Biomedical subjects

Uwe Schmidt

Publications and source records attributed to Uwe Schmidt.

18 recordsLinked to original sources

PubMed2006

Characterization, isolation, and differentiation of murine skin cells expressing hematopoietic stem cell markers.

As the phenotype of adult dermal stem cells is still elusive, and the hematopoietic stem cell is one of the best-characterized stem cells in the body, we tested dermal cell suspensions, sections, and wholemounts in newborn and adult mice for hematopoietic stem cell marker expression. Phenotypic analysis revealed that a small population of CD45(+) cells and a large population of CD45(-) cells expressed CD34, CD117, and stem cell antigen-1 molecules. When cultivated in selected media supplemented with hematopoietic cytokines, total dermal cells, lineage(-), and/or highly enriched phenotypically defined cell subsets produced hematopoietic and nonhematopoietic colonies. When injected into lethally irradiated recipient mice, a small percentage of newborn dermal cells was able to migrate into hematopoietic tissues and the skin and survived through the 11-month monitoring period. Our ability to isolate a candidate autologous stem cell pool will make these cells ideal vehicles for genetic manipulation and gene therapy.

Animals↗

PubMed2006

The stairway: a novel behavioral test detecting sensomotoric stroke deficits in rats.

New therapeutic concepts of cell and tissue replacement therapies have been introduced in treatment of neurological disorders which require robust and sensitive sensomotoric behavioral diagnostic test systems for experimental research. However, most test arrays available are either expensive and/or sensitive to environmental disturbances. Moreover, an extensive training phase for experimental animals is often required by conventional tests to get reproducible data. In this study, we describe a new test array, the Stairway, that is robust, cost-effective, and needs only a minimum training phase. Its efficiency is evaluated in comparison to the well-established RotaRod and modified neurological severity score. Stroke was induced by middle cerebral artery occlusion. Human umbilical cord blood transplantation (n = 18) was performed 24 h after stroke by intravenous injection of suspended cells in comparison to control injections (n = 18), while behavioral assessment was carried out continuously for 29 days. Furthermore, development of lesions was monitored by magnetic resonance imaging. The results reveal the Stairway test as a simple, highly reproducible, and easy manageable test system thus reflecting therapeutic benefits precisely.

Animals↗

PubMed2005

The humoral immuneresponse to Helicobacter pylori infection in children with gastrointestinal symptoms.

The prevalence of Helicobacter pylori is high in Eastern Europe. The purpose of this study was to estimate the prevalence of H. pylori in symptomatic Lithuanian children and to identify the infection by clinicopathological and serological analyses. One hundred sixteen symptomatic children (age 8-16) with gastritis and duodenal ulcer were included. Biopsies were histologically assessed according to the Sydney-System. Serum IgG antibodies against H. pylori were detected by an enzyme-linked immunosorbent assay (ELISA), using low molecular mass antigen. The western blot technique was used to detect serum antibodies against the cytotoxin-associated protein (CagA) using whole cell antigen. Histologically the prevalence of H. pylori infection was 79% and not influenced by demographic factors. Mucosal inflammation and atrophy were associated with a H. pylori infection. Intestinal metaplasia was found in eight children, suggesting early H. pylori acquisition in life. Increased levels of IgG antibodies were detected in 57% of children. The prevalence of IgG antibodies was significantly higher in patients with duodenal ulcer compared to children with gastritis. Forty-four (67%) H. pylori-seropositive children had antibodies against CagA. Low molecular weight-ELISA and whole cell-western blot results were significantly associated with histopathology, the presence of duodenal ulcer and the CagA status. A high number of false seronegative cases were due to poor immunological responses in children and poor locally validated tests. The prevalence of H. pylori infection in Lithuanian children is higher compared to Western Europe. The infection is acquired in early life. Diagnosing H. pylori infection, serology is helpful, but endoscopy/histology remains as gold standard.

Adolescent↗

PubMed2005

The impact of the risk factor "age" on the early postoperative results of surgery for colorectal carcinoma and its significance for perioperative management.

The risks and benefits of surgery for colorectal cancer in old patients have not been unequivocally defined. The present investigation was carried out in 309 hospitals as a prospective multicenter study. In the period between 1 January 2000 and 31 December 2001, a total of 19,080 patients were recruited for the study; 16,142 (84.6%) patients were younger than 80 years (<80) and 2932 (15.4%) were 80 years and older (> or =80). Significant differences between the age groups were observed for general postoperative complications (22.3% for <80 years; 33.9% for > or =80). Specific postoperative complications were identical in both groups. Overall, significantly elevated morbidity and mortality rates were found with increasing age (morbidity: 33.9% vs. 43.5%; mortality: 2.6% vs. 8.0%). The distribution of tumor stages revealed a significantly higher percentage of locally advanced tumors in the older age group (stage II: 28.0% vs. 34.4%). In contrast, no increase in metastasizing tumors was found in the older age group (stage IV: 17.4% vs. 14.1%). Logistic regression showed that, in concert with a number of other parameters, age is a significant influencing factor on postoperative morbidity and mortality. The increase in postoperative morbidity and mortality rates associated with aging is a result of the increase in general postoperative complications, in particular, pneumonia and cardiovascular complications. Age as such does not represent a contraindication for surgical treatment. The short-term outcome and quality of life are of overriding importance for the geriatric patient.

Age Factors↗

PubMed2005

Expansion and differentiation of immature mouse and human hematopoietic progenitors.

A prerequisite for proper investigation of self-renewal and differentiation of hematopoietic cells is the possibility to obtain large quantities of homogenous primary progenitors under defined conditions, allowing meaningful biochemical and molecular analyses. These cells should show renewal and differentiation characteristics similar to the in vivo situation. The serum-free culture systems delineated in this chapter meet these requirements, employing primary hematopoietic cells derived from murine fetal liver and human umbilical cord blood, which show physiological self-renewal responses to cytokine/hormone combinations, which in vivo are involved in stress hematopoiesis. We describe the expansion and sustained proliferation of multipotent (mouse) and erythroid (mouse and human) progenitors, responding to physiological signals. Moreover, both mouse and human erythroid progenitors can be induced to undergo synchronous terminal differentiation by addition of high levels of erythropoietin. If fetal liver cells from p53-/- mice are used, respective multipotent and erythroid cells undergo immortalization without an obvious Hayflick crisis, but otherwise retain their primary cell characteristics. Finally, both primary and immortal mouse progenitors can be subjected to genetic manipulation via retroviral constructs with high efficiency.

Animals↗

PubMed2004

Control of erythropoiesis by erythropoietin and stem cell factor: a novel role for Bruton's tyrosine kinase.

Erythropoietin (Epo) and stem cell factor (SCF) are essential factors in the control of survival, expansion and differentiation of erythroid progenitors. Upon activation, their receptors, the EpoR and c-Kit, initiate multiple signalling pathways that control many cellular processes. To control erythropoiesis, the strength, duration and specificity of signalling must be tightly controlled. Negative feed-back regulation is extensively studied, but positive feed-forward control is relatively little studied. The cytoplasmic tyrosine kinase Bruton's tyrosine kinase (Btk) was found to be phosphorylated by Jak2 in response to Epo and appeared to be required for fast and efficient phosphorylation of Epo-induced targets including the EpoR itself and downstream targets such as PLCgamma and Stat5. Erythroid progenitors deficient in Btk fail to undergo renewal divisions and differentiate instead at low, physiologic concentrations of Epo and SCF. In addition, Btk is phosphorylated by SCF, which causes association of Btk with TRAIL-receptor1. In absence of Btk, erythroid progenitors are hypersensitive to TRAIL. Thus, Btk modulates signalling in erythroid progenitors to enhance expansion of erythroid progenitors. The complexity of signalling by the EpoR/c-Kit signalosome and its control by Btk is discussed with respect to normal and aberrant erythropoiesis.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2004

Directed differentiation and mass cultivation of pure erythroid progenitors from mouse embryonic stem cells.

