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Biomedical subjects

J Widder

Publications and source records attributed to J Widder.

At least 19 recordsLinked to original sources
PubMed2006

Endothelial mechanotransduction, nitric oxide and vascular inflammation.

Numerous aspects of vascular homeostasis are modulated by nitric oxide and reactive oxygen species (ROS). The production of these is dramatically influenced by mechanical forces imposed on the endothelium and vascular smooth muscle. In this review, we will discuss the effects of mechanical forces on the expression of the endothelial cell nitric oxide synthase, production of ROS and modulation of endothelial cell glutathione. We will also review data that exercise training in vivo has a similar effect as laminar shear on endothelial function and discuss the clinical relevance of these basic findings.

Animals↗
PubMed2005

Preoperative short-term radiation therapy (25 Gy, 2.5 Gy twice daily) for primary resectable rectal cancer (phase II).

To evaluate the feasibility, effectiveness, and long-term bowel function of preoperative hyperfractionated accelerated radiotherapy in primary resectable rectal cancer. A total of 184 consecutive patients (median age 65 years, male : female=2 : 1) with clinical T3Nx rectal adenocarcinoma received preoperative pelvic radiation therapy with single fractions of 2.5 Gy twice daily (interval 6 h between fractions) to a total dose of 25 Gy within 1 week. Surgery was conducted the following week. Postoperative histology revealed UICC stage I in 33%, stage II in 26%, stage III in 34%, and stage IV in 7% of the patients. Median follow-up was 43 months (53 months for surviving patients). The actuarial 4-year-local-recurrence rate was 2.1%, overall recurrence 23%. Disease-specific and disease-free survivals at 4 years (excluding stage IV) were 82 and 69%, respectively. Overall survival for 4 years was 68%. Postoperative mortality was 0.5% (one patient), early anastomotic leakage occurred in 11.4%, and anastomotic stenosis requiring treatment in 6%, of 132 patients with primary anastomosis. Seven of 184 patients (3.8%) died of abdominal complications, all within the first year. Bowel function was satisfactory after more than 5 years. Local control in primarily resectable rectal cancer after 10 x 2.5 Gy is excellent, warranting further evaluation of this treatment.

Adenocarcinoma↗
PubMed2004

Hyperfractionated accelerated radiochemotherapy (HFA-RCT) with mitomycin C for advanced head and neck cancer.

To investigate efficacy and feasibility of hyperfractionated accelerated radiotherapy combined with mitomycin C, patients with locally advanced unresectable squamous cell carcinomas of the head and neck region were administered 64-66 Gy in four weeks and mitomycin C (20 mg/m(2)) on day five. Twenty-one consecutive patients were included between November 1997 and June 1999 (median age: 57 years). All tumours were stage T3-4 and 18/21 were N2-3. Eighteen patients experienced grade 3 and three patients grade 2 mucosal toxicity. With median follow up for surviving patients of 42 months, loco-regional control was 55% at three years, overall survival was 33% at three years. This treatment is at the edge of local tolerability, but there is a good curative chance even for very advanced localised tumours, provided a complete remission is induced at primary treatment.

Adult↗
PubMed2003

The early response of p53-dependent proteins during radiotherapy in human rectal carcinoma and in adjacent normal tissue.

The aim of this study was to investigate the activation of the p53 pathway and the induction of apoptosis during preoperative radiotherapy in normal human rectal tissue and in rectal carcinoma. Twelve patients with rectal cancer of the lower third were enrolled in this study. Tumor specimens and adjacent normal tissue were obtained before radiation, after the third radiation cycle and from the surgically removed rectum. All specimens were analyzed be means of immunohistochemistry for expression of p53 and its downstream target genes MDM2 and p21. In normal mucosal crypts, irradiation led to p53 accumulation and MDM2 induction in more than 70% of the cells. The accumulation of p53 in basal crypts was associated with high expression of p21. Apoptosis was also induced in crypts and occurred in 15% of the cells. Activation of the p53 pathway was not seen in the resting cells at the luminal border of the epithelium. In interstitial cells, p21 was highly upregulated, whereas p53 and MDM2 showed weak expression. The level of bcl-2 was not altered during radiotherapy in healthy tissue. In rectal carcinoma cells, p53 expression was unaltered by irradiation in 11 out of 12 tumors. The p53 non-functional tumors were characterized by a weak induction of MDM2 and p21 and by the lack of apoptosis in the presence of bcl-2. Our findings demonstrate that sequential immunohistochemical analysis is suitable to detect a deregulation of the p53 pathway in human rectal cancer cells during radiotherapy. Further investigations are necessary to elucidate its value as a prognostic marker and potential predictor of therapy responsiveness.

