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Biomedical subjects

A Sonnenberg

Publications and source records attributed to A Sonnenberg.

At least 91 records · Page 5Linked to original sources
PubMed2000

Cost effectiveness of competing strategies to prevent or treat GORD-related dysphagia.

OBJECTIVES: The variety of influences that contribute to the occurrence of dysphagia in gastro-oesophageal reflux disease (GORD) provide the physician with many options to intervene in the pathophysiology of the disease process. The aims of the present analysis were to compare the relationships between the costs and effectiveness of competing therapeutic interventions in preventing dysphagia. METHODS: Dysphagia was modelled as the focal point of multiple influences leading to its development. The costs associated with different forms of drug therapy were based on the average wholesale prices listed in the Red Book of 1998. Procedural costs were estimated from Medicare reimbursements. Different treatment options were assessed by their incremental cost-effectiveness ratio. RESULTS: Lifestyle modifications, treatment with prokinetic agents or antacids reduce the occurrence of dysphagia by 22, 21 or 25%, respectively. Acid inhibition results in a 57 to 89% reduction of dysphagia, depending on treatment with histamine-2-receptor antagonists (H2RAs) or proton pump inhibitors (PPIs). Oesophageal dilation results in a reduction ranging between 54 and 81%. The incremental ratio of cost effectiveness associated with prokinetic agents or H2RAs is much higher than that of PPIs. Based on the concept of extended dominance, therefore, prokinetic drugs and H2RAs do not constitute cost-effective means to prevent dysphagia and should be excluded in favour of treatment with PPIs. CONCLUSIONS: An economic analysis of various treatment strategies to reduce the risk of GORD-related dysphagia indicates that PPIs are the most cost-effective means to prevent its occurrence.

Algorithms↗
PubMed1999

Induction of cell scattering by expression of beta1 integrins in beta1-deficient epithelial cells requires activation of members of the rho family of GTPases and downregulation of cadherin and catenin function.

Adhesion receptors, which connect cells to each other and to the surrounding extracellular matrix (ECM), play a crucial role in the control of tissue structure and of morphogenesis. In this work, we have studied how intercellular adhesion molecules and beta1 integrins influence each other using two different beta1-null cell lines, epithelial GE11 and fibroblast-like GD25 cells. Expression of beta1A or the cytoplasmic splice variant beta1D, induced the disruption of intercellular adherens junctions and cell scattering in both GE11 and GD25 cells. In GE11 cells, the morphological change correlated with the redistribution of zonula occluden (ZO)-1 from tight junctions to adherens junctions at high cell confluency. In addition, the expression of beta1 integrins caused a dramatic reorganization of the actin cytoskeleton and of focal contacts. Interaction of beta1 integrins with their respective ligands was required for a complete morphological transition towards the spindle-shaped fibroblast-like phenotype. The expression of an interleukin-2 receptor (IL2R)-beta1A chimera and its incorporation into focal adhesions also induced the disruption of cadherin-based adhesions and the reorganization of ECM-cell contacts, but failed to promote cell migration on fibronectin, in contrast to full-length beta1A. This indicates that the disruption of cell-cell adhesion is not simply the consequence of the stimulated cell migration. Expression of beta1 integrins in GE11 cells resulted in a decrease in cadherin and alpha-catenin protein levels accompanied by their redistribution from the cytoskeleton-associated fraction to the detergent-soluble fraction. Regulation of alpha-catenin protein levels by beta1 integrins is likely to play a role in the morphological transition, since overexpression of alpha-catenin in GE11 cells before beta1 prevented the disruption of intercellular adhesions and cell scattering. In addition, using biochemical activity assays for Rho-like GTPases, we show that the expression of beta1A, beta1D, or IL2R-beta1A in GE11 or GD25 cells triggers activation of both RhoA and Rac1, but not of Cdc42. Moreover, dominant negative Rac1 (N17Rac1) inhibited the disruption of cell-cell adhesions when expressed before beta1. However, all three GTPases might be involved in the morphological transition, since expression of either N19RhoA, N17Rac1, or N17Cdc42 reversed cell scattering and partially restored cadherin-based adhesions in GE11-beta1A cells. Our results indicate that beta1 integrins regulate the polarity and motility of epithelial cells by the induction of intracellular molecular events involving a downregulation of alpha-catenin function and the activation of the Rho-like G proteins Rac1 and RhoA.

Actins↗
PubMed1999

Binding of integrin alpha6beta4 to plectin prevents plectin association with F-actin but does not interfere with intermediate filament binding.

Hemidesmosomes are stable adhesion complexes in basal epithelial cells that provide a link between the intermediate filament network and the extracellular matrix. We have investigated the recruitment of plectin into hemidesmosomes by the alpha6beta4 integrin and have shown that the cytoplasmic domain of the beta4 subunit associates with an NH(2)-terminal fragment of plectin that contains the actin-binding domain (ABD). When expressed in immortalized plectin-deficient keratinocytes from human patients with epidermol- ysis bullosa (EB) simplex with muscular dystrophy (MD-EBS), this fragment is colocalized with alpha6beta4 in basal hemidesmosome-like clusters or associated with F-actin in stress fibers or focal contacts. We used a yeast two-hybrid binding assay in combination with an in vitro dot blot overlay assay to demonstrate that beta4 interacts directly with plectin, and identified a major plectin-binding site on the second fibronectin type III repeat of the beta4 cytoplasmic domain. Mapping of the beta4 and actin-binding sites on plectin showed that the binding sites overlap and are both located in the plectin ABD. Using an in vitro competition assay, we could show that beta4 can compete out the plectin ABD fragment from its association with F-actin. The ability of beta4 to prevent binding of F-actin to plectin explains why F-actin has never been found in association with hemidesmosomes, and provides a molecular mechanism for a switch in plectin localization from actin filaments to basal intermediate filament-anchoring hemidesmosomes when beta4 is expressed. Finally, by mapping of the COOH-terminally located binding site for several different intermediate filament proteins on plectin using yeast two-hybrid assays and cell transfection experiments with MD-EBS keratinocytes, we confirm that plectin interacts with different cytoskeletal networks.

Actins↗
PubMed1999

Birth-cohort phenomenon in the time trends of mortality from ulcerative colitis.

It has been suggested that the mortality trends of ulcerative colitis in England and Wales are shaped by an underlying birth-cohort phenomenon. This pattern implies that exposure to an environmental risk factor early in life plays a crucial role in the development of the disease. The authors tested whether the birth-cohort pattern is unique to British mortality statistics or a common feature of ulcerative colitis in western countries by using the vital statistics from England and Wales, Canada, Scotland, Switzerland, The Netherlands, and the United States. Ulcerative colitis death rates from the six countries were plotted against the periods of death or periods of birth. Mortality from ulcerative colitis increased in successive generations born throughout the second half of the 19th century. It peaked in subjects born between 1880 and 1890 and has declined since then. Strikingly similar patterns were found in the six countries and when women and men were analyzed separately. The birth-cohort pattern indicates that development of ulcerative colitis is strongly influenced by one or several environmental risk factors, which act during a short period early in life. In western countries, exposure to this risk has changed in a similar fashion.

Age Distribution↗
PubMed1999

Secondary reduction of alpha7B integrin in laminin alpha2 deficient congenital muscular dystrophy supports an additional transmembrane link in skeletal muscle.

The integrins are a large family of heterodimeric transmembrane cellular receptors which mediate the association between the extracellular matrix (ECM) and cytoskeletal proteins. The alpha7beta1 integrin is a major laminin binding integrin in skeletal and cardiac muscle and is thought to be involved in myogenic differentiation and migration processes. The main binding partners of the alpha7 integrin are laminin-1 (alpha1-beta1-gamma1), laminin-2 (alpha2-beta1-gamma1) and laminin-4 (alpha2-beta2-gamma1). Targeted deletion of the gene for the alpha7 integrin subunit (ITGA7) in mice leads to a novel form of muscular dystrophy. In the present study we have investigated the expression of two alternative splice variants, the alpha7B and beta1D integrin subunits, in normal human skeletal muscle, as well as in various forms of muscular dystrophy. In normal human skeletal muscle the expression of the alpha7 integrin subunit appeared to be developmentally regulated: it was first detected at 2 years of age. In contrast, the beta1D integrin could be detected in immature and mature muscle in the sarcolemma of normal fetal skeletal muscle at 18 weeks gestation. The expression of alpha7B integrin was significantly reduced at the sarcolemma in six patients with laminin alpha2 chain deficient congenital muscular dystrophy (CMD) (age >2 years). However, this reduction was not correlated with the amount of laminin alpha2 chain expressed. In contrast, the expression of the laminin alpha2 chain was not altered in the skeletal muscle of the alpha7 knock-out mice. These data argue in favor that there is not a tight correlation between the expression of the alpha7 integrin subunit and that of the laminin alpha2 chain in either human or murine dystrophic muscle. Interestingly, in dystrophinopathies (Duchenne and Becker muscular dystrophy; DMD/BMD) expression of alpha7B was upregulated irrespective of the level of dystrophin expression as shown by a strong sarcolemmal staining pattern even in young boys (age <2 years). The expression of the beta1D integrin subunit was not altered in any of our patients with different types of muscular dystrophy. In contrast, sarcolemmal expression of beta1D integrin was significantly reduced in the alpha7 integrin knock-out mice, whereas the expression of the components of the DGC was not altered. The secondary loss of alpha7B in laminin alpha2 chain deficiency defines a biochemical change in the composition of the plasma membrane resulting from a primary protein deficiency in the basal lamina. These findings, in addition to the occurrence of a muscular dystrophy in alpha7 deficient mice, implies that the alpha7B integrin is an important laminin receptor within the plasma membrane which plays a significant role in skeletal muscle function and stability.

Adolescent↗
PubMed1999

Identification of novel interaction partners for the conserved membrane proximal region of alpha-integrin cytoplasmic domains.

The alpha3Abeta1 integrin is a laminin receptor with a broad specificity for different laminin isoforms. Furthermore, it regulates the function of other integrins, like alpha2beta1, alpha5beta1 and alpha6Abeta1. In a yeast two hybrid screen of a human placenta cDNA library, we identified cDNAs coding for four different proteins that strongly interact with the conserved region of the cytoplasmic domain of the alpha3A integrin subunit. In addition to the cDNA for nucleotide exchange factor Mss4 and the putative tumour suppressor protein BIN1, two novel cDNAs were identified. Association analysis with different integrin subunits revealed them as cDNAs that encode binding proteins which react with a broad spectrum of alpha subunits. The conserved membrane proximal region of the alpha3A chain was identified as the binding site for all four proteins. They, therefore, may be involved in the regulation of general functions of integrins.

Amino Acid Sequence↗
PubMed1999

Integrins: alternative splicing as a mechanism to regulate ligand binding and integrin signaling events.

Integrins are a family of transmembrane proteins composed of heterodimers of alpha and beta subunits. With their extracellular domain they bind extracellular matrix proteins or other cell surface molecules, and their cytoplasmic domain binds to cytoskeletal and signaling proteins. Thus, they are in an ideal position to transfer information from the extracellular environment to the interior of the cell and vice versa. For several integrin subunits, alternative splicing of mRNA leads to variations in the sequence of both extracellular and cytoplasmic domains. Many integrin splice variants have specific expression patterns, but for some time, functional differences between these variants were not evident. Recent experiments using transfected cell lines and gene targeting of specific splice variants have contributed significantly to our understanding of the function of these splice variants. The results indicate that alternative splicing is a mechanism to subtly regulate the ligand binding and signaling activity of integrins.

Alternative Splicing↗
PubMed1999

Biology and function of hemidesmosomes.

Hemidesmosomes are cell-substratum adhesion sites that connect the extracellular matrix to the keratin cytoskeleton. Our knowledge of the function of these structures has greatly increased as a result of studies on patients with aberrant expression of hemidesmosome components and studies using targeted inactivation of mouse genes encoding these components. Insight into the formation of hemidesmosomes, as well as into protein-protein interactions that occur in these junctional complexes, has recently been gained by in vitro cell transfections, blot overlay and yeast two-hybrid assays. In addition, recent results indicate that the alpha6 beta4 integrin is involved in the transduction of signals that are induced by the extracellular matrix and which modulate processes as diverse as cell proliferation, differentiation, apoptosis, migration and tissue morphogenesis. Thus it seems that hemidesmosomes do not merely maintain dermo-epidermal adhesion and tissue integrity, but that they are also implicated in intracellular signaling. Here we discuss recently published data on the biology and function of hemidesmosomes.

Animals↗
PubMed1999

Reliability block diagrams to model the management of colorectal cancer.

The present study aims to show how various medical and nonmedical components contribute to success and failure in the management of colorectal cancer. The first encounter, subsequent diagnosis, and surgical therapy of a patient with Dukes B sigmoid cancer is modeled as a reliability block diagram with a serial and parallel arrangement of various components. The overall probability of a patient with new-onset colorectal cancer to visit a physician, be correctly diagnosed, and undergo successful therapy is 69%. The reduction in the overall success, despite the fact that the majority of components are assumed to function with failure rates of 5% or less, is a reflection of the multitude of serial subsystems involved in the management of the patient. In contrast, the parallel arrangement of subsystems results in a relative insensitivity of the overall system to failure, a greater stability, and an improved performance. Since no medical system functions perfectly, redundancy associated with parallel subsystems assures a better overall outcome. System analysis of health care provides a means to improve its performance.

Colorectal Neoplasms↗
PubMed1999

Celiac sprue among US military veterans: associated disorders and clinical manifestations.

The present study aimed to describe the clinical manifestations of celiac sprue related to malnutrition and to analyze the associations between celiac sprue and other diagnoses. A case-control study compared the occurrence of comorbid diagnoses in case and control subjects with and without celiac sprue, respectively. All patients with a primary or secondary diagnosis of celiac sprue (ICD-579.0) who were discharged from hospitals of the Department of Veterans Affairs between 1986 and 1995 were selected as case subjects. In a multivariate logistic regression analysis, the occurrence of celiac disease served as outcome variable, while age, gender, ethnicity, and the comorbid occurrences of other diagnoses served as predictor variables. A total of 458 individual patients with celiac sprue were identified. The data confirmed the known associations of celiac sprue with dermatitis herpetiformis, lactase deficiency, enlargement of lymph nodes, and lymphoma. Celiac sprue was also found to be statistically significantly associated with pancreatic insufficiency, Crohn's disease, functional bowel symptoms, chronic nonalcoholic hepatitis, and pulmonary eosinophilia. The nutritional manifestations associated with celiac disease included nutritional marasmus, cachexia, weight loss, hypocalcemia, osteoporosis, vitamin B-complex deficiency, and various types of iron- and vitamin-deficiency anemias. The large variety of complex associations clearly indicates that celiac sprue is a systemic disease that involves multiple organs and exceeds an isolated nutritional intolerance to gluten.

Aged↗
PubMed1999

Outcome of surgical and endoscopic management of biliary pancreatitis.

The aims of the study were to compare the outcomes of biliary pancreatitis after endoscopic and surgical treatment and define the demographic and clinical characteristics that affect the outcomes. All inpatients with biliary pancreatitis followed at hospitals of the Department of Veterans Affairs during 1988-1994 were included in a case-control study. Of 2075 patients with biliary pancreatitis, 650 were first treated by biliary endoscopy and 1425 by cholecystectomy. Compared with cholecystectomy, biliary endoscopy was associated with older age, admission to nonsurgical service, more complicated pancreatitis, and choledocholithiasis. Seventy-one patients died. Death occurred more often in older patients with multiple comorbid conditions and complications of biliary pancreatitis. Overall length of hospital stay was positively correlated with complications, choledocholithiasis, comorbidity, and deferment of endoscopic or surgical procedure. After adjusting for other confounding variables, both types of treatment resulted in similar death rates and lengths of hospitalization. In conclusion, compared with cholecystectomy, biliary endoscopy is chosen preferentially in older patients with choledocholithiasis or a complication of their pancreatitis. Despite such selection bias, biliary endoscopy results in similar outcomes as surgery. Early intervention by either strategy reduces the length of hospital stay.

Aged↗
PubMed1999

Economic analysis of step-wise treatment of gastro-oesophageal reflux disease.

BACKGROUND: To expose patients with gastro-oesophageal reflux disease (GERD) to the least amount of medication and to reduce health expenditures, it is recommended that their treatment is started with a small dose of an antisecretory or prokinetic medication. If patients fail to respond, the dose is increased in several consecutive steps or the initial regimen is changed to a more potent medication until the patients become asymptomatic. Although such treatment strategy is widely recommended, its impact on health expenditures has not been evaluated. METHODS: The economic analysis compares the medication costs of competing medical treatment strategies, using two different sets of cost data. Medication costs are estimated from the average wholesale prices (AWP) and from the lowest discount prices charged to governmental health institutions. A decision tree is used to model the step-wise treatment of GERD. In a Monte Carlo simulation, all transition probabilities built into the model are varied over a wide range. A threshold analysis evaluates the relationship between the cost of an individual medication and its therapeutic success rate. RESULTS: In a governmental health care system, a step-wise strategy saves on average $916 per patient every 5 years (range: $443-$1628) in comparison with a strategy utilizing only the most potent medication. In a cost environment relying on AWP, the average savings amount to $256 (-$206 to +$1561). The smaller the cost difference between two consecutive treatment steps, the longer one needs to follow the patients to reap the benefit of the small cost difference. However, even a small cost difference can turn into tangible cost savings, if a large enough fraction of GERD patients responds to the initial step of a less potent but also less expensive medication. CONCLUSIONS: The economic analysis suggests that a step-wise utilization of increasingly more potent and more expensive medications to treat GERD would result in appreciable cost savings.

Algorithms↗
PubMed1999

Structure and function of hemidesmosomes: more than simple adhesion complexes.

The attachment of cells to the extracellular matrix is of crucial importance in the maintenance of tissue structure and integrity. In stratified epithelia such as in skin as well as in other complex epithelia multiprotein complexes called hemidesmosomes are involved in promoting the adhesion of epithelial cells to the underlying basement membrane. In the past few years our understanding of the role of hemidesmosomes has improved considerably. Their importance has become apparent in clinical conditions, in which absence or defects of hemidesmosomal proteins result in devastating blistering diseases of the skin. Molecular genetic studies have increased our knowledge of the function of the various components of hemidesmosomes and enabled the characterization of protein-protein interactions involved in their assembly. It has become clear that the alpha6beta4 integrin, a major component of hemidesmosomes, is able to transduce signals from the extracellular matrix to the interior of the cell, that critically modulate the organization of the cytoskeleton, proliferation, apoptosis, and differentiation. Nevertheless, our knowledge of the mechanisms regulating the functional state of hemidesmosomes and, hence, the dynamics of cell adhesion, a process of crucial importance in development, wound healing or tumor invasion, remains limited. The aims of this review are to highlight the recent progresses of our knowledge on the organization and assembly of hemidesmosomes, their involvement in signaling pathways as well as their participation in clinical pathologic conditions.

Animals↗
PubMed1999

Ethnic variations in the occurrence of gastroesophageal cancers.

Cancers of the esophagus, gastroesophageal junction (including the gastric cardia), and stomach represent three separate diseases with marked epidemiologic variations. The Department of Veterans Affairs computerized database records the ethnicity of all hospitalized patients throughout the United States, which provides an opportunity to study the influence of ethnicity on cancer rates in a uniform health-care system. All hospitalized patients, from 1980 through 1995, with a diagnosis of upper gastrointestinal cancer were identified. For each ethnic group and cancer type, hospitalization was expressed as an age-adjusted proportional rate per 10,000 hospitalizations from all causes. Hospitalization with gastric cancer was most frequent among Asians (48.4 per 10,000 hospitalizations) followed by blacks (33.3), Hispanics (28.7), American Indians (20.3), and whites (12.0). Adenocarcinoma of the gastroesophageal junction accounted for 5.9 per 10,000 hospitalizations among Asians, 4.5 among whites, and 4.5 among Hispanics. Gastroesophageal junction cancer was lowest among blacks (2.9) and American Indians (2.4). Finally, squamous cell carcinoma of the esophagus was frequent among blacks, 68.2 per 10,000, followed by Hispanics (36.4) and Asians (27.8), and was low among whites 24.0 and American Indians (21.5). Esophageal cancer rates remained stable in all ethnic groups from 1980 through 1995; gastroesophageal junction cancer rates increased particularly among whites, whereas gastric cancer rates declined in whites and blacks but not in Hispanics. There were significant ethnic differences in the occurrence of gastroesophageal malignancies among US military veterans. Environmental factors may explain some of these differences. Differential rates of Helicobacter pylori infection with resultant gastric atrophy and reduced acid output led to a greater risk for gastric cancer, but a reduced risk for reflux disease and cardiac cancer.

Carcinoma, Squamous Cell↗
PubMed1999

At what age should a one-time only colonoscopy for screening of colorectal cancer be performed?

OBJECTIVE: To determine at what age the only screening colonoscopy during lifetime should be performed to achieve the highest yield. METHODS: Medical decision analysis to calculate the loss in life years associated with mortality from colorectal cancer at different ages. RESULTS: The expected loss in life years from colorectal cancer is highest between the ages 70 to 80 years, with a peak occurring at age 75. The length of protection provided by colonoscopy plus polypectomy is estimated to last 5-10 years after the procedure. A screening colonoscopy at age 65 would, thus, protect a subject from age 65 until age 70 or 75 years. Similarly, a screening colonoscopy at age 70 would protect the subject from age 70 until age 75 or 80 years. CONCLUSIONS: The highest yield in life years by preventing death from colorectal cancer is achieved if the only colonoscopy per lifetime is scheduled between the ages of 65 and 70 years.

Age Distribution↗
PubMed1999

Characteristics of intestinal metaplasia in the gastric cardia.

OBJECTIVE: Intestinal metaplasia of the gastroesophageal junction is frequently grouped together with Barrett's esophagus. The area of the gastroesophageal junction is comprised of the distal esophagus and the gastric cardia. The aim of the present study was to assess whether intestinal metaplasia in the distal esophagus and gastric cardia represent two different entities with a different set of risk factors. METHODS: Patients presenting for elective upper endoscopy were enrolled into a prospective study. The presence of gastritis and intestinal metaplasia was evaluated in gastric biopsies taken from the antrum, corpus, and cardia. Barrett's esophagus was defined by the presence of any length of columnar mucosa above the gastroesophageal junction. RESULTS: Of 302 patients, 50 patients had intestinal metaplasia of the gastric cardia, 73 Barrett's esophagus, and 116 erosive esophagitis. Men were more prone than women to develop Barrett's esophagus or erosive esophagitis. Both conditions were also more common among whites than nonwhites. Smoking was particularly common among patients with Barrett's esophagus. Patients with cardiac intestinal metaplasia did not share these demographic characteristics. The prevalence of daily reflux symptoms, erosive esophagitis, and Barrett's esophagus was similar among patients both with and without cardiac intestinal metaplasia. However, atrophy and intestinal metaplasia of the gastric antrum and corpus were found more frequently among patients with than without cardiac intestinal metaplasia. CONCLUSIONS: Intestinal metaplasia of the gastric cardia is different from Barrett's esophagus. Although cardiac intestinal metaplasia is closely associated with signs of gastritis in other parts of the stomach, gastroesophageal reflux disease does not seem to be a risk factor. A diagnosis of Barrett's esophagus should not be made based on the presence of intestinal metaplasia within the cardiac portion of the gastroesophageal junction.

Barrett Esophagus↗