Differentiating embryonic stem (ES) cells are an increasingly important source of hematopoietic progenitors, useful for both basic research and clinical applications. Besides their characterization in colony assays, protocols exist for the cultivation of lymphoid, myeloid, and erythroid cells. With the possible exception of mast cells, however, long-term expansion of pure hematopoietic progenitors from ES cells has not been possible without immortalization caused by overexpression of exogenous genes. Here, we describe for the first time an efficient yet easy strategy to generate mass cultures of pure, immature erythroid progenitors from mouse ES cells (ES-EPs), using serum-free medium plus recombinant cytokines and hormones. ES-EPs represent long-lived, adult, definitive erythroid progenitors that resemble immature erythroid cells expanding in vivo during stress erythropoiesis. When exposed to terminal differentiation conditions, ES-EPs differentiated into mature, enucleated erythrocytes. Importantly, ES-EPs injected into mice did not exhibit tumorigenic potential but differentiated into normal erythrocytes. Both the virtually unlimited supply of cells and the defined culture conditions render our system a valuable tool for the analysis of factors influencing proliferation and maturation of erythroid progenitors. In addition, the system allows detailed characterization of processes during erythroid proliferation and differentiation using wild-type (wt) and genetically modified ES cells.

Aging↗

PubMed2004

The role of Tec family kinases in myeloid cells.

Members of the Tec kinase family (Bmx, Btk, Itk, Rlk and Tec) are primarily expressed in the hematopoietic system and form, after the Src kinase family, the second largest class of non-receptor protein tyrosine kinases. During lymphocyte development and activation Tec kinases have important functions in signaling pathways downstream of the antigen receptors. Tec family kinases are also expressed in cells of the myeloid lineage. However, with the exception of mast cells and platelets, their biological role in the myeloid system is only poorly understood. This review summarizes the current knowledge about the function of Tec family kinases in hematopoietic cells of the myeloid lineage.

Blood Platelets↗

PubMed2004

Btk is required for an efficient response to erythropoietin and for SCF-controlled protection against TRAIL in erythroid progenitors.

Regulation of survival, expansion, and differentiation of erythroid progenitors requires the well-controlled activity of signaling pathways induced by erythropoietin (Epo) and stem cell factor (SCF). In addition to qualitative regulation of signaling pathways, quantitative control may be essential to control appropriate cell numbers in peripheral blood. We demonstrate that Bruton's tyrosine kinase (Btk) is able to associate with the Epo receptor (EpoR) and Jak2, and is a substrate of Jak2. Deficiency of Btk results in reduced and delayed phosphorylation of the EpoR, Jak2, and downstream signaling molecules such as Stat5 and PLCgamma1 as well as in decreased responsiveness to Epo. As a result, expansion of erythroid progenitors lacking Btk is impaired at limiting concentrations of Epo and SCF. In addition, we show that SCF induces Btk to interact with TNF-related apoptosis-inducing ligand (TRAIL)-receptor 1 and that lack of Btk results in increased sensitivity to TRAIL-induced apoptosis. Together, our results indicate that Btk is a novel, quantitative regulator of Epo/SCF-dependent expansion and survival in erythropoiesis.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2004

Procaine hydrochloride fails to relieve pain in patients with acute pancreatitis.

BACKGROUND: Several analgesics are in use for pain control in patients with acute pancreatitis. Procaine hydrochloride (procaine) has a long tradition and is recommended by the German Society of Gastroenterology and Metabolic Diseases for pain treatment in patients with acute pancreatitis. There is no controlled trial showing that procaine could be effective for pain treatment. METHODS: In an open, randomized, controlled trial, 107 patients (76 male, 31 female; mean age 45 +/- 12 years) were included and randomized either to receive procaine (n = 55) or pentazocine (n = 52) for pain relief. Procaine 2 g/ 24 h was administered by continuous intravenous infusion, pentazocine 30 mg was administered every 6 h as a bolus intravenous injection. Pentazocine was additionally administered on demand whenever required in patients of both treatment groups and its total consumption was recorded. Pain scores were assessed twice daily on a visual analogue scale. RESULTS: Patients receiving procaine were significantly more likely to request additional analgesics compared to patients treated with pentazocine alone, 98 vs. 44%, respectively (p < 0.001). Procaine did not reduce the amount of pentazocine required for pain control. The amount of pentazocine given in both groups was not statistically significantly different. Recorded pain scores were significantly lower (p < 0.001) in patients in the pentazocine group during the first 3 days of analgesic treatment. From day 4 on there was no significant difference in pain scores among the two groups. CONCLUSION: Thus, intravenous procaine treatment is not effective for pain control in patients with acute pancreatitis.