Aged↗
PubMed2000

Endothelin-receptor blockade improves endothelial vasomotor dysfunction in heart failure.

OBJECTIVES: To elucidate the effect of selective endothelin ET(A)- and mixed ET(A/B)-receptor antagonists on endothelial vasomotor dysfunction in rats with heart failure after myocardial infarction (MI). METHODS: Vasoreactivity and superoxide anion formation were determined in aortic rings from Wistar rats 12 weeks after extensive MI (>46% of left ventricle) compared to sham-operated animals. Rats were either treated with the selective ET(A)-receptor antagonist LU 135252 (30 mg/kg/day), the mixed ET(A/B)-receptor antagonist Bosentan (100 mg/kg/day) or placebo. RESULTS: In MI rats, the concentration-response curve of the endothelium-dependent, nitric oxide-mediated relaxation induced by acetylcholine was significantly shifted to the right and the maximum relaxation was attenuated. Long-term treatment with both ET antagonists significantly improved acetylcholine-induced relaxation in MI rats. LU 135252 was more effective than Bosentan. Endothelium-independent relaxations induced by sodium nitroprusside as well as endothelin- and phenylephrine-induced contractions were similar in all groups of rats. Plasma renin activity and aortic superoxide formation, which were enhanced in rats with heart failure, were normalized by LU 135252, but not by Bosentan treatment. CONCLUSIONS: Long-term treatment with ET-receptor antagonists improves endothelial vasomotor dysfunction in rats with chronic MI. This mechanism may essentially contribute to the beneficial effects of ET receptor blockade in heart failure.

Acetylcholine↗
PubMed2000

Quality assurance in preoperative radiotherapy of rectal cancer: evaluation of a pre-trial dummy-run.

PURPOSE: To assess inter-institution variability of treated volumes in preoperative radiotherapy for rectal cancer among Austrian radiotherapy institutions in the framework of a multi-centre phase-III clinical trial. MATERIALS AND METHODS: All eleven Austrian radiotherapy departments were invited to participate in this pre-study dummy-run. They received a short history of two 'dummy patients' (case A and case B); three computer assisted tomography (CT) slices; simulation films; and the protocol describing the radiation technique to be used. Participants were asked to prepare a treatment plan for either case on the basis of the materials provided and to use their computerized planning systems. Additionally and independently of the CT-based treatment plans, they were asked to delineate the fields to be treated on the simulation films. RESULTS: Nine of eleven departments participated. All participants used a three or four field technique as requested. The variation of beam widths and planning target volumes (PTVs) in the central plane was 6-11% and 11-16%, respectively. The standard deviations (SD) were 21 and 24% for the two cases for mean treated volumes of 2.1 and 2.9 l, respectively. The variation of beam widths in the central plane was less pronounced in the simulation based treatment plans as compared with the CT-based treatment plans for the dorsal fields, the opposite was true for the laterals. CONCLUSION: Considerable variation of treated volumes is inevitable in multi-institution trials despite detailed treatment guidelines. Simulator based treatment fields seem to result in less pronounced inter-institution variations compared with CT-based treatment planning, if bony landmarks can be used as is the case in rectal cancer. Continuous quality control is thus warranted in multi-centre trials to increase homogeneity of volumes treated.

Adenocarcinoma↗
PubMed2000

Improvement of renal dysfunction in rats with chronic heart failure after myocardial infarction by treatment with the endothelin A receptor antagonist, LU 135252.

OBJECTIVE: To investigate the role of an activated endothelin system in the renal dysfunction observed in chronic heart failure after myocardial infarction. METHODS: In rats with heart failure after myocardial infarction and in sham-operated animals (Sham), we investigated the effect on renal function of long-term oral treatment with the selective endothelin A (ETA) receptor antagonist, LU 135252 (30 mg/kg per day; groups MI/LU and Sham/LU) or placebo (groups MI/P, Sham/P). Only animals with extensive myocardial infarction (at least 46% of the left ventricle) were included in the study. Infarct size was matched between groups MI/P and MI/LU. Endogenous creatinine clearance, fractional sodium excretion, and plasma and urinary concentrations of endothelin were determined 12 weeks after myocardial infarction. RESULTS: Endogenous creatinine clearance was significantly lower in group MI/P than in group Sham/P (MI/P: 0.64 +/- 0.05, Sham/P: 0.81 +/- 0.04 ml/min per 100 g body weight; P= 0.01 (means +/- SEM)). Treatment with LU 135252 completely prevented the decline in creatinine clearance in rats with chronic myocardial infarction (MI/LU: 0.98 +/- 0.21; Sham/LU: 0.83 +/- 0.10). Fractional sodium and protein excretion did not differ among the four groups. Group MI/P had a marked increase in plasma endothelin concentrations, which was not affected by treatment with LU 135252. Urinary endothelin excretion was significantly lower in group MI/P than in group Sham/P. In the treatment groups, no difference could be observed between animals that had suffered myocardial infarction and the sham-operated group, although LU 135252 markedly increased the urinary excretion of endothelin. CONCLUSION: Our data demonstrate a restoration of impaired renal function in chronic ischaemic heart failure by treatment with the selective ETA receptor antagonist, LU 135252. These results offer a promising therapeutic option for the treatment of renal insufficiency in patients with chronic heart failure.

Animals↗
PubMed2000

Endothelium-dependent and -independent vasoreactivity of rat basilar artery in chronic heart failure.

Alterations of vasoreactivity are a well-known phenomenon in chronic heart failure (CHF), and activation of the endogenous endothelin (ET) system is suspected to contribute significantly. Regional differences in alterations of vasoreactivity exist; however, nothing is known about cerebrovascular reactivity in CHF. This is of interest in view of increased stroke risk in CHF. Therefore, 12 weeks after coronary artery ligation to induce CHF in rats, studies of vasoreactivity of the isolated basilar artery (BA) were performed and compared with third-order branches (MA-A3) and the main trunk (MA) of the superior mesenteric artery. Some of the animals received long-term ET-receptor antagonism by 11 weeks of treatment with the selective ET(A)-receptor antagonist LU 135252 or the mixed ET(A)/ET(B)-receptor antagonist bosentan. In rats with CHF, endothelium-dependent relaxation by acetylcholine and A23187 as well as endothelium-independent relaxation by sodium nitroprusside (SNP) was largely unaffected in BA or MA. However, in MA-A3, potency of SNP was diminished without change of maximal effect. ET-1-induced contraction did not differ in arteries from CHF and control rats, either in placeboor ET-receptor antagonist-treated animals. In summary, there was essentially no change of vascular reactivity in similar sized arteries obtained from brain and mesentery. This is in contrast to results on arteries from a variety of vascular regions published previously, thus supporting the concept of organ- and probably time-related changes of vascular function in the development of CHF. The absence of significant alteration of cerebral vasoreactivity may be taken to indicate that changes in cerebral blood flow and increased incidence of ischemic stroke in patients with CHF are caused not by local alterations of vascular function.

Acetylcholine↗
PubMed1998

Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancer.

PURPOSE: To evaluate the effect of mitomycin C to an accelerated hyperfractionated radiation therapy. The aim was to test a very short schedule with/without mitomycin C (MMC) with conventional fractionation in histologically verified squamous cell carcinoma of the head and neck region. METHODS AND MATERIALS: From October 1990 to December 1996, 188 patients entered the trial. Tumors originated in the oral cavity in 54, oropharynx in 82, larynx in 20, and hypopharynx in 32 cases, respectively. Patients' stages were predominantly T3 and T4 (158/188, 84%) and most patients had lymph node metastases (144/188, 77%) at diagnosis. Only 22 patients were female, 166 were male, the median age of patients was 57 years (range 34 to 76 years). Patients were randomized to one of the following three treatment options: conventional fractionation (CF) consisting of 70 Gy in 35 fractions over 7 weeks (65 patients) or continuous hyperfractionated accelerated radiation therapy (V-CHART; 62 patients) or continuous hyperfractionated accelerated radiation therapy with 20 mg/sqm MMC on day 5 (V-CHART + MMC; 61 patients). By the accelerated regimens, the total dose of 55.3 Gy was delivered within 17 consecutive days, by 33 fractions. On day 1, a single dose of 2.5 Gy was given, from day 2 to 17 a dose of 1.65 Gy was delivered twice: the interfraction interval was 6 hours or more. RESULTS: Mucositis was very intense after accelerated therapy, most patients experiencing a grade III/IV reaction. The mucosal reaction did not differ whether MMC was administered or not. Patients treated by accelerated fractionation experienced a confluent mucosal reaction 12-14 days following start of therapy and recovered (no reaction) within 6 weeks. The skin reaction was not considered different in the three treatment groups. Those patients treated with additional chemotherapy experienced a grade III/IV hematologic toxicity in 12/61 patients. Initial complete response (CR) was recorded in 43% following CF, 58% after V-CHART, and 67% after V-CHART + MMC, respectively (p < 0.05). Actuarial survival (Kaplan-Meier) was significantly improved in the combined treated patients. Local tumor control was 28%, 32%, and 56% following CF, V-CHART, and V-CHART + MMC, respectively (p < 0.05). CONCLUSION: We conclude that our continuous hyperfractionated accelerated radiation therapy regimen is equal to conventional fractionation, suggesting that by shortening the overall treatment time from 7 weeks to 17 days a reduction in dose from 70 Gy to 55.3 Gy is possible, with maintenance of local tumor control rates. The administration of MMC to the accelerated regimen is tolerable and improves the outcome for patients significantly.

Adult↗
PubMed1998

The fallibility of medical judgment as a consequence of the inexactness of observations.

The paper attempts to give an account of the fallibility of medical judgments without recourse to the incompleteness of scientific knowledge. It is argued that because of the inexactness of observations and thus the existence of borderline cases any theory applied for explanation and predicition will produce some false results. This state of affairs is independent of the nature of a theory, i.e., it applies both for non-probabilistic and for probabilistic theories. Some epistemological issues and consequences with regard to a better understanding of clinical reasoning are discussed and the view is compared with the theory of medical fallibility of Gorovitz and MacIntyre.

Decision Making↗
PubMed1996

[Medical performance: ethical and conceptual issues].

Following an introductory criticism of the Hippocratic Oath and a health-maximizing principle as ethical basis for health care, an evaluation of medical performance is presented according to 3 underlying concepts, namely 1) the act of performing medical procedures itself, 2) effectiveness and 3) efficiency. A discussion of these issues shows that statements on increasing effectiveness and efficiency only make sense if a prior clear definition of the aims of medicine can be presumed. Moreover, the achievement of an increase in medical efficiency requires quantification of the aims of medicine, whereby it is not self evident that these are quantifiable. Certain ethically relevant principles, such as justice and self determination, may remain unaffected by such considerations, however. Consequently, none of the 3 discussed concepts to measure medical performance can be regarded as a sufficient basis for a comprehensive ethical evaluation of a health care system.

Animals↗
PubMed1994

[Restriction of ethics in medicine].

The influence of bioethics upon medicine as a new discipline is seen in a change of the style of the medical discourse, but also in a substantial change of medicine. The latter consists in the integration of patient's subjectivity into medical knowledge proper. As a result, bioethics cannot be confined to elaboration and justification of guidelines alone, but it questions the very self-image of medicine.

Bioethics↗