infiltration (sm3). Another patient, primarily sm2 without local recurrence, developed a metachronous singular liver metastasis which was curatively resected. The risk of developing a recurrent tumor was significant for sm3 carcinomas (sm1+sm2 vs sm3, P=0.046). CONCLUSION: Transanal endoscopic microsurgery is an excellent method of treating low-risk pT1 carcinomas of the rectum. Deep submucosal infiltration (sm3) seems to be an additional high-risk factor for developing local recurrence.

Adult↗
PubMed2005

Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2's regulatory region (rs4570625, P=0.049; rs11178997, P=0.034), but not for the third SNP in intron 2 (rs4565946, P=0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P=0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes.

Adolescent↗
PubMed2004

[Preoperative colonoscopy before esophagectomy and reconstruction with gastric interposition].

INTRODUCTION: The standard treatment of esophageal carcinoma is esophagectomy and reconstruction with gastric interposition. In many centers, preoperative colonoscopy is routinely performed in order to exclude any significant colonic pathology. This is important in case of the intraoperative necessity to use a colon interposition due to gastric pathology, anatomical variation, or injury of gastric vascularization. PATIENTS AND METHODS: Two hundred twenty-eight consecutive patients with esophageal carcinoma (adenocarcinoma 102, squamous cell carcinoma 126) who underwent esophagectomy were included in this study. Of them, 171 (75%) had preoperative colonoscopy. Reconstruction was done by gastric tube in 219 and colon interposition in nine. RESULTS: Intraoperative conversion to colon interposition was necessary in none of the 219 patients with intended reconstruction by a gastric conduit. In two of 171 patients (1.2%), preoperative colonoscopy revealed pT1 adenocarcinomas of the colon which were completely removed by endoscopy, and a total of 62 adenomas were histopathologically diagnosed. Fifty-three patients (31%) had endoscopic evidence of asymptomatic diverticulosis. No complications were observed after colonoscopy. CONCLUSION: Preoperative colonoscopy prior to esophagectomy and intended gastric tube formation appears unnecessary from the surgical point of view, as intraoperative conversion to a colon interposition is rare. The rate of colon adenomas or carcinomas was not increased in patients with adeno- or squamous cell carcinoma of the esophagus than in an age-matched, normal population.

Adenocarcinoma↗
PubMed2004

First case of isolated small bowel transplantation at the university of cologne: rejection-free course under quadruple immunosuppression and endoluminal monitoring with video-capsule.

Intestinal transplantation is the only curative form of treatment for fulminant short bowel syndrome. Results have been hampered by frequent rejection episodes as well as technical and infectious complications. We report the first case of complete small bowel transplantation performed at our institution. A 37-year-old male patient suffered from massive gut infarction due to a superior mesenteric artery embolus from a thrombus in the descending aorta resulting from hereditary protein S and C deficiency. The primary surgery resulted in a duodenocolostomy requiring total parenteral nutrition. The course was further complicated by multiple central line infections and pre-renal kidney failure induced by dehydration. After 17 months, we performed a cadaveric small bowel transplant using systemic venous drainage. The ileum was anastomosed end-to-end to the recipient ascending colon. The proximal jejunum was used to create a jejunostomy, with an end-to-side duodenojejunostomy. Immunosuppression consisted of a single-administration of antithymocyte globulin (ATG), tacrolimus, mycophenolate mofetil (MMF), and methylprednisolone given enterally from day 1. Biopsies of the upper jejunum showed no signs of rejection. The graft was monitored via capsule video endoscopy after 9 weeks and appeared normal. The patient was discharged on day 35, completely on an enteral diet and gaining weight with a good quality of life. Oral valganciclovir was given for the cytomegalovirus prophylaxis infection (donor-positive, recipient-negative constellation), with no clinical or serologic signs of infection. The early course after small bowel transplantation using a quadruple regimen was clinically successful. The use of video-capsules allows for noninvasive visual monitoring of bowel segments that cannot be reached endoscopically.

Adult↗
PubMed2004

The expression of immediate early gene X-1 (IEX-1) is differentially induced by retinoic acids in NB4 and KG1 cells: possible implication in the distinct phenotype of retinoic acid-responsive and -resistant leukemic cells.

In a cell-type- and stimulus-dependent fashion, the early response gene immediate early gene X-1 (IEX-1) is involved in growth control and modulation of apoptosis. The present study demonstrates that, in the two acute promyelocytic leukemia (APL) cell lines NB4 and KG1, exhibiting distinct responsiveness to retinoic acids (RAs), IEX-1 expression is rapidly (30-60 min) induced by all-trans- or cis-RA and independently of other signal transduction mediators, such as TNFalpha, NF-kappaB or MAP kinases. In NB4 cells (expressing PML-RARalpha), this increase is transient and completely reversible, along with a cell cycle arrest, ongoing differentiation and lower sensitivity to anti-cancer-drug-induced apoptosis. In contrast, the RA-induced IEX-1 expression in KG1 cells (expressing PLZF-RARalpha) persists over days, along with continued cell cycle progression and increased apoptotic sensitivity. Furthermore, two functional RA-response elements in the IEX-1 promoter were identified by gel shift and luciferase reporter gene assays. IEX-1 might be a rather unique transcriptional target of the two X-RARalpha fusion receptors exhibiting distinct responsiveness to RAs. Following a different time course of direct transcriptional induction by PML-RARalpha and PLZF-RARalpha in NB4 and KG1 cells, respectively, IEX-1 expression may be involved in the modified actions of these receptors and the distinct phenotypes of APL cells.

Antineoplastic Agents↗
PubMed2004

Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations.

Recently, Branson and coworkers reported a strong association between binge-eating disorder (BED) and variants in the melanocortin-4 receptor gene (MC4R). In the current study, we compared the eating behavior of 43 obese probands with functionally relevant MC4R mutations and of 35 polymorphism carriers (V103I or I251L) with wild-type carriers. The module for eating disorders of the Composite International Diagnostic Interview was used to identify binge-eating behavior. The Three-Factor Eating Questionnaire and the Leeds Food Frequency Questionnaire were used to assess restrained eating, disinhibition, hunger and percent total energy intake as fat. No significant differences between carriers of MC4R variants and wild-type carriers were detected. In particular, we found no evidence for an increased rate of binge-eating behavior in obese carriers of MC4R variants. Our findings do not support the strong association between BED and MC4R carrier status.

Adolescent↗