Acute Disease↗

PubMed2004

Laparoscopic approach to treatment of sigmoid diverticulitis: changes in the spectrum of indications and results of a prospective, multicenter study on 1,545 patients.

BACKGROUND: The aim of the present study was to analyze changes regarding the indications for and results of laparoscopic treatment of sigmoid diverticulitis. METHODS: The data were collected within the framework of an ongoing prospective multicenter study carried out by the Lapa roscopic Colorectal Surgery Study Group and were submitted to a statistical subgroup analysis. The institutions participating in the study were divided into three groups by experience (Group I, >100 procedures; Group II, 30-100 procedures; Group III, < 30 procedures). RESULTS: Among the 3,868 recruited patients, sigmoid diverticulitis (n = 1,545, 40 percent) was by far the most common indication for surgery, and sigmoid resection (n = 2,160, 55.9 percent) was by far the most common laparoscopic procedure. A total of 1,353 patients (87.6 percent) had uncomplicated diverticulitis, whereas 192 (12.4 percent) had a complicated form of diverticular disease (Hinchey I-IV, diverticular bleeding, fistula formation). Cases of complicated diverticulitis were significantly more frequently operated on at institutions with greater experience (Group I, 20.8 percent; Group II, 8.7 percent; Group III, 7.9 percent). Despite this fact, these institutions still had better intraoperative complication rates (Group I, 5.0 percent; Group II, 5.8 percent; Group III, 6.9 percent), conversion rates (Group I, 4.4 percent; Group II, 6.7 percent; Group III, 7.7 percent), and postoperative morbidity (Group I, 15.9 percent; Group II, 16.6 percent; Group III, 18.6 percent) and mortality (Group I, 0.2 percent; Group II, 0.5 percent; Group III, 0.4 percent) rates. CONCLUSION: An increase in experience is associated with an expansion of laparoscopic indications to include complicated forms of diverticulitis, with comparable ntraoperative and postoperative complication rates, operating time, and mortality rates.

Anastomosis, Surgical↗

PubMed2004

The Btk inhibitor LFM-A13 is a potent inhibitor of Jak2 kinase activity.

LFM-A13, or alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide, was shown to inhibit Bruton's tyrosine kinase (Btk). Here we show that LFM-A13 efficiently inhibits erythropoietin (Epo)-induced phosphorylation of the erythropoietin receptor, Janus kinase 2 (Jak2) and downstream signalling molecules. However, the tyrosine kinase activity of immunoprecipitated or in vitro translated Btk and Jak2 was equally inhibited by LFM-A13 in in vitro kinase assays. Finally, Epo-induced signal transduction was also inhibited in cells lacking Btk. Taken together, we conclude that LFM-A13 is a potent inhibitor of Jak2 and cannot be used as a specific tyrosine kinase inhibitor to study the role of Btk in Jak2-dependent cytokine signalling.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2003

Loss of imprinting of IGF-II gene in children with acute lymphoblastic leukemia.

