Search PubMed⌕ Search

Biomedical subjects

S Schreiber

Publications and source records attributed to S Schreiber.

At least 163 records · Page 9Linked to original sources
PubMed1998

The interferon-gamma gene as a positional and functional candidate gene for inflammatory bowel disease.

Epidemiological and genome-wide linkage analyses have provided firm evidence for a genetic component in the pathogenesis of inflammatory bowel disease. The linkage regions on chromosomes 12 and 16 have been replicated in several independent samples. These represent the best positional evidence in the search for inflammatory bowel disease susceptibility genes. While systematic association and physical mapping studies in these regions are under way, the direct analysis of immunologically relevant genes as positional and functional candidates may provide a shortcut in this process. The interferon-gamma gene resides in the chromosome 12 linkage region near the marker D12S83. Interferon-gamma is an important proinflammatory cytokine in the interleukin-12 cascade and has been implicated in the pathogenesis of mucosal inflammation. We tested this gene for evidence of linkage and association in 133 German multiplex families and 506 single patients with their parents. An intragenic, highly informative CA-repeat marker in intron 1 of the gene was typed using fluorescence-labeled polymerase chain reaction and analysis on an automated sequencer. In the nonparametric linkage analysis using GENEHUNTER, a nonsignificant maximum LOD score of 0.67 was obtained. The transmission disequilibrium test for association was negative (P > or = 0.22) for Crohn's disease, ulcerative colitis, and the combined inflammatory bowel disease phenotype. In summary, the findings make interferon-gamma a very unlikely candidate for the major susceptibility gene in the chromosome 12 linkage interval. Future efforts can concentrate on other transcripts in the region.

Base Sequence↗
PubMed1998

Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a complex disorder of unknown etiology. Epidemiological investigations suggest a genetic basis for IBD. Recent genetic studies have identified several IBD linkages. The significance of these linkages will be determined by studies in large patient collections. The aim of this study was to replicate IBD linkages on chromosomes 12 and 16 in a large European cohort. METHODS: Three hundred fifty-nine affected sibling pairs from 274 kindreds were genotyped using microsatellite markers spanning chromosomes 12 and 16. Affection status of the sibling pairs was defined as Crohn's disease (CD) or ulcerative colitis (UC). RESULTS: Nonparametric statistical analyses showed linkage for both chromosomes. Two-point results for chromosome 12 peaked at D12S303 (logarithm of odds [LOD], 2.15; P = 0.003) for CD and at D12S75 (LOD, 0.92; P = 0.03) for UC. Multipoint analyses produced a peak LOD of 1.8 for CD. Chromosome 16 showed linkage for CD at marker D16S415 (LOD, 1.52; P = 0.007). Multipoint support peaked above markers D16S409 and D16S411 (LOD, 1.7). CONCLUSIONS: These data are consistent with linkage of IBD to chromosomes 12 and 16. The replication of genetic risk loci in a large independent family collection indicates important and common susceptibility genes in these regions and will facilitate identification of genes involved in IBD.

Chromosomes, Human, Pair 12↗
PubMed1998

Association between intraepithelial Escherichia coli and colorectal cancer.

BACKGROUND & AIMS: Although multiple studies have focused on Helicobacter pylori, little is known about the mucosa-associated flora of the colon. The aim of this study was to detect bacteria directly in colonic mucosa from patients screened for colorectal cancer. METHODS: Bacteria were quantified with the polymerase chain reaction and identified by comparative sequence analysis in colonoscopic biopsy specimens from 31 asymptomatic and 34 symptomatic controls with normal colonoscopic findings, 29 patients with colonic adenoma, and 31 patients with colorectal carcinoma. In 41 patients, intra- and extracellular location of bacteria was confirmed with the gentamicin protection assay. RESULTS: No bacteria were detected in biopsy specimens from 97% of asymptomatic and 69% of symptomatic controls. In contrast, bacterial concentrations of 10(3)-10(5) colony-forming units per microliter were detected in biopsy specimens from both malignant and macroscopically normal tissue in 90% and 93% of patients with adenoma and carcinoma, respectively. E. coli and coli-like bacteria were shown to colonize the colonic mucosa in 82% of these patients. The gentamicin protection assay indicated that E. coli was partially intracellular in 87% of patients with adenoma and carcinoma and in none of the controls. CONCLUSIONS: The colonic mucosa of patients with colorectal carcinoma but not normal colonic mucosa is colonized by intracellular E. coli.

Adenoma↗
PubMed1998

Photodynamic therapy of nonresectable cholangiocarcinoma.

BACKGROUND & AIMS: Successful treatment in nonresectable Bismuth type III and IV cholangiocarcinoma is seldom achieved. The aim of this study was to evaluate the effect of photodynamic therapy on cholestasis, quality of life, and survival in these patients. METHODS: Nine patients with advanced nonresectable cholangiocarcinomas Bismuth type III and IV, who showed no sufficient drainage (bilirubin decrease <50%) after endoscopic stent insertion, underwent photodynamic therapy. Two days after intravenous application of a hematoporphyrin derivate, intraluminal photoactivation was performed cholangioscopically. Serum bilirubin, quality of life, and survival time were assessed in two monthly intervals after photodynamic therapy. RESULTS: After photodynamic therapy, bilirubin serum levels declined from 318 +/- 72 to 103 +/- 35 micromol/L (P = 0.0039) with no significant increase during the two monthly follow-ups. Quality of life indices improved dramatically and remained stable (e.g., Karnofsky index from 32.2% +/- 8.13% to 68.9% +/- 6.1%; P = 0.0078). Thirty-day mortality was 0%, and median survival time was 439 days. CONCLUSIONS: This study provides clear evidence that photodynamic therapy is effective in restoring biliary drainage and improving quality of life in patients with nonresectable disseminated cholangiocarcinomas Bismuth type III and IV. Compared with published data, survival time seems to be prolonged.

Bile Duct Neoplasms↗
PubMed1998

Experimental immunomodulatory therapy of inflammatory bowel disease.

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) of unknown etiology but demonstrate a rising incidence in many western countries. Although little is known about inflammatory pathomechanisms which are specific to either Crohn's disease or ulcerative colitis, a distinction between both diseases can often be made by typical clinical manifestations, endoscopic appearance or histologic characteristics. The immunology if mucosal inflammation in both diseases is characterized by an overwhelming preponderance of pro-inflammatory cytokine expression with an apparent inability to adequately downregulate immune activation. Moreover, it appears that Crohn's disease does not describe a single clinical entity: The ability to develop certain disease characteristics (e.g. fistula or stenosis formation, respectively) varies between individuals and may be a constant characteristic not being altered in the natural course of disease. From clinical observations it can be therefore concluded that disease subgroups may exist which could be distinctly different in disease pathophysiology and treatment response. With the development of defined immune interventions single steps in the immune cascade can be targeted and evaluated for therapy. Humanized monoclonal antibodies have been engineered which bind with a high affinity to tumor necrosis factor-alpha, a pro-inflammatory cytokine with particular importance in the immunoregulation of inflammation. Although the precise mechanism of action is not completely understood, it appears that a single infusion of this monoclonal antibody (cA2) can induce remission in a high percentage of steroid dependent, chronic active patients with Crohn's disease. The parenteral administration of interleukin-10 (IL-10), a contra-inflammatory cytokine, which downregulates immune activation in most immune and non-immune cells, also induces improvement in this patient group. At present it is still unclear, how interleukin-10 needs to be administered: Studies using intravenous application of IL-10 lead to very promising results, whereas the subcutaneous administration induced a considerable less impressive therapeutic effect. New therapeutic principles are appearing on the horizon, which have not been evaluated in a critical number of patients yet but appear promising because of the concept. One strategy will be the use of anti-sense oligonucleotides. Anti-sense oligonucleotides in the appropriate chemical structure can penetrate cells and neutralize a complementary sense-mRNA of the target molecule. Therefore, targeted molecules can be specifically eliminated in their expression directly on the transcriptional level. Interesting therapeutic trials are expected against adhesion molecules (ICAM-1) and pro-inflammatory signaling molecules (i.e. nuclear factor kappa B). The future development of immune therapies in IBD therefore holds great promises for better treatment modalities of inflammatory bowel disease but will also open important new insights into a further understanding of inflammation pathophysiology.

Adjuvants, Immunologic↗
PubMed1998

Interaction between the tetracyclic antidepressant mianserin HCl and opioid receptors.

The antinociceptive effects of the tetracyclic antidepressant mianserin and its interaction with various opioid receptor subtypes was evaluated. Mice were tested with a hotplate analgesia meter. Mianserin elicited an antinociceptive effect in a dose-dependent manner following doses from 1-25 mg/kg. As the mianserin dose increased beyond 30 mg/kg, latencies returned to baseline, yielding a biphasic effect. This effect of mianserin was antagonized by naloxone (P<0.005), implying a possible opioid mechanism of action involved in the mianserin induced antinociceptive effect. When administered with various opioid antagonists, the sensitivity of mianserin to selective opioid antagonists was found significant for mu and kappa1 opioid receptor subtypes (P<0.005), but not for delta-receptor. At the next stage mianserin was administered together with various agonists of opioid receptors. When administered together with opiates, mianserin significantly potentiates analgesia at the mu, kappa1 and kappa3 opioid receptor subtype (P<0.005) and to a lesser extent, at the delta opioid receptors. These results suggest a potential use of mianserin in the management of some pain syndromes. However, further research is needed in order to establish both the exact clinical indications and the effective doses of mianserin when prescribed for pain.

Animals↗
PubMed1998

Olsalazine versus mesalazine in the treatment of mild to moderate ulcerative colitis.

AIM: To compare the efficacy and tolerability of olsalazine sodium with enteric-coated mesalazine in inducing endoscopic remission in patients with mild to moderate active ulcerative colitis. PATIENTS AND METHODS: Patients with mild to moderate active ulcerative colitis were randomized to receive either olsalazine sodium, 3 g/day (n = 88), or mesalazine, 3 g/day (n = 80), for up to 12 weeks. RESULTS: Of the patients treated with olsalazine sodium, 52.2% achieved endoscopic remission, compared with 48.8% of patients treated with mesalazine. This difference was not significant (P = 0.67). There was a nonsignificant trend for patients with left-sided colitis or a more severe endoscopic grade to achieve remission if they were treated with olsalazine sodium than if they were treated with mesalazine. Both treatments were comparable with respect to clinical activity index and an investigator's global assessment. Seventy patients reported one or more adverse events; adverse events were seen in 45% of olsalazine sodium-treated patients and in 36% of mesalazine-treated patients. Eleven patients treated with olsalazine sodium and nine patients treated with mesalazine withdrew from the study because of adverse events. One patient treated with olsalazine sodium compared with two treated with mesalazine stopped treatment because of diarrhoea. Serious adverse events occurred in three patients treated with olsalazine sodium and in four treated with mesalazine. CONCLUSION: Therapeutic effectiveness and tolerance to the treatment did not differ between olsalazine sodium, 3 g/day, and mesalazine, 3 g/day, in inducing endoscopic remission in patients with mild to moderate active ulcerative colitis within 12 weeks of treatment.

Adult↗
PubMed1998

Systematic genomic screening and analysis of mRNA in untranslated regions and mRNA precursors: combining experimental and computational approaches.

MOTIVATION: The untranslated regions (UTRs) of mRNA upstream (5'UTR) and downstream (3'UTR) of the open reading frame, as well as the mRNA precursor, carry important regulatory sequences. To reveal unidentified regulatory signals, we combine information from experiments with computational approaches. Depending on available knowledge, three different strategies are employed. RESULTS: Searching with a consensus template, new RNAs with regulatory RNA elements can be identified in genomic screens. By this approach, we identify new candidate regulatory motifs resembling iron-responsive elements in the 5'UTRs of HemA, FepB and FrdB mRNA from Escherichia coli. If an RNA element is not yet defined, it may be analyzed by combining results from SELEX (selective enrichment of ligands by exponential amplification) and a search of databases from RNA or genomic sequences. A cleavage stimulating factor (CstF) binding element 3 of the polyadenylation site in the mRNA precursor serves as a test example. Alternatively, the regulatory RNA element may be found by studying different RNA foldings and their correlation with simple experimental tests. We delineate a novel instability element in the 3'UTR of the estrogen receptor mRNA in this way. AVAILABILITY: Strategy, methods and programs are available on request from T.Dandekar. CONTACT: dandekar@embl-heidelberg.de

3' Untranslated Regions↗
PubMed1998

POPSIM: a general population simulation program.

MOTIVATION: The investigation of common disorders of polygenic inheritance using both population-based association designs and non-parametric linkage analysis within families is gaining increasing importance. We have created a program that allows for the flexible simulation of populations as a tool to investigate the properties of population-based mapping approaches. RESULTS: We have created a population simulation program, POPSIM, that (i) creates a virtual representation of every individual, (ii) makes no prior assumptions but the Mendelian rules and (iii) allows populations of several million individuals in size to be generated and to be followed over hundreds of generations. The parameters of the disease model, population structure and population expansion rate can be specified. Flexible sampling options exist that allow samples of families and individuals to be drawn at any given point during the population history. The program may be a useful tool in the study of the influence of genetic drift, recombination and admixture on the generation and maintenance of linkage disequilibrium in populations, as well as the evaluation of stochastic sampling characteristics of families and individuals conditional on a complex genetic phenotype from homogeneous and heterogeneous populations. AVAILABILITY: The source code as well as Sun and Windows NT4.0 console executables of the program are available under http://www.ukrv. de/ch/medgen/html/benutzer/j.hampe/popsim. html. CONTACT: J. Hampe@mucosa.de

Computational Biology↗
PubMed1998

Beneficial effect of risperidone on sleep disturbance and psychosis following traumatic brain injury.

Severe disturbances of sleep architecture and circadian rhythms are common in traumatic brain injured patients; however, complete absence of the rapid eye movement sleep stage is very rare. We describe a brain injured patient with cognitive disturbances who developed severe alterations of sleep architecture, accompanied by paranoid and jealousy delusions. Following several trials with conventional antipsychotics his psychotic state stabilized but he continued to complain of insomnia and daytime fatigue. When treated with risperidone 2 mg/day, both his sleep and the delusional thoughts improved markedly and his daytime alertness increased. Severe deterioration of his support system brought about discontinuation of treatment with re-emergence of all symptoms.

Antipsychotic Agents↗
PubMed1998

Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear neutrophils and regulation by interleukin 10 during intestinal inflammation.

BACKGROUND: Concentrations of pro-inflammatory cytokines are increased in the intestinal mucosa of patients with active inflammatory bowel disease (IBD). Polymorphonuclear neutrophil granulocytes (PMN) are the most abundant cell type in intestinal lesions in IBD. Interleukin 10 (IL-10) is an important contra-inflammatory cytokine which induces downregulation of pro-inflammatory cytokines. AIMS: To investigate whether PMN from patients with IBD or infectious colitis, respectively, secrete increased amounts of pro-inflammatory cytokines and can be regulated by IL-10. METHODS: Secretion (ELISA) as well as corresponding mRNA levels (semiquantitative RT-PCR) of pro-inflammatory cytokines (IL-1 beta, TNF-alpha) and of IL-1 receptor antagonist were assessed in peripheral PMN. RESULTS: PMN from patients with IBD are primed to secrete enhanced amounts of pro-inflammatory cytokines accompanied by detection of corresponding mRNAs in comparison with normal controls. This finding is not specific for IBD but rather reflects intestinal inflammation in general. IL-10 markedly inhibited proinflammatory cytokine secretion as well as corresponding mRNA concentrations. CONCLUSIONS: PMN are an important source of pro-inflammatory cytokines in patients with intestinal inflammation and can be downregulated by IL-10.

Adolescent↗
PubMed1998

Activation of nuclear factor kappa B inflammatory bowel disease.

BACKGROUND: Expression of pro-inflammatory cytokines is increased in the intestinal lamina propria of patients with inflammatory bowel disease (IBD). Nuclear factor kappa B (NF kappa B) controls transcription of inflammation genes. On activation, NF kappa B is rapidly released from its cytoplasmic inhibitor (I kappa B), transmigrates into the nucleus, and binds to DNA response elements in gene promoter regions. AIMS: To investigate whether increased activation of NF kappa B is important in IBD and may be down-regulated by anti-inflammatory treatment. METHODS: Activation of NF kappa B was determined by western blot assessment and electrophoretic mobility shift assay in nuclear extracts of colonic biopsy samples as well as lamina propria mononuclear cells. RESULTS: Nuclear levels of NF kappa B p65 are increased in lamina propria biopsy specimens from patients with Crohn's disease in comparison with patients with ulcerative colitis and controls. Increased activation of NF kappa B was detected in lamina propria mononuclear cells from patients with active IBD. Corticosteroids strongly inhibit intestinal NF kappa B activation in IBD in vivo and in vitro by stabilising the cytosolic inhibitor I kappa B alpha against activation induced degradation. CONCLUSIONS: In both IBDs, but particularly Crohn's disease, increased activation of NF kappa B may be involved in the regulation of the inflammatory response. Inhibition of NF kappa B activation may represent a mechanism by which steroids exert an anti-inflammatory effect in IBD.

Adolescent↗
PubMed1997

Effect of the pregnane-related GABA-active steroid alphaxalone on mice performance in the staircase test.

We evaluated the modulatory effect of the GABA-active neurosteroid alphaxalone on the staircase test behavior of mice. Results were compared with the benzodiazepine alprazolam, the GABA(A) agonist muscimol and the peripheral steroids corticosterone and progesterone. Alphaxalone and alprazolam reduced rearing activity in a dose-dependent manner, at doses that did not suppress climbing. The rearing-suppression effect of alprazolam, but not of alphaxalone, was blocked by the benzodiazepine antagonist flumazenil. No such dissociation between the effect on rearing and climbing was obtained with muscimol, and both activities were suppressed, in a flumazenil-insensitive pattern, at high doses. Corticosterone and progesterone did not affect the behavior of the mice. The lack of sensitivity of both phenobarbital and alphaxalone to flumazenil indicates that neither agents act via the benzodiazepine recognition site at the GABA(A) receptor complex.

Alprazolam↗
PubMed1997

Augmentation of opioid induced antinociception by the atypical antipsychotic drug risperidone in mice.

Risperidone is a novel atypical neuroleptic with a favorable profile of side effects due to its unique pharmacological activity: it exhibits both potent dopamine D2 and 5-HT2 receptor blocking activity, as well as high affinity for alpha1 and alpha2 adrenergic receptors and histamine H1 receptor. We found that risperidone has a potent antinociceptive effect in the tailflick assay with an ED50 of 26.4 mg/kg. This effect of risperidone was antagonized by naloxone (P < 0.05). This sensitivity to naloxone indicates that at least some of the analgesic effects of risperidone are mediated by an opioid mechanism of action. beta-FNA (mu1 mu2-antagonist), naloxonazine (mu1-antagonist) and norbinaltorphamine (nor-BNI; kappa1-analgesia) reversed risperidone antinociceptive effect (P < 0.05). Naltrindole (delta-antagonist) only partially reversed risperidone antinociceptive effect. We found that the sensitivity of risperidone antinociceptive effect to selective antagonists implies involvement of mu1-, mu2- and kappa1-opioid and to a lesser extent delta-opioid mechanisms. These results suggest a possible role for risperidone both in the management of pain and in the management of opiate withdrawal and detoxification.

Animals↗
PubMed1997

Pharmacological characterization of buprenorphine, a mixed agonist-antagonist with kappa 3 analgesia.

Buprenorphine is a mixed opioid agonist/antagonist analgesic. This study was designed to determine the role of opioid receptor subtypes, especially kappa 3, in buprenorphine-induced analgesia in mice. Buprenorphine, when injected systemically, revealed a potent analgesic effect by tailflick assay, with a biphasic dose-response curve, which was reversed by naloxone. The presence of analgesic cross-tolerance between buprenorphine and naloxone benzoylhydrazone (NalBzoH) and morphine indicated a role for kappa 3 and mu receptor subtype in buprenorphine analgesia. Additional studies with selective opioid antagonists indicated kappa 1 mechanisms of action. We did not detect any involvement of the delta receptor subtype. Low doses of buprenorphine antagonized morphine analgesia, while high doses of buprenorphine coadministered with morphine elicited increasing analgesia in a dose-dependent manner. These findings suggest that buprenorphine elicits analgesia through an interaction with kappa 3 receptors and to a lesser extent with kappa 1 as well as its activity as partial mu receptor agonist.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