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Biomedical subjects

M Hildebrandt

Publications and source records attributed to M Hildebrandt.

At least 19 recordsLinked to original sources
PubMed2006

Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss.

BACKGROUND: The hippocampal formation is essentially involved in the formation of conscious memories for facts and events and neurologic diseases affecting the hippocampus associate with severe memory deficits, i.e., temporal lobe epilepsies. METHODS: We studied the degree of declarative memory dysfunction in 24 human subjects with unilateral mesial temporal lobe epilepsy, using the unique possibility to access memory performance of each isolated hippocampus by intracarotid amobarbital anesthesia. Subsequently, hippocampal specimens from the same patients were available for neuropathologic analysis following surgical treatment of intractable seizures. RESULTS: Neuronal cell loss in the dentate gyrus and all hippocampal subfields correlated with memory performance with the exception of CA2. Moreover, multiple regression and partial correlation analyses identified neuronal cell loss within the internal limb of the dentate gyrus, a developmentally distinct subregion of the hippocampal formation known to generate new neurons throughout life, as highly significant predictor for the patient's ability to learn and recall memories. CONCLUSIONS: In accordance with animal studies, the dentate gyrus may play a critical role in the neuronal network associated with memory formation.

Adult↗
PubMed2003

Clinical research and industrial sponsoring: avenues towards transparency and credibility.

Clinical research is intended to serve the patient, in the pursuit of a deepened understanding of physiological interactions and their changes in disease, and of potentially beneficial implications for the patient. The impetus to perform clinical research is shaped by various intentions, such as the desire to provide cure or relief, striving for personal and professional success, public attention, financial considerations, or simply scientific curiosity. A similarly wide range of diverging interests must be assumed to impinge on diagnostic and therapeutic decisions in clinical work. How are we to perform clinical research and therapy with the patients' benefit in mind, in view of such a complex motivational status, and how are we to perceive the peculiar interests of those influencing clinical work, including ourselves? In this review, we attempt to elucidate the complex pathways of interaction between physicians and industrial sponsors. Special attention will be paid to the following topics: the pharmaceutical market, public interests, legal and ethical issues, conflicts of interest, and the potential impact of industry-sponsored drug trials on medical information and subsequent therapeutic decisions. We will conclude with recommendations for an acceptable position in the tension between cooperation and corruptibility, a position that grants priority to the patient's needs rather than third party interests.

Biomedical Research↗
PubMed2001

Eating disorders: a role for dipeptidyl peptidase IV in nutritional control.

Dipeptidyl peptidase IV (DPP IV), a serine protease with broad tissue distribution and known activity in serum, has been postulated to modulate nutrition control by modification or inactivation of peptide hormones operating in the enteroinsular axis. We hypothesized that changes of DPP IV activity in serum are related to the nutrition status of patients with eating disorders. Serum DPP IV activity was measured in 52 patients (28 with anorexia nervosa and 24 with bulimia nervosa) in four consecutive weekly analyses. Simultaneously, the number of CD26 (DPP IV)-positive peripheral blood lymphocytes was counted. The same analyses were carried out in 28 healthy female volunteers. In week 1 and throughout the observation period, DPP IV activity in the sera of patients with anorexia nervosa and, to a lesser extent, those with bulimia nervosa was elevated in comparison to that of healthy controls (week 1: means = 92.8 U/L for anorexia-nervosa patients and 89.3 U/L for bulimia-nervosa patients versus 74.7 U/L for healthy control subjects, P = 0.014; weeks 1-4: 91.8 U/L for anorexia-nervosa patients and 86.2 U/L for bulimia-nervosa patients versus 77.6 U/L for healthy controls, P < 0.001). We assume that the increase in DPP IV serum activity will increase the turnover of distinct peptide hormones with known effects on nutrition control and susceptibility to degradation by DPP IV. The potential impact of an increase in DPP IV activity in serum on satiety and nutrition control contributes to previously reported implications for immune function.

Anorexia Nervosa↗
PubMed2001

Inhibition of dipeptidyl peptidase IV (DP IV, CD26) activity abrogates stress-induced, cytokine-mediated murine abortions.

In the CBA x DBA/2 mouse model, stress-triggered abortions are mediated by a Th1-like cytokine response of decidual lymphocytes. The factors that determine the cytokine pattern leading to abortion are currently unknown. Dipeptidyl Peptidase IV (DP IV) enhances Th1-cytokine responses and impairs the evolvement of a Th2 cytokine profile. The T-cell-activation antigen, CD26, possesses DP IV activity. The aim of the present study was to investigate the role of DP IV activity and CD26-positive decidual lymphocytes in murine stress-triggered abortions by inhibition of DP IV activity. DBA/2-mated CBA mice were stressed on day 5.5 of pregnancy and received daily injections of an inhibitor of DP IV activity, Ile-thiazolidide (20 micromol/kg). On day 13 of gestation, the animals were sacrificed and the percentage of implants and abortions documented. CD26-positive lymphocytes in spleen and uterine decidua and the intracellular cytokines interferon (IFN)-gamma and interleukin (IL)-10 were determined by flow cytometry. Stressed and nonstressed animals receiving an inactive stereoisomeric form were used as controls. In mice receiving the DP IV inhibitor, stress failed to boost the abortion rate (37.2% versus 13.6%, P < 0.01). IFN-gamma producing cells were increased in stressed animals, but returned to the baseline upon the inhibition of DP IV. The number of IL-10 producing cells was reduced in stressed animals, independent from DP IV inhibition.

Animals↗
PubMed2001

PBPC mobilization with paclitaxel, ifosfamide, and G-CSF with or without amifostine: results of a prospective randomized trial.

BACKGROUND: The impact of amifostine on PBPC mobilization with paclitaxel and ifosfamide plus G-CSF was assessed. STUDY DESIGN AND METHODS: Forty patients with a median age of 34 years (range, 19-53) who had germ cell tumor were evaluated for high-dose chemotherapy. Patients were randomly assigned to receive either a single 500-mg dose of amifostine (Group A, n = 20) or no amifostine (Group B, n = 20) before mobilization chemotherapy with paclitaxel (175 mg/m(2)) given over 3 hours and ifosfamide (5 g/m(2)) given over 24 hours (TI) on Day 1. G-CSF at 10 microg per kg per day was given subsequent to TI with or without amifostine from Day 3 until the end of leukapheresis procedures. RESULTS: In 2 (10%) of 20 patients receiving amifostine and 3 (15%) of 20 patients not receiving it, no PBPC separation was performed because of mobilization failure. No significant differences were observed in the study arms with regard to the time from chemotherapy until first PBPC collection or the number of apheresis procedures needed to harvest more than 2.5 x 10(6) CD34+ cells per kg. Furthermore, leukapheresis procedures yielded comparable doses of CD34+ cells per kg (3.4 x 10(6) vs. 3.6 x 10(6); p = 0.82), MNCs per kg (2.7 x 10(8) vs. 2.6 x 10(8); p = 0.18), and CFU-GM per kg (15.9 x 10(4) vs. 19.3 x 10(4); p = 0.20). Patients in Group A had higher numbers of circulating CD34+ cells on Day 10 (103.0/microL vs. 46.8/microL; p = 0.10) and on Day 11 (63.0/microL vs.14.3/microL; p = 0.04) than did patients in Group B. CONCLUSION: Administration of a single dose of amifostine before chemotherapy with TI mobilized higher numbers of CD34 cells in the circulation, but did not enhance the overall collection efficiency in the present trial.

Adult↗
PubMed2001

Dipeptidyl peptidase IV (DP IV, CD26) in patients with inflammatory bowel disease.

BACKGROUND: Dipeptidyl peptidase IV (DP IV, CD26), a serine protease with broad tissue distribution and known activity in serum, participates in T cell activation and promotes a Th1 cytokine response, a function in part attributable to its enzymatic activity. We hypothesized that the activity of DP IV in serum and expression of CD26/DP IV in lymphocytes may be altered in patients with inflammatory bowel disease (IBD). METHODS: Serum DP IV activity and CD26 (DP IV)-positive peripheral blood lymphocytes were measured in 110 patients with IBD (Crohn disease (CD): n = 63, ulcerative colitis (UC): n = 47). Additionally, T cell activation antigens (CD25, CD95) and costimulatory molecules (CD28) were evaluated. The same analyses were carried out in healthy volunteers (HC, n = 28). Thirty-nine patients with CD and 28 patients with UC were reassessed 3-6 months after the first visit. RESULTS: In patients with IBD, the DP IV activity in serum was reduced (mean +/- s (standard deviation): 52.8 U/l +/- 16.9 (CD) and 55.7 +/- 15.1 U/l (UC) versus 71.9 +/- 18.4 (HC), P < 0.001). Furthermore, patients with IBD had higher numbers of CD26-positive cells coexpressing CD25 and a higher surface expression of CD26 (DP IV) (mean fluorescence intensity, mean 57.1 (CD) and 59.8 (UC) versus 29.9 (HC), P < 0.001). The DP IV activity in serum showed an inverse correlation with known disease activity scores as well as with the concentrations of orosomucoid in serum. CONCLUSION: The changes of DP IV in patients with IBD highlight alterations at an interface between immune function and metabolism of peptide hormones, with potential importance for the pathophysiology of IBD. Furthermore, these changes may help to refine the assessment of IBD activity.

Adult↗
PubMed2001

Stress and immune mediators in miscarriage.

BACKGROUND: Stress is thought to be abortogenic and psycho-neuro-immunological pathways have been suggested to be involved in triggering miscarriages. From experiments in pregnant mice exposed to stress some insights into the underlying mechanisms have been gained, delineating immunological imbalances as a cause of pregnancy failure. In order to test the validity of the conclusions drawn from murine experiments and the role of stress in human pregnancy loss, the following study was performed. METHODS: We used an established perceived stress questionnaire and measured the stress score of women with a confirmed diagnosis of first trimester spontaneous abortion (n = 94). Decidual tissue was investigated by immunohistochemistry and in-situ hybridization to detect the presence and distribution of immunocompetent decidual cells [CD56(+) natural killer (NK) cells, CD8(+)and CD3(+) T cells, tryptase(+) mast cells (MCT(+)) and tumour necrosis factor (TNF)-alpha(+) cells]. The patient cohort was divided into women experiencing low or high levels of stress. RESULTS: In the decidua of women with high stress scores we observed significantly higher numbers of MCT(+), CD8(+) T cells and TNF-alpha(+) cells per mm(2) tissue (P < or = 0.05). No significant differences between individuals with lower or higher stress scores could be observed with respect to decidual CD56(+) NK and CD3(+) T cells. CONCLUSIONS: Using a questionnaire to score perceived stress in humans may be a valid approach to assess non-biased stress scores. Stress-triggered abortion in humans, identified by a questionnaire, can be linked to immunological imbalances.

Abortion, Spontaneous↗
PubMed2001

Murine stress-triggered abortion is mediated by increase of CD8+ TNF-alpha+ decidual cells via substance P.

PROBLEM: Stress is known to induce abortions in mice and humans. Increased levels of abortogenic type 1 helper T-cell cytokines and decreased levels of pregnancy protective cytokines could be linked to stress-triggered embryonic loss. Stress promotes neurotransmitter substance P (SP) release in tissues. SP increases the production of decidual tumor necrosis factor (TNF)-alpha, whereby the phenotype of these TNF-alpha-producing cells is hypothetical. The objective of the present study was to identify decidual TNF-alpha-producing cell populations that are involved in stress-induced murine abortion. METHOD: DBA/2J-mated CBA/J female mice were exposed to ultrasonic sound stress on day 5.5 of pregnancy. The mice were randomized and half were treated with the SP NK1-receptor antagonist (SP-RA) RP 67580 (200 microg/mouse). Frequency and cytokine profile of CD8+ cells were evaluated by immunohistochemistry and flow cytometry. Degranulation of uterine mast cells was examined histologically. RESULTS: On day 13.5 of pregnancy, the uteri were removed and the resorption rate was calculated. A mean resorption rate of 38.4% was detected in stressed mice (n = 10) compared to 13.1% in non-stressed control mice (n = 11, P < 0.01). Injection of SP-RA decreased the abortion rate to 18.4% in stressed mice (n = 19, P < 0.01). Flow cytometry revealed a stress-related increase of TNF-alpha+/CD8+ decidual T cells, which could be abrogated by SP-RA (P < 0.05). No significant differences could be observed in numbers of mast cells and total CD8+ cells in situ. CONCLUSION: Our data suggest that stress-triggered abortion is mediated by SP, and SP receptor blockade abrogates stress-triggered abortion via reduced production of TNF-alpha by CD8+ T cells.

Abortion, Veterinary↗
PubMed2001

Role of stress in functional gastrointestinal disorders. Evidence for stress-induced alterations in gastrointestinal motility and sensitivity.

Psychological stress is widely believed to play a major role in functional gastrointestinal (GI) disorders, especially irritable bowel syndrome (IBS), by precipitating exacerbation of symptoms. The available data clearly demonstrate that inhibition of gastric emptying and stimulation of colonic transit is the most consistent pattern in the motility response of the GI tract to acute or short-term stress. Thus, one might propose that these alterations might play a pathophysiological role in dyspeptic symptoms and alterations in stool frequency and consistency in patients with stress-related functional GI disorders. Taken together, the above-mentioned studies suggest that the colonic motor response to stress is exaggerated in IBS. There is evidence that an increased emotional response is associated with this difference in colonic, and perhaps also gastric motor responses to certain stressors. However, almost no valid data are available so far from human studies addressing the question if differences in motility responses to stress between patients with functional GI disorders and healthy subjects are due to an altered stress response associated with an imbalance of the autonomic nervous system or increased stress susceptibility. We can summarize that in experimental animals the most consistent pattern of GI motor alterations induced by various psychological and physical stressors is that of delaying gastric emptying and accelerating colonic transit. Endogenous corticotropin-releasing factor (CRF) in the brain plays a significant role in the central nervous system mediation of stress-induced inhibition of upper GI and stimulation of lower GI motor function through activation of brain CRF receptors. The inhibition of gastric emptying by CRF may be mediated by interaction with the CRF-2 receptor, while CRF-1 receptors are involved in the colonic and anxiogenic responses to stress. Endogenous serotonin, peripherally released in response to stress, seems to be involved in stress- and central CRF-induced stimulation of colonic motility by acting on 5HT-3 receptors. Taken together, the limited data available from investigations in healthy subjects and patients with functional GI disorders provide some evidence that stress affects visceral sensitivity in humans. Acute psychological stress seems to facilitate increased sensitivity to experimental visceral stimuli, if the stressor induces a significant emotional change. In summary, studies in experimental animals suggest that stress-induced visceral hypersensitivity is centrally mediated by endogenous CRF and involvement of structures of the emotional motor system, e.g. the amygdala. Stress-induced activation or sensitization of mucosal mast cells in the GI tract seem to be involved in stress-associated alterations of visceral sensitivity.

Colon↗
PubMed2000

Dipeptidyl peptidase IV (DPP IV, CD26) in patients with mental eating disorders.

The notion that patients with eating disorders maintain a functional immunosurveillance in spite of severe malnutrition has attracted researchers for years. Dipeptidyl Peptidase IV (DPP IV), a serine protease with broad tissue distribution and known activity in serum, operates in the cascade of immune responses. Membrane-bound DPP IV expressed on lymphocytes, also known as the leukocyte antigen CD26, is considered to participate in T cell activation. We hypothesized that the activity of DPP IV in serum and expression of CD26 in lymphocytes may be altered in patients with eating disorders. Serum DPP IV activity and the number of CD26 (DPP IV)-positive peripheral blood lymphocytes were measured in 44 patients (anorexia nervosa (AN): n = 21, bulimia (B): n = 23) in four consecutive weekly analyses. The analysis of CD26-positive cells included the characterization of CD26-bright and CD26-dim positive subsets. Additionally, the expression of CD25 (IL-2 Receptor alpha chain) was evaluated to estimate the degree of T cell activation. The same analyses were carried out in healthy female volunteers (HC, n = 20). CD26-positive cells were reduced in patients as compared to healthy controls (mean 40.2% (AN) and 41.1% (B) vs. 47.4% (HC), p < 0.01), while the DPP IV activity in serum was elevated (mean 108.4 U/l (AN) and 91.1 U/l (B) vs. 80.3 U/l (HC), p < 0.01). The potential implications of changes in DPP IV expression and serum activity on--and beyond--immune function are discussed.

Adult↗
PubMed2000

Immunomagnetic selection of CD34+ cells: factors influencing component purity and yield.

BACKGROUND: In immunomagnetic selection of CD34+ cells from HPC transplants, not all factors that affect yield and purity of CD34+ cells are known. METHODS: Forty-three consecutive procedures of immunomagnetic selection of CD34+ cells from peripheral blood HPCs and bone marrow harvests (autologous harvests, n = 27; allogeneic harvests; n=16) were performed by use of a cell selection system (Isolex 300i, Baxter Immunotherapy). The composition of the starting component and the subsets of CD34+ cells were analyzed for correlation with the yield and purity of the final component. RESULTS: The mean purity of the final components was 84.3 percent (range, 27-99%), and the mean yield was 51.4 percent (range, 9.4-80. 4%). Partial regression analysis showed that, among the factors correlating with purity and/or yield, the RBC volume in the starting fraction had the highest predictive impact on the purity and yield of CD34+ cells, even after the exclusion of procedures using bone marrow harvests as an HPC source (beta coefficient, -0.704; p = 0. 001). CONCLUSION: The use of the Isolex 300i system allows efficient recovery of CD34+ cells in routine selection procedures. The volume of RBCs in the starting component should be minimized to ensure a high yield and purity of the final component.

Antigens, CD34↗
PubMed2000

[Validation of the new German translation version of the "Short Inflammatory Bowel Disease Questionnaire" (SIBDQ)].

In the face of a hardly predictable course of illness--potentially effecting a severe diminution of daily activities--the quality of life (QOL) represents a chief outcome measure in the treatment of inflammatory bowel diseases (IBD). For the German-speaking area an economical disease-specific instrument measuring QOL has been missing, so far. Therefore, we translated and adapted the recently validated "Short Inflammatory Bowel Disease Questionnaire" SIBDQ (11). Bowel symptoms, systemic symptoms, moods, and social activities are represented by a total of 10 items. Along with this questionnaire 7 accepted instruments assessing QOL-components were administered to 125 outpatients (54 ulcerative colitis, 71 Crohn's disease) and 51 healthy controls. The psychometric properties are good. Consistency is alpha = .84, thereby slightly surpassing the Anglo-American SIBDQ (alpha = .78). Retest-reliability after 26 weeks is r = .60. Systematic covariations with accepted QOL-instruments give evidence for its convergent and discriminatory validity. Differences between groups (high vs. low inflammatory activity vs. healthy controls) substantiate its sensitivity. Thus, the German adaptation of the accepted SIBDQ supplies an economic, reliable, and valid instrument that proved able to assess clinically relevant differences in QOL in patients with IBD. We suggest that it should be used by its overall score rather than its subscales. The instrument is appropriate to be used in therapy outcome and evaluation studies. It allows international comparison.

Activities of Daily Living↗
PubMed2000

Pregnancy as a model of controlled invasion might be attributed to the ratio of CD3/CD8 to CD56.

PROBLEM: Pregnancy can be considered as a model of successfully controlled tissue invasion. Cellular mediated immunity appears to regulate the controlled invasion of fetal trophoblast cells. In endometrium cancer, a dysregulation of invasive malignant cells can be observed. Since immunocompetent cells are known to be involved in recognition and rejection of 'non-self' antigens, we investigated the presence and distribution pattern of CD3, CD8, CD56, and CD68 positive cells in decidua from normal and failing pregnancies, compared with malignant and benign endometrium. METHOD OF STUDY: Decidual tissue from first trimester normal pregnancies (NP; n = 15) and abortion (AB; n = 12), endometrial samples from premenopausal women (NE; n = 8), and endometrioid adenocarcinoma (EA; n = 8) were examined by immunohistochemistry using monoclonal antibody against large spectrum cytokeratin, and against the receptors CD3, CD8, CD56 and CD68, respectively. RESULTS: In NP, we observed 32.5% CD3, 44.7% CD56, and 22.9% CD68+ cells. In AB, we found 36.9% CD3, 45.3% CD56, and 17.8% CD68+ cells. The differences in ratio between normal pregnancy and abortion were not statistically significant. In NE, we counted 39.5% CD3, 30.2% CD56 and 30.2% CD68 cells. In EA, we observed 47.9% CD3, 12.4% CD56 and 39.7% CD68+ cells. The decrease of CD56 positive cells in endometrioid adenocarcinoma was statistically significant. Interestingly, we found 4.1% of cells positive for CD8 in NP, 4.9% in AB, 22.7% in NE, and 48.2% in EA. CONCLUSIONS: The increase of CD8 cells in NE, and particularly in EA, and decrease of CD56 cells, compared with NP or AB, suggests an interaction between CD8 cells and CD56 cells. Studying different pathological situations in the uterus, such as malignancies or ectopic pregnancies, might help us to understand the mechanisms involved in the maintenance of pregnancy.

Abortion, Induced↗
PubMed2000

Determination and Successful Transfusion of Anti-Gerbich-Positive Red Blood Cells in a Patient with a Strongly Reactive Anti-Gerbich Antibody.

Background: The clinical relevance of antibodies directed against members of the Gerbich (GE) family of antigens is not invariably clear. Given the scarcity of serologically compatible red blood cells (RBC), various methods may have to be applied to assess the safety of transfusing serologically incompatible RBC. Patient and Methods: The serum of a 57-year-old male Caucasian admitted to hospital for gastrectomy was found to contain a highly reactive anti-GE2 antibody (IgG(1)). In addition to a monocyte monolayer assay, 50 ml of GE2-positive RBC were transfused, and blood samples were taken before and 1 and 24 h after transfusion for flow-cytometric determination of transfused cells. Results: Both tests showed no increased destruction of GE2-positive RBC. The transfusion of 4 units of GE2-positive RBC was well tolerated, and hemoglobin increased adequately. Conclusion: This case may extend the information available not only on antibodies directed against members of the GE family of antigens but also on methods to estimate the survival of transfused RBC. Copyright 2000 S. Karger GmbH, Freiburg

Journal Article↗