Insulin-like growth factor-II (IGF-II) is known to be involved in the regulation of growth, differentiation and cell death in normal human tissues. In a variety of human tumors, the IGF-II gene is overexpressed and considered to be a stimulator for tumor growth through autocrine and paracrine mechanisms. The IGF-II gene is normally parental imprinted, only the paternal allele being expressed in most tissues. Several reports about biallelic expression (loss of imprinting (LOI)) of the IGF-II gene in different tumors suggest a role of dysregulation of IGF-II imprinting in tumorigenesis. However, biallelic expression of IGF-II gene has also been reported in different tissues of a significant number of normal controls, indicating either a normal phenomenon or an elevated cancer risk in this group of persons. Although LOI of IGF-II presumably promotes tumorigenesis by increasing IGF-II expression, elevated IGF-II levels in those patients have not been reported. We studied IGF-II gene expression in malignant lymphoblasts of 124 children suffering from acute lymphoblastic leukemia, 196 cord blood samples from healthy newborns and mononuclear cells (MNC) from 50 healthy age matched children. The ApaI polymorphism in exon 9 of the IGF-II gene and allele-specific exon-connection RT-PCR was used for determination of the imprinting status. From 44 informative ALL-patients, 24 (54%) showed LOI of the IGF-II gene. Twenty percent of the informative cord blood samples (N=56) and 14% of the informative MNC samples from healthy controls (N=22) showed biallelic expression of IGF-II. In the ALL-patients, no statistical significant correlation between LOI patients and relapse rate, surviving rate and risk groups could be detected. We conclude that LOI of IGF-II occurs in malignant lymphoblasts of children suffering from acute lymphoblastic leukemia in more than 50% of the patients. In MNC from cord blood and peripheral MNC from healthy controls, biallelic expression could be detected in up to 20% of all cases. The importance of LOI in ALL-patients needs to be further evaluated to determine its impact in leukemogenesis.

Alleles↗

PubMed2003

Risk factors for failure of endoscopic stenting of biliary strictures in chronic pancreatitis: a prospective follow-up study.

OBJECTIVES: The aims of this study were to investigate the value of interventional endoscopy in patients with strictures of the common bile duct (CBD) caused by chronic pancreatitis (CP), and to define the subset of patients who may be at risk for failure of endoscopic intervention, in a prospective follow-up study. METHODS: A total of 61 patients with symptomatic CBD strictures caused by alcoholic CP were treated by endoscopic stent insertion for 1 yr with scheduled stent changes every 3 months. After the treatment period, all patients entered a follow-up program. RESULTS: Initial endoscopic drainage was successful in all cases, with complete resolution of obstructive jaundice. After 1 yr from the initial stent insertion, in 19 patients (31.1%) the obstruction was resolved, and stents were removed without any need of additional procedures. During a median follow-up of 40 months (range 18-66 months), 16 patients had no recurrence of symptomatic CBD stricture (long term success rate 26.2%). Of 45 patients who needed definitive therapy, 12 patients (19.7%) were treated with repeated plastic stent insertion and three (4.9%) with insertion of a metal stent, and 30 patients (49.2%) underwent surgery. Among the variables tested, calcification of the pancreatic head was the only factor that was found to be of prognostic value. Of 39 patients with calcification of the pancreatic head, only three (7.7%) were successfully treated by a 1-yr period of plastic stent therapy, whereas in 13 of 22 patients (59.1%) without calcification, this treatment was successful (p<0.001). CONCLUSIONS: Endoscopic drainage of biliary obstruction provides excellent short term but only moderate long term results. Patients without calcifications of the pancreatic head benefit from biliary stenting. Patients with calcifications were identified to have a 17-fold (95% CI=4-74) increased risk of failure of a 12 month course of endoscopic stenting.

Adult↗

PubMed2003

Clinical studies' assessment.

The paper gives some more general remarks on clinical studies from the perspective of a biometrician. Prospective randomised clinical trials are the study type with highest evidence. But there are other study types, too, which have their legitimacy in the process of medical knowledge finding and quality assurance. It is important to use each type in the right place and in the right way. Analysis and interpretation have to take care for the study type.

Clinical Trials as Topic↗

PubMed2002

Early postoperative results of surgery for rectal carcinoma as a function of the distance of the tumor from the anal verge: results of a multicenter prospective evaluation.

BACKGROUND: The problems associated with rectal surgery are frequently discussed with no reference being made to the distance of the tumor from the anal verge. This study examined the effect of the location of the tumor on early postoperative results. PATIENTS AND METHODS: This was a multicenter study involving 75 German hospitals and 3756 patients, of whom 1463 had rectal carcinoma. On the basis of the location of the tumor (distance from the anal verge), four groups were distinguished: <4, 4-7.9, 8-11.9, and 12-16 cm. RESULTS: Resection and abdominoperineal resection rates and the incidence of postoperative complications depended on the location of the tumor. Significantly higher resection rates and fewer specific complications, and a significant reduction in overall postoperative morbidity were found with tumor locations more than 8 cm from the anal verge. The highest anastomotic leak rate was observed with anastomoses less than 7 cm from the anal verge. The logistic regression showed that the distance of the tumor from the anal verge is an independent variable for the development of an anastomotic leak. CONCLUSIONS: Early results are greatly affected by the location of the rectal carcinoma. This applies to both abdominoperineal resection rates and specific postoperative complications, such as anastomotic leak rate and operation morbidity in general.

Adult↗

PubMed2002

Impact of age on the short-term postoperative outcome of patients undergoing surgery for colorectal carcinoma.

BACKGROUND: Patient age has a decisive impact on the short-term postoperative results in surgery for carcinoma. PATIENTS AND METHODS: This prospective multicenter study involved 75 German hospitals and 3756 patients undergoing treatment in 1999: 1447 aged under 65 years, 1847 aged 65-79 years, and 458 aged over 80 years. RESULTS: In the oldest patient group, there was a significantly higher proportion of extensive, localized tumors (UICC stage II: 25.9%, 28.4%, and 36.1%, respectively) and significant differences were found among the three groups in operation rates (98.8%, 98.6%, and 96.5%), resection rate (94.2%, 93.2%, and 83.9%), general postoperative complications (21.5%, 28.6%, and 41.2%), morbidity (36.5%, 42.6%, and 50.0%) and mortality (2.7%, 6.6%, and 11.8%). CONCLUSION: In the elderly, locally advanced tumors, but not metastasizing tumors, are to be expected. The increase in postoperative morbidity and mortality rates with increasing age was due to the increase in general postoperative complications. Surgery for colorectal carcinoma in patients of advanced age is not associated with any increase in intraoperative or specific postoperative complications.

Adenocarcinoma↗

PubMed2002

Value of a protective stoma in low anterior resections for rectal cancer.

INTRODUCTION: Anastomotic leakage is a major problem in colorectal surgery and in particular in operations for low rectal cancer. The present study investigates the question whether a protective stoma can reduce the (clinical and radiologic) anastomotic leakage rate and/or the rate of leakage requiring surgery. METHODS: The investigation took the form of a prospective multicenter study involving 75 German hospitals and was performed between January 1, 1999, and December 31, 1999. A comparison was made of the postoperative results of procedures performed with and those performed without a protective stoma in patients undergoing low anterior rectal resection. In addition, logistic regression using the target criteria, overall anastomotic leakage and anastomotic leakage requiring surgery, was applied. RESULTS: Among the 3,695 operations performed for carcinoma of the rectum or colon, 482 were low anterior resections. In 334 patients (69.3 percent) no protective stoma was constructed, whereas 148 (30.7 percent) received such protection. Age, American Society of Anesthesiologists physical status, and body mass index were identical in both groups. In the group receiving a protective stoma, however, neoadjuvant radiochemotherapy was more common, the tumors were lower-and thus the total mesorectal excision rate higher, the intraoperative complication rate was higher, and the duration of the operation was longer. The differences were all significant. The major criterion (overall anastomotic leakage rate) was identical in the two groups, but the rate of leakage requiring surgery was significantly lower in patients receiving a protective stoma (p = 0.028). The logistic regression revealed that use of a protective stoma is a predictor of protection against anastomotic leakage requiring surgery. The distance of the tumor from the anal verge and the duration of the operation are further predictors. CONCLUSION: The particular benefit of a covering stoma is reduction in the rate of leaks requiring surgery and thus in the severe consequences of an anastomotic leakage.

Adult↗