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Biomedical subjects

M Weinmann

Publications and source records attributed to M Weinmann.

At least 19 recordsLinked to original sources
PubMed2004

Tumour hypoxia: impact on biology, prognosis and treatment of solid malignant tumours.

Tumour hypoxia is a major constraint for radiotherapy and many types of chemotherapy. A variety of different pathogenetic mechanisms contribute to the development of hypoxia in solid tumours. Hypoxia is associated with unfavourable prognosis, regardless of the treatment modality applied. Two different effects have been considered to explain the deleterious effects of hypoxia on the outcome of tumour patients. The first aspect encompasses the direct interference of hypoxia with antineoplastic treatment modalities. The efficacy of ionizing radiation, but also of a variety of cytotoxic drugs and cytokines rely directly on adequate oxygen tensions. The second aspect concerns the effects of hypoxia on the biology of tumour and stromal cells. Hypoxia is related to malignant progression, increased invasion, angiogenesis and an increased risk of metastasis formation. Possibly, hypoxia is furthermore a stressor which selects cells with increased resistance to apoptosis and thereby indirectly contributes to treatment resistance. This article reviews in brief the specific pathophysiology of tumour oxygenation and its implications for prognosis, tumour treatment and biology.

Apoptosis↗
PubMed2002

Expression pattern of the urokinase-plasminogen activator system in rat DS-sarcoma: role of oxygenation status and tumour size.

The urokinase plasminogen activator system plays a central role in malignant tumour progression. Both tumour hypoxia and enhancement of urokinase plasminogen activator, urokinase plasminogen activator-receptor and plasminogen activator inhibitor type 1 have been identified as adverse prognostic factors. Upregulation of urokinase plasminogen activator or plasminogen activator inhibitor type 1 could present means by which hypoxia influences malignant progression. Therefore, the impact of hypoxia on the expression pattern of the urokinase plasminogen activator system in rat DS-sarcoma in vivo and in vitro was examined. In the in vivo setting, tumour cells were implanted subcutaneously into rats, which were housed under either hypoxia, atmospheric air or hyperoxia. For in vitro studies, DS-sarcoma cells were incubated for 24 h under hypoxia. Urokinase plasminogen activator and urokinase plasminogen activator-receptor expression were analysed by flow cytometry. Urokinase plasminogen activator activity was measured using zymography. Plasminogen activator inhibitor type 1 protein levels in vitro and in vivo were examined with ELISA. PAI-1 mRNA levels were determined by RT-PCR. DS-sarcoma cells express urokinase plasminogen activator, urokinase plasminogen activator-receptor, and plasminogen activator inhibitor type 1 in vitro and in vivo. The urokinase plasminogen activator activity is enhanced in DS-sarcomas compared to normal tissues and rises with increasing tumour volume. The oxygenation level has no impact on the urokinase plasminogen activator activity in cultured DS-sarcoma cells or in solid tumours, although in vitro an increase in plasminogen activator inhibitor type 1 protein and mRNA expression after hypoxic challenge is detectable. The latter plasminogen activator inhibitor type 1 changes were not detectable in vivo. Hypoxia has been demonstrated to contribute to the upregulation of some components of the system in vitro, although this effect was not reproducible in vivo. This may indicate that the serum level of plasminogen activator inhibitor type 1 is not a reliable surrogate marker of tumour hypoxia.

Animals↗
PubMed2001

Clinical indications and biological mechanisms of splenic irradiation in autoimmune diseases.

BACKGROUND: Splenic irradiation (SI) is a fairly unknown treatment modality in autoimmune disorders like autoimmune thrombocytopenia (AIT) or autoimmune hemolytic anemia (AIHA), which may provide an effective, low toxic and cost-effective treatment for selected patients. PATIENTS, MATERIALS AND METHODS: This article reviews the limited experiences on splenic irradiation in autoimmune thrombocytopenia by analyzing the current studies including 71 patients and some preliminary reports on splenic irradiation in autoimmune hemolytic anemia. RESULTS: In autoimmune thrombocytopenia between 40 and 90% of all patients responded, but most of them relapsed within 4 to 6 months after splenic irradiation. Between 10 and 20% of all patients had a sustained response. The efficacy of splenic irradiation in HIV-associated cases of thrombocytopenia is probably lower than in other forms of autoimmune thrombocytopenia, but especially in this group immunosuppressive drug treatment of autoimmune thrombocytopenia exposes some problems. In autoimmune hemolytic anemia there are some case reports about efficacy of splenic irradiation. Toxicity of splenic irradiation in both diseases was very moderate. CONCLUSIONS: For HIV patients, for elderly patients or patients at high risk for complications following splenectomy splenic irradiation might be a treatment option. Splenic irradiation as preoperative treatment in patients not responding to or not suitable for immunosuppressive drugs prior to splenectomy may be a promising new application of splenic irradiation to reduce adverse effects of splenectomy in thrombocytopenic patients. A further analysis of the biological mechanisms underlying splenic irradiation may help to improve patient selection, to optimize dose concepts and treatment schedules and will improve understanding of radiotherapy as an immunomodulatory treatment modality.

Age Factors↗
PubMed2001

Clinical indications and biological mechanisms of splenic irradiation in chronic leukaemias and myeloproliferative disorders.

Splenic irradiation (SI) was the first efficient treatment for chronic leukaemia, but with the emergence of effective drugs its use has been more and more restricted to advanced cases presenting with splenomegaly. But in selected patients who are not responsive or not suitable to drug treatment, SI may offer still an effective, low toxic and cost-effective palliative modality. Eight studies of SI in chronic lymphatic leukaemia (CLL) including 198 patients, six reports about SI in prolymphocytic leukaemia (PLL), including 18 patients, one study and six case reports about SI in hairy cell leukaemia (HCL) and nine studies about SI in myeloproliferative disorders has been analyzed. In CLL, symptoms of splenomegaly have been improved in 50-87% of all patients with overall doses between 4 and 10 Gy in mostly 1-Gy fractions. PLL seems to be more resistant to SI with a median response rate of 66%. Casuistic reports described also efficacy of SI in HCL patients using similar radiation schedules. Symptomatic relief is also provided by SI in myeloproliferative disorders using lower overall doses between 1 and 9 Gy with small single fractions of 0.25 Gy (median). Acute toxicity was low in lymphoid disorders, but higher in myeloproliferative disorders with severe cytopenia in 10-30% of all cases, indicating the need for a cautious fractionation schedule. Interestingly, even complete systemic remissions after SI in all types of lymphoproliferative disorders have been described. Different mechanisms underlying SI such as direct cell kill, immune modulation via changes in lymphocyte subsets or cytokine induction or "radiotherapeutic" splenectomy with high doses are discussed.

Chronic Disease↗
PubMed2001

Stress-induced hormonal alterations.

The hormonal alterations observed during critical illness are extremely diverse, being both adaptive and maladaptive. Central and peripheral mechanisms are at play depending on the duration and severity of the insult. Perturbations in the endocrine axes are exacerbated by endogenous mediators and by pharmacologic intervention. The emergence of the concept of the wound, or inflammatory lesion, as an endocrine organ introduces new potential mechanisms of stress physiology and possible interventional strategies. Whether the physiology of the wound can be manipulated to heighten organism resistance to stress either emergently or electively is theoretically appealing and supported by animal models. Currently, however, it remains a subject of ongoing controversy and research.

Adrenal Glands↗
PubMed2000

Cation metabolism during propofol sedation with and without EDTA in patients with impaired renal function.

OBJECTIVE: To compare the effects of propofol with and without disodium edetate (EDTA) on cation metabolism in intensive care unit (ICU) patients with renal insufficiency who received propofol or propofol plus EDTA (propofol EDTA) for sedation and mechanical ventilation. DESIGN: Double-blind, randomised, multicentre study. SETTING: Medical and surgical ICUs from 5 hospitals. PATIENTS: Thirty-nine ICU patients with acute and chronic renal impairment expected to require at least 24 hours of continuous sedation and respiratory failure necessitating mechanical ventilation. INTERVENTIONS: Propofol or propofol EDTA administered for sedation by continuous intravenous infusion. MEASUREMENTS AND RESULTS: The depth of sedation, as measured by the Modified Ramsay Sedation Scale, was similar in the 2 groups, when adjusted for dosing differences. The amount of propofol required to maintain adequate sedation was decreased in both groups compared to propofol requirements in ICU patients with normal renal function. EDTA levels were elevated at baseline in both groups. In the propofol EDTA group, the EDTA levels increased further by 20 % but decreased to below baseline EDTA levels at 48 hours after sedation. In the propofol group, EDTA levels decreased during sedation and remained below baseline levels at 48 hours after sedation. PATIENTS in both groups were hypocalcaemic and hyperphosphataemic at baseline with low levels of 1,25-dihydroxyvitamin D and elevated parathyroid hormone (PTH) levels. Other than a slight difference in ionised serum calcium levels at 4 h after the start of sedation, there were no significant differences observed in serum calcium levels between the two groups. There were no significant differences in 1,25-dihydroxyvitamin D or PTH levels over time between the two groups. There was no significant effect on renal function in either group. CONCLUSIONS: The results of this study suggest that adding EDTA to propofol does not adversely affect cation homeostasis or renal function when used for sedation of ICU patients with renal insufficiency. Although EDTA levels increased over time from baseline levels in patients with renal insufficiency who receive propofol EDTA, this increase does not appear to be clinically significant, and EDTA levels return to below baseline levels within 48 hours of discontinuing the propofol EDTA infusion. The efficacy of propofol with and without EDTA also appears comparable in these patients.

Adolescent↗
PubMed2000

Biological effects of ionizing radiation on human blood compounds ex vivo.

PURPOSE: Blood compounds are irradiated ex vivo to prevent transfusion-associated graft-versus-host-disease. Recently, ex vivo irradiation of re-transfused wound blood has been proposed to prevent metastatic spread in patients with malignant tumors, an issue requiring different dose concepts. To determine effects on blood cells we examined the impact of various doses of ionizing radiation. METHODS: Full blood was irradiated with doses of 10-150 Gy. Potassium, LDH and hemoglobin levels were determined 2 h-96 h after irradiation. The lymphocyte proliferation after irradiation was measured by means of a lymphocyte-transformation assay. The impact of irradiation on mitogen-induced secretion of cytokines was determined by the ELISA technique, and P-selectin expression as an indicator of platelet activation was analyzed by flow-cytometry. RESULTS: Potassium levels increase with aging and irradiation dose. Mitogenic capacity is reduced by over 90% with moderate doses of 10-20 Gy, but a residual proliferation is still detectable up to 50 Gy. No enhancement of extracellular cytokine levels is detectable, but the cytokine release is reduced by radiation. Neither induction of platelet activation nor abrogation of activation has been detected. CONCLUSIONS: Doses of 30-50 Gy abrogate lymphocyte proliferation almost completely. In this range we did not observe severe adverse effects on blood transfusions. Hemolysis might be enhanced when the samples are stored for a longer period after irradiation.

Blood Platelets↗
PubMed1999

Chemotherapy in the treatment of recurrent glioblastoma multiforme: ifosfamide versus temozolomide.

PURPOSE: Despite the progress made in neurosurgery and radiotherapy, the prognosis of glioblastoma multiforme (GB) is poor, due to the lack of an effective salvage therapy. In vitro analysis revealed activity for ifosfamide and temozolomide. The usefulness of these agents in recurrent disease was investigated. METHODS: Six adult patients with recurrent GB received one to four courses of 1,500 mg/m2 ifosfamide given over 5 days intravenously. Furthermore, temozolomide (100-200 mg/m2) was given orally over 5 days to 14 patients. RESULTS: After ifosfamide treatment, one partial response and two cases of stable disease were observed. The median survival time was 24 weeks (range of 9-52 weeks). Toxicity analysis revealed one paranoid reaction, three grade III leukocytopenia, and one grade I-II nausea, anemia, and hematuria. Temozolomide therapy resulted in three partial responses and four cases of stable disease. The median survival time (Kaplan-Meier) was 21 weeks (range 4-64 weeks). The major toxicities were grade I-II nausea and hematological side effects (one case of grade IV leuko- and thrombocytopenia). CONCLUSIONS: Ifosfamide treatment might be a feasible approach, but it necessitates hospitalization. Temozolomide showed promising results. Due to its oral application, the patient's quality of life (time out of hospital) is favorable. Subgroups with improved survival were observed.

Adult↗
PubMed1999

Impact of localized radiotherapy on blood immune cells counts and function in humans.

Immune cells subsets were prospectively analyzed after localized radiotherapy (LRT). LRT reduced the levels of all lymphocyte subsets, with B-cells and naive T-cells being most sensitive. Lymphocyte function was suppressed, but still within the normal range. Rapid recovery of cytotoxic T-cells/natural killer cells after LRT and the functional suppression within normal levels explains the low incidence of infections after LRT.

Adolescent↗
PubMed1999

Impressive remission in a patient with locally advanced malignant pleural mesothelioma treated with gemcitabine.

The results of treatment of malignant pleural mesothelioma are quite unsatisfactory regardless of the substance or schedule employed. Although some activity is proved for anthracyclines, platinum compounds and alkylating substances, no chemotherapeutic regimen has emerged as a standard of care. Response rates documented in literature are between 10 and 20% for all these regimens. We report about a patient with locally advanced, unresectable pleural mesothelioma treated with the nucleoside analog gemcitabine (2,2-difluorodeoxycytidine). A 54-year-old male patient with unresectable pleural mesothelioma confirmed by thoracoscopic biopsy was treated with seven cycles of gemcitabine (1000 mg/m2 on day 1, 8 and 15) over a period of 36 weeks. Restaging by thoracic computed tomography (CT) scan was performed after 8, 20 and 36 weeks. At week 36 after beginning of treatment, the CT scan exhibited a substantial partial remission with a reduction of tumor volume of over 50%. The adverse effects of the therapy were very moderate with a hematotoxicity not exceeding WHO grade I and a mild 'flu-like syndrome' during the first three cycles which responded quite well to steroids. The compliance of the patient was excellent and his general condition improved significantly under therapy. Gemcitabine seems to be an active drug for the treatment of pleural mesothelioma. Compared to other active regimens it is normally very well tolerated by the patients. Because of these characteristics gemcitabine seems a suitable antineoplastic substance, especially in palliative settings. It would be worthwhile to test its activity in pleural mesotheliomas in controlled trials.

Antimetabolites, Antineoplastic↗
PubMed1996

Introduction of a new tracheostomy exchange device after percutaneous tracheostomy in a patient with coagulopathy.

Presented is a case of a 22-year-old male bone marrow transplant recipient who developed severe methotrexate-induced oropharyngeal mucositis and respiratory insufficiency caused by sepsis. Coagulopathy and severe thrombocytopenia precluded surgical tracheostomy; however, dilatational percutaneous tracheostomy was performed uneventfully. The tracheostomy tube was later changed using a newly developed exchange device permitting intraprocedural oxygenation and stomal redilatation. We conclude that severe thrombocytopenia and coagulopathy are not an absolute contraindication for percutaneous tracheostomy and that the new tracheostomy exchange device optimizes airway management and safety during this procedure.

Adult↗
PubMed1995

Intramolecular immunodominance and intermolecular selection of H2d-restricted peptides define the same immunodominant region of the measles virus fusion protein.

The generation of a sustained antibody response requires the participation of MHC class II-restricted T helper cells. We have identified class II-restricted sequences by immunizing BALB/c (H-2d) mice with 108 overlapping synthetic pentadecapeptides covering the whole sequence of the measles virus fusion protein (MV-F). Several strong T cell epitopes were found including a major cluster of H-2d-restricted peptides between amino acids 256 and 305. Some of these peptides including peptide F(421-435) and F(256-270) induced MV-specific T lymphocytes in vivo while other H2d-restricted MV-F sequences did not. Immunization with mixtures of selected peptides indicated a hierarchy among H2d-restricted sequences due to competition between peptides. The dominant peptide F(421-435) impaired the response to other T cell epitopes including F(256-270). The response to F(91-105) was obliterated by F(421-435) and F(256-270) but not by peptides devoid of a T cell epitope. When BALB/c mice were immunized with the MV, the immunodominant sequence F(421-445) was identified which included the synthetic peptide F(421-435). Our data suggest that competition during processing and/or presentation between H2d-restricted peptides defines the immunodominant sequence of the viral protein. Even though only a single immunodominant region was defined after immunization with the MV, peptides from other regions were able to induce MV-specific T cell responses. This finding is of interest for the design of subunit vaccines in general and for studying MV-specific T helper cells in an animal model in particular.

Amino Acid Sequence↗
PubMed1995

Natriuretic peptides and acute renal failure.

The characterization of a complex cerebrocardio-renal axis responsible for fluid and electrolyte homeostasis, with the isolation and identification of natriuretic peptides, has provided a potential therapeutic window into a condition associated with high morbidity and mortality in the ICU--acute renal failure (ARF). The potent natriuretic, diuretic, and renovascular actions of this family of peptides directly challenge the pathologic aberration in intrarenal hemodynamic and tubular function characterized by this condition. Unfortunately, human studies have not shown atrial natriuretic peptide to be the panacea as animal studies originally suggested. However, studies were clouded by the impact of polypharmacy, multisystem pathology, the timing of intervention, and the lack of any clear dose-response relationship for these peptides. Nonetheless, hormonal manipulation of physiologic aberration remains a potential therapeutic reality with ongoing isolation and understanding of new peptides, such as urodilatin, which may yet impact upon the treatment and outcome of ARF in the near future.

Acute Kidney Injury↗
PubMed1993

Analysis of antibody response to the measles virus using synthetic peptides of the fusion protein. Evidence of non-random pairing of T and B cell epitopes.

The measles virus induces a life-long immune response associated with antibodies specific for the fusion protein. To map the linear immunodominant recognition sites of the fusion (F) protein of the measles virus, we have reacted a complete set of 108 overlapping pentadecapeptides with purified IgG obtained from donor sera with elevated anti-measles titers. The antibodies recognized about 20% of the peptides and generated a characteristic binding pattern, defining about 6 or 7 distinctive regions (31-75; 111-145; 151-165; 191-215; 271-320; 421-440; 481-530) which include the major hydrophobic segment (111-145) of the intersubunit region and the C-terminal Cys-cluster region. The binding sites were located in close proximity of the few experimentally defined T cell epitopes. This pairing of T and B cell epitopes was corroborated by computer-assisted T cell prediction. The significance of a non-random association of T and B cell epitopes for processing and presentation is discussed. It is speculated that in long-term immunity against measles (F protein), B cells of the same sIg specificity play an important role both as antigen presenting cells and as antibody producing cells. In contrast to human sera from late convalescent donors, mouse and rabbit MV antisera with high neutralizing titers as well as neutralizing MV-F specific monoclonal antibodies did not react with the peptides.

Adult↗
PubMed1992

Myopathy in severe asthma.

Myopathy complicating the therapy of severe asthma has been recently described in several case reports. Twenty-five consecutive patients admitted to the intensive care unit (ICU) at this hospital for mechanical ventilation for severe asthma were studied for the incidence of creatine kinase (CK) enzyme rise and for the development of clinical myopathy. Pharmacologic therapy was standardized, every patient receiving corticosteroids and aminophylline intravenously and salbutamol both nebulized and intravenously. Twenty-two patients received muscle relaxant therapy with vecuronium. In 19 of 25 (76%) of patients there was elevation of CK levels to a median of 1,575 U/L (range, 66 to 7,430) occurring 3.6 +/- 1.5 days after admission. In nine patients there was clinically detectable myopathy. The presence of either myopathy or CK enzyme rise was associated with a significant prolongation of ventilation time. Arterial blood gas measurements on admission to the ICU revealed a pH (mean +/- SD) of 7.07 +/- 0.21, a PaCO2 of 87.2 +/- 32.7, and a PaO2 (with a high FIO2) of 129 +/- 97 mm Hg; however, no correlation was found between the severity of initial metabolic disturbance and the subsequent development of myopathy. There was no association between the type of corticosteroid administered and the subsequent development of myopathy. Patients with myopathy had received a significantly higher total dose of vecuronium when compared with those who did not develop myopathy (p < 0.001, Kruskal Wallis test). We have therefore found a surprisingly high incidence of CK enzyme rise and myopathy in this group of mechanically ventilated patients with severe asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1989

[Incidence and concomitant factors of tricuspid valve insufficiency in patients with aortic and mitral valve diseases].

Invasive data about the frequency and associated factors of tricuspid regurgitation in normals and in patients with aortic and mitral valve disease are still rare. Thus, right ventricular biplane angiograms (RAO/LAO projection), the mean pulmonary artery pressure and the presence of atrial fibrillation were analyzed with regard to tricuspid regurgitation in 30 normals and 165 patients with pure mitral regurgitation, mitral stenosis, aortic regurgitation, aortic stenosis, combined mitral valve disease or combined aortic valve disease. Patients with tricuspid stenosis or coronary artery disease were excluded. In 52 of the 195 patients tricuspid regurgitation was present. Tricuspid regurgitation occurred statistically more often in patients with mitral stenosis (33%), mitral regurgitation (48%) or combined mitral valve disease (68%) than in patients with aortic regurgitation (4%) or combined aortic valve disease (3%). In patients with aortic stenosis and in normals tricuspid regurgitation was not present. In patients with combined mitral valve disease, tricuspid regurgitation was more often present than in patients with pure mitral stenosis (p less than 0.002), despite comparable values of the mean pulmonary artery pressure, the right ventricular enddiastolic and endsystolic volume indexes, the right ventricular ejection fraction and the frequency of atrial fibrillation. Only in patients with pure mitral regurgitation tricuspid regurgitation was associated with an elevated mean pulmonary artery pressure (p less than 0.02). Differences in the right ventricular size and function did not occur between normals and patients with mitral or aortic valve disease. Therefore, the mean pulmonary artery pressure, atrial fibrillation and the size and function of the right ventricle are not major determinants for the occurrence of tricuspid regurgitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic Valve↗