Reliability-based optimization of maintenance scheduling of mechanical components under fatigue.

This study presents the optimization of the maintenance scheduling of mechanical components under fatigue loading. The cracks of damaged structures may be detected during non-destructive inspection and subsequently repaired. Fatigue crack initiation and growth show inherent variability, and as well the outcome of inspection activities. The problem is addressed under the framework of reliability based optimization. The initiation and propagation of fatigue cracks are efficiently modeled using cohesive zone elements. The applicability of the method is demonstrated by a numerical example, which involves a plate with two holes subject to alternating stress.

UFT (tegafur-uracil) in rectal cancer.

BACKGROUND: Major achievements in the treatment of localised rectal cancer include the development of total mesorectal excision and the perioperative administration of radiotherapy in combination with continuous infusion (CI) 5-fluorouracil (5-FU). This multimodal approach has resulted in extended survival and lower local relapse rates, with the potential for sphincter-preserving procedures. However, CI 5-FU is inconvenient for patients and is costly. Oral fluoropyrimidines like UFT (tegafur-uracil) offer a number of advantages over 5-FU. METHODS: We undertook a review of published articles and abstracts relating to clinical studies of UFT in the treatment of locally advanced rectal cancer (LARC). Pre- and postoperative studies carried out in patients with newly diagnosed or recurrent disease were included. RESULTS: The combination of UFT and radiotherapy was effective and well tolerated in the preoperative setting, while adjuvant UFT improved survival and reduced distant relapse compared with surgery alone. The efficacy of UFT appears comparable with that of 5-FU and capecitabine and its side-effect profile is favourable. CONCLUSION: Clinical experience to date suggests that UFT is a valuable treatment option for the perioperative treatment of LARC. Further improvements in patient outcomes may result from the combination of UFT with targeted agents.

Essential hypertension: sodium-lithium countertransport in erythrocytes from patients and from children having one hypertensive parent.

This report deals with the possibility that there is a specific change of the lithium transport across the membrane of erythrocytes from patients with essential hypertension. Sodium-lithium countertransport was significantly increased (p less than 0.005) in erythrocytes from 17 males with essential hypertension (mean 0.7 mmole (liter cells X hr)-1, range 0.4-1.6) compared to a group of 16 normotensive males (mean, 0.4 mmole (liter cells X hr)-1, range 0.3-0.6). A considerable overlap between the values from patients and controls was found. No significant increase of the transport function was found in a group of 14 female patients (mean 0.4 mmole (liter cells X hr)-1, range 0.2-0.6) compared with 10 normotensive female controls (mean 0.3 mmole (liter c hr)-1, range 0.3-0.6). A considerable overlap between the values from patients and controls was found. No significant increase of the transport function was found in a group of 14 female patients (mean 0.4 mmole (liter cells X hr)-1, range 0.2-0.6) compared with 10 normotensive female controls (mean 0.3 mmole (liter c hr)-1, range 0.3-0.6). A considerable overlap between the values from patients and controls was found. No significant increase of the transport function was found in a group of 14 female patients (mean 0.4 mmole (liter cells X hr)-1, range 0.2-0.6) compared with 10 normotensive female controls (mean 0.3 mmole (liter cells X hr)-1, range 0.1-0.6). Determination of sodium-lithium countertransport in red blood cells from nine children with and 14 without known familial disposition for essential hypertension did not demonstrate a close coupling between genetic disposition and the membrane transport function. In spite of the very small intraindividual variability of the transport function, studies of changes in sodium-lithium counter-transport are hampered by considerable interindividual variability of the transport in red cells from apparently normal individuals.

Efficacy and safety of cilazapril in hypertensive patients with moderate to severe renal impairment.

This open uncontrolled trial was undertaken to evaluