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Biomedical subjects

R Arnold

Publications and source records attributed to R Arnold.

At least 109 records · Page 6Linked to original sources
PubMed2000

Integrative mitogenic role of protein kinase B/Akt in beta-cells.

Protein kinase B/Akt (PKB/Akt) is activated by phosphatidylinositol 3-kinase (PI 3-K) and is a central mediator of cellular proliferation and protection against apoptosis. Insulin, insulin-like growth factor (IGF-1), and glucagon-like peptide-1 (GLP-1) act as glucose-dependent growth factors for pancreatic beta-cells. We assessed signaling pathways and stimulation patterns of PKB/Akt activation by these ligands in the beta-cell line INS-1. Insulin, IGF-1, and GLP-1 induced distinctive time dependent, dose dependent, and glucose dependent phosphorylation of PKB/Akt. Insulin and IGF-1 stimulated PI 3-K activity was mainly associated with insulin receptor substrate (IRS) isoforms IRS-1 and IRS-2 and less so with the IRS-isoform Grb-2 associated binder-1 (Gab-1). In contrast, GLP-1 induced PI 3-K activity mainly in Gab-1 and also in IRS-2 immunoprecipitates, although in an attenuated kinetic. Thus, activation pathways of PKB/Akt by insulin, IGF-1, and GLP-1 converge at the level of IRS-isoforms and PI 3-K inducing differential activation of PKB/Akt. These data indicate an essential role of PKB/Akt in regulation of beta-cell proliferation.

Animals↗
PubMed2000

Effects of glucagon-like peptide-1(7-36)amide on antro-pyloro-duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans.

BACKGROUND: Glucagon-like peptide-1(7-36)amide (GLP-1) is a gut hormone released postprandially. Synthetic GLP-1 strongly inhibits gastric emptying in healthy subjects and in patients with diabetes mellitus. AIMS: To investigate the effects of GLP-1 on antro-pyloro-duodenal motility in humans. METHODS: Eleven healthy male volunteers were studied on two separate days. On the interdigestive study day, a basal period was followed by a 60 minute period of saline infusion and two further 60 minute periods of intravenous infusion of GLP-1 0.4 and 1.2 pmol/kg/min to achieve postprandial and supraphysiological plasma levels, respectively. On the postprandial study day, the same infusions were coadministered with intraduodenal lipid perfusion at 2.5 ml/min (2.5 kcal/min) followed by another 60 minutes of recording after cessation of GLP-1. Antro-pyloro-duodenal motility was measured by perfusion manometry. RESULTS: GLP-1 significantly inhibited the number and amplitudes of antral and duodenal contractions in the interdigestive state and after administration of duodenal lipid. It abolished interdigestive antral wave propagation. In the interdigestive state, GLP-1 dose dependently increased pyloric tone and significantly stimulated isolated pyloric pressure waves (IPPW). Pyloric tone increased with duodenal lipid, and this was further enhanced by GLP-1. GLP-1 transiently restored the initial IPPW response to duodenal lipid which had declined with lipid perfusion. Plasma levels of pancreatic polypeptide were dose dependently diminished by GLP-1 with and without duodenal lipid. CONCLUSIONS: GLP-1 inhibited antro-duodenal contractility and stimulated the tonic and phasic motility of the pylorus. These effects probably mediate delayed gastric emptying. Inhibition of efferent vagal activity may be an important mechanism. As postprandial plasma levels of GLP-1 are sufficient to appreciably affect motility, we believe that endogenous GLP-1 is a physiological regulator of motor activity in the antro-pyloro-duodenal region.

Adult↗
PubMed2000

Short course acid suppressive treatment for patients with functional dyspepsia: results depend on Helicobacter pylori status. The Frosch Study Group.

BACKGROUND AND AIMS: Treatment of functional dyspepsia with acid inhibitors is controversial and it is not known if the presence of Helicobacter pylori infection influences the response. METHODS: After a complete diagnostic workup, 792 patients with functional dyspepsia unresponsive to one week of low dose antacid treatment were randomised to two weeks of treatment with placebo, ranitidine 150 mg, omeprazole 10 mg, or omeprazole 20 mg daily. Individual dyspeptic and other abdominal symptoms were evaluated before and after treatment according to H pylori status. RESULTS: The proportions of patients considered to be in remission (intention to treat) at the end of treatment with placebo, ranitidine 150 mg, omeprazole 10 mg, and omeprazole 20 mg were, respectively, 42%, 50%, 48%, and 59% in the H pylori positive group and 66%, 73%, 64%, and 71% in the H pylori negative group. In H pylori positive patients, the therapeutic gain over placebo was significant for omeprazole 20 mg (17.6%, 95% confidence intervals (CI) 4.2-31.0; p<0.014 using the Bonferroni-adjusted p level of 0.017) but not for omeprazole 10 mg (6.8%, 95% CI -6.7-20.4) or ranitidine 150 mg (8.9%, 95% CI -4.2-21. 9). There was no significant therapeutic gain from active treatment over placebo in H pylori negative patients. Complete disappearance of symptoms and improvement in quality of life also occurred most frequently with omeprazole 20 mg and was significant in both H pylori positive and H pylori negative groups. The six month relapse rate of symptoms requiring treatment was low (<20%) in all groups. CONCLUSIONS: Omeprazole 20 mg per day had a small but significant favourable effect on outcome in H pylori positive patients. The differential response in these patients may be explained by an enhanced antisecretory response in the presence of H pylori. The effect of weaker acid inhibition was unsatisfactory.

Adolescent↗
PubMed2000

Risk of mortality, cancer incidence, and stroke in a population potentially exposed to cadmium.

OBJECTIVES: To follow up mortality and cancer incidence in a cohort potentially exposed to cadmium and to perform a geographical (ecological) analysis to further assess the health effects of potential exposure to cadmium. METHODS: The English village of Shipham has very high concentrations of cadmium in the soil. A previous cohort study of residents of Shipham in 1939 showed overall mortality below that expected, but a 40% excess of mortality from stroke. This study extends the follow up of the cohort for mortality to 1997, and includes an analysis of cancer incidence from 1971 to 1992, and a geographical study of mortality and cancer incidence. Standardised mortality and incidence ratios (SMRs and SIRs) were estimated with regional reference rates. Comparisons were made with the nearby village of Hutton. RESULTS: All cause cohort mortality was lower than expected in both villages, although there was excess cancer incidence in both Shipham (SIR 167, 95% confidence interval (95% CI) 106 to 250) and Hutton (SIR 167, 95% CI 105 to 253). There was an excess of mortality from hypertension, cerebrovascular disease, and nephritis and nephrosis, of borderline significance, in Shipham (SMR 128, 95% CI 99 to 162). In the geographical study, all cause mortality in Shipham was also lower than expected (SMR 84, 95% CI 71 to 100). There was an excess in genitourinary cancers in both Shipham (SIR 160, 95% CI 107 to 239) and Hutton (SIR 153, 95% CI 122 to 192). CONCLUSION: No clear evidence of health effects from possible exposure to cadmium in Shipham was found despite the extremely high concentrations of cadmium in the soil.

Cadmium Poisoning↗
PubMed2000

Involvement of CCK in the paraventricular nucleus of the hypothalamus in the CNS regulation of colonic motility.

The effects of cholecystokinin octapeptide (CCK(8)), the CCK-A receptor antagonist, MK-329, and the CCK-B receptor antagonist, L-365, 260, microinfused into the paraventricular nucleus of hypothalamus (PVN) on colonic motor function was investigated in awake rats, chronically implanted with a microinjection cannula into the PVN and a catheter into the proximal colon. In fasted rats, bilateral microinfusion of CCK(8) at doses of 1.5 and 3.0 microg/rat into the PVN stimulated colonic transit, as shown by a significant increase in the geometric center by 47 and 54%, respectively. This effect of CCK(8) was site-specific to the PVN, since microinjection of the peptide into sites outside of but adjacent to PVN had no effect. In non-fasted rats, L-365,260 bilaterally microinjected into the PVN at a dose of 1.5 microg/rat inhibited propulsive colonic motor function; colonic transit time significantly increased by 73% in comparison to the control condition. Microinfusion of the CCK-A antagonist into in the PVN did not affect colonic transit. These results show that the PVN is a responsive site for the central CCK(8)-induced modulation of colonic motility. The data suggest, that endogenous CCK in the paraventricular nucleus of the hypothalamus unfolds a stimulatory effect on colonic transit through action on CCK-B receptors.

Animals↗
PubMed2000

Treatment of neuroendocrine GEP tumours with somatostatin analogues: a review.

BACKGROUND: Somatostatin and its long-acting analogues are effective in symptom control in patients with functionally active neuroendocrine GEP tumours. Several in vitro and in vivo reports suggest that they are also able to control tumour growth. METHODS: Critical review of published data on the effect of long-acting somatostatin analogues on symptom and growth control in patients with metastatic neuroendocrine GEP tumours. RESULTS: With the exception of insulinoma and gastrinoma, octreotide acetate and other long-acting somatostatin formulations are currently the therapeutic principle of first choice to control hormone-mediated symptoms. The consequences of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome are best controlled by proton pump inhibitors. Available data on growth control indicate that stabilization of tumour growth seems to be the most beneficial antiproliferative effect occurring in up to 50% of patients. This effect is limited. However, it is unknown which tumour entity responds best to long- acting somatostatin analogues. CONCLUSION: Additional studies in patients with known spontaneous tumour growth and avoiding a mix-up of different entities of neuroendocrine malignancies are necessary to identify subpopulations of neuroendocrine tumours which respond to long-acting somatostatin analogues in terms of longer lasting growth inhibition.

Antineoplastic Agents↗
PubMed2000

Salvage therapy for relapsed mediastinal B-cell lymphoma with allogeneic HLA-identical related donor bone marrow transplantation, donor lymphocyte infusion and IDEC-C2B8.

Primary B-cell lymphoma of the mediastinum is an aggressive non-Hodgkin's lymphoma with distinct clinicopathologic features. Response rates are between 60-80% following intensive chemotherapy regimens. Poor responders or patients with an early relapse usually do not achieve a prolonged second remission with conventional salvage therapy protocols and therefore qualify for intensive or experimental approaches. Here we describe two patients of same age, gender and stage with primary mediastinal B-cell lymphoma and an early relapse after the first courses of combination chemotherapy and irradiation of the mediastinum. One patient relapsed after a salvage therapy with allogeneic donor-related bone marrow transplantation and donor lymphocyte infusion but responded again with a continuing good partial remission after infusion of the chimeric anti-CD20 antibody IDEC-C2B8. For the other patient an allogeneic bone marrow transplantation was not possible. He finally failed to respond to salvage therapy with IDEC-C2B8 and died of progressive disease. The anti-CD20 antibody IDEC-C2B8 induced a partial remission in a patient with primary mediastinal B-cell lymphoma refractory to other therapeutic approaches, including allogeneic bone marrow transplanatation (alloBMT), donor lymphocyte infusion (DLI) and irradiation. The role of IDEC-C2B8 as a component of salvage regimens appears to be worthy for further evaluation in high-risk patients with primary mediastinal B-cell lymphoma

Adolescent↗
PubMed1999

Crosstalk between keratinocytes and T lymphocytes via Fas/Fas ligand interaction: modulation by cytokines.

Apoptosis mediated by Fas/FasL interaction plays an important role during many inflammatory skin disorders. To estimate whether the expression of FasL, the ligand for Fas, might be regulated by cytokines we stimulated primary human keratinocytes with several pro- and anti-inflammatory cytokines. Keratinocytes cultured to subconfluence expressed FasL constitutively. Cells stimulated with the proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and IL-15, respectively, increased significantly their intracellular as well as cell surface-bound FasL expression in a time- and dose-dependent manner. This cytokine-induced FasL expression was dependent on new protein synthesis. Despite enhanced expression of cell surface-bound FasL, no release of soluble FasL was measured in the cell supernatants determined by ELISA. Stimulation of the cells with IL-6, IL-10, IL-12, TGF-beta1, and GM-CSF did not modulate the constitutive FasL expression, but IFN-gamma-mediated FasL up-regulation was significantly diminished by IL-10 and TGF-beta1, respectively. Up-regulation of FasL on IFN-gamma-stimulated keratinocytes led to increased apoptosis within monolayers cultured for 48 h. Moreover, coculture experiments performed with Fas+ Jurkat T cells revealed that enhanced FasL expression on IFN-gamma-stimulated keratinocytes induced apoptosis in cocultured T cells, demonstrating that up-regulated FasL was functionally active. In summary, our data suggest the important regulatory role of cytokine-controlled Fas/FasL interaction in the cross-talk between keratinocytes and skin-infiltrating T cells for maintenance of homeostasis in inflammatory skin processes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Comparison of the Sideris and Amplatzer septal occlusion devices.

The results of transcatheter atrial septal defect (ASD) occlusion with 2 different devices (Sideris adjustable buttoned device vs Amplatzer Septal Occluder) were compared in 2 consecutive series of patients. Comparative outcomes were assessed by whether a device was implanted or not, by complications and fluoroscopy time of implantation, and by the incidence of residual shunting on transthoracic echocardiography at follow-up. The patient and defect characteristics were similar in both groups. Twenty-eight of 33 Sideris devices and 37 of 39 Amplatzer devices were implanted. The fluoroscopy time for the Amplatzer implants was 13.4 minutes (range 8 to 41) compared with 23.7 minutes (range 11 to 60.6) for the Sideris implants (p <0.001). The complete occlusion rate for the Amplatzer device was 93% compared with 44% for the Sideris device at 1 year (p <0.001). In conclusion, the Amplatzer device produces higher occlusion rates of ASDs with shorter fluoroscopy times.

Adolescent↗
PubMed1999

[Treatment of adult acute lymphoblastic leukemia].

In patients with adult ALL, substantial progress has been made in the past 20 years. At present a cure rate of 30-40% can be achieved and varies in defined subgroups between 10-51%. ALL does not represent an uniform disease but is formed by biologic subentities, which differ in their natural history, clinical presentation and prognosis. A comprehensive diagnostic examination, including morphology, cytochemistry, immunology, cytogenetic and molecular genetic analysis is a precondition for prognostic assessment and therapeutic stratification. The basic principle of ALL treatment is a combination chemotherapy with sequential administration of induction, consolidation and maintenance therapy. Bone marrow transplantation has become an important part of the treatment strategy and is performed in patients with high risk. In the subgroup of T-ALL a significant progress has been made in the last years with survival rates of 40-50%. In B-ALL the results have been greatly improved to 48-51% by introduction of a specific treatment strategy. However, the results (about 30%) stagnate for the total group of B-lineage-ALL (common ALL, pre-B-ALL, pro-B-ALL). Patients with B-lineage-ALL can be subdivided in a high and low risk group according to the presence of risk factors (age, white blood cell count, time to achieve a complete remission, pro-B-ALL and the translocations t[4;11], t[9;22]). The outcome of the subgroup of adult pro-B-ALL has been substantially improved (50%). An increase of treatment results (20%) appears in outlines for patients above 50 years. The Ph/bcr-abl positive ALL has in spite of improved complete remission rates (60-70%) consistently unfavourable survival rates (10%).

Adult↗
PubMed1999

The (gt)n(ga)m containing intron 2 of HLA-DRB alleles binds a zinc-dependent protein and forms non B-DNA structures.

We studied protein binding and structural features of perfect and imperfect composite (gt)n(ga)m blocks from different HLA-DRB1 alleles in their original genomic and artificial environments. The major retarded protein/DNA complex of the genomic (gt)n(ga)m fragments comprises a zinc-dependent protein present in nuclear extracts from different cell types. The protein binding is characterized by moderate affinities independent of the polymorphic form of the physiological microsatellite allele. The binding affinity depends on the 5' and 3' adjacent single copy parts. DNase I footprinting of genome-derived fragments revealed that the 5' adjacent sequence and the (gt)n repeat are preferentially protected on the (gt)n(ga)m strand. Comparing three alleles, a regular pattern of footprints was not detectable in the (gt)n part, indicating that the zinc-dependent protein recognizes structural rather than sequence-specific features in this region. Chemical probing resulted in a pattern characteristic for Z-DNA in the (gt)n tract of the fragments. However, EMSA experiments using the Z-DNA specific monoclonal antibody mABZ-22 did not prove the presence of Z-DNA. As demonstrated by chemical modifications of the different (ga)m targets, only one of three (gt)n(ga)m fragments formed intramolecular triplexes of the type H-y3 and H-y5. DNase I footprinting revealed only weak protection, if any, in the homopurine tract. Rather, the (tc)m strands are hypersensitive for DNase I. This is probably due to structural conversions into intramolecular *H-triplexes after binding of HIZP.

Base Sequence↗
PubMed1999

Heart rate variability in carcinoid heart disease.

Time domain heart rate variability measurements and echocardiographic studies were performed in 35 patients with carcinoid syndrome. Carcinoid heart disease was present in 18 patients (51%). Heart rate variability parameters (standard deviation of all normal RR intervals, percentage of the number of pairs of adjacent normal RR intervals differing by >50 ms) were significantly reduced in patients with than in those without carcinoid heart disease.

Adult↗
PubMed1999

Association between structural and numerical chromosomal aberrations in acute myeloblastic leukemia: a study by RT-PCR and FISH in 447 patients with de-novo AML.

We analyzed 447 patients with de novo AML using alpha-satellite probes for the chromosomes 7, 8, X, and Y and RT-PCR for t(8;21), t(15;17) and inv(16). In 130/447 patients (29%) chromosomal aberrations were found. Thirty-three patients (7%) had a t(8;21); 11 of these had the additional loss of a sex chromosome (p<0.001) and two a trisomy 8. Twenty-nine patients (6%) had a t(15;17); four of these had a trisomy 8. Sixteen patients (4%) displayed an inv(16); four of these had a trisomy 8. Twenty-two patients (5%) had a sole trisomy 8 and one patient the combination of trisomy 8 and trisomy X. Five patients (1%) displayed the loss of a Y-chromosome as the sole abnormality and two patients had a sole trisomy X. In 22 patients (5%) a monosomy 7 was found, and in none of these patients were additional chromosomal aberrations detected by RT-PCR (p < 0.05). In conclusion, trisomy 8 and the loss of a gonosome are frequently associated with structural chromosomal aberrations with a significant association of -X/Y and t(8;21). The absence of these genomic lesions in AMLs with monosomy 7 suggests that the monosomy 7 has a specific role in the development of these leukemias and their clinical course.

Adolescent↗
PubMed1999

Temporary tracheobronchial stenting in malignant lymphoma.

BACKGROUND: Temporary stenting is a new strategy in the treatment of malignant airway stenoses. Patients receive stents as primary palliation followed by tumor-specific therapy in order to reduce the stenosis and subsequently remove the stent. METHODS: We investigated this strategy of temporary airway stenting in 5 consecutive patients with malignant lymphoma (Non-Hodgkin's lymphoma, n = 3; Hodgkin's lymphoma, n = 2) who presented with severe dyspnoea. Nine stents (six Strecker, three Dumon stents) were implanted into the trachea or main bronchi. After stenting, patients underwent tumor-specific therapy (chemotherapy, n = 4; percutaneous radiotherapy, n = 1). RESULTS: Clinical improvement of dyspnoea and stridor was observed in each patient after stent implantation. In 4 patients (80%), stents could easily be removed after successful tumor-specific therapy, which led to reduction of stenosis after a mean interval of 26 days (14 to 52 days). One patient died during chemotherapy 6 days after stenting. CONCLUSIONS: The results show that temporary stenting is a valuable strategy in chemo- and radiosensitive malignancies, as it ameliorates the patients' respiratory condition until tumor-specific therapy is effective, and prevents poststenotic complications. It integrates stent implantation in a multi-therapy concept.

Adolescent↗
PubMed1999

A phase II study of high-dose octreotide in patients with unresectable pancreatic carcinoma.

This report describes the results of a phase II trial to evaluate the safety, feasibility and response of patients with irresectable, histologically proven, stage II-IV adenocarcinoma of the pancreas receiving high-dose octreotide treatment. Octreotide was self-administered subcutaneously (3 x 2000 micrograms per day) by 49 patients. Therapy was discontinued after progression of the disease. Due to the subseqment diagnosis of bile duct carcinoma and stage I disease, 2 patients were excluded, leaving 47 evaluable patients with measurable disease. The median Karnofsky score was 80%. 3 patients had stage II (6%), 19 stage III (40%), and 25 (53%) stage IV disease. Octreotide treatment resulted in stable disease in 9 patients (19%) for more than 12 weeks. No complete or partial response was observed. The median overall survival was 21.4 weeks and the median progression-free survival 9.0 weeks. Therapy with high-dose octreotide is feasible, well tolerated and might prolong survival. In a placebo-controlled phase III study the effects of octreotide in patients with pancreatic cancer will be confirmed.

Adenocarcinoma↗
PubMed1999

Cetirizine counter-regulates interleukin-8 release from human epithelial cells (A549)

BACKGROUND: Cetirizine, a H1-receptor antagonist, exerts besides its well-known anti-allergic potential an array of anti-inflammatory activities. In particular epithelial cells activated in the presence of cetirizine showed a reduced ICAM-1 cell surface expression and a diminished release of sICAM-1. OBJECTIVE: We wondered whether cetirizine might influence the release of interleukin-8 (IL-8) from human epithelial cells activated with agonists distinct from histamine. METHODS: We used the human lung epithelial cell line A549 for our in vitro studies. IL-8 release was determined by IL-8 enzyme immunoassay, the intracellular staining for IL-8 and NF-kB was analysed by FACS analysis and IL-8 mRNA steady state level was studied by Northern blot analysis. Confluent epithelial cell monolayer were pre-incubated with cetirizine (0.01 -1.0 micromol/L) for 30 min and afterwards activated with pro-inflammatory cytokines (TNF-alpha IL-1beta, IL-6, IFN-gamma) or different agonists (PMA, NaF, respiratory syncytial virus [RSV]) for 24 h. RESULTS: Epithelial cells stimulated with TNF-alpha IL-1beta, PMA and RSV, respectively, showed a significantly increased release of IL-8. Pre-incubation with cetirizine diminished the IL-8 release from cells activated with TNF-alpha or PMA in a significant manner. The reduced IL-8 release coincided with a diminished percentage of cells expressing IL-8. Northern blot analysis revealed a reduced steady state level of IL-8 mRNA in cells pretreated with cetirizine and stimulated with TNF-alpha. Furthermore, a decreased amount of accessible DNA-binding sites of the nuclear factor kappa B (NF-kB) was determined by FACS analysis. CONCLUSIONS: These results suggest that cetirizine reduced the release of IL-8 from A549 cells stimulated with PMA and TNF-alpha, respectively, by lowering IL-8 gene expression. Therefore, cetirizine might exert anti-inflammatory effects beyond its H1-receptor antagonistic activity in the course of inflammatory respiratory tract disorders such as bronchial asthma and allergic rhinitis.

Blotting, Northern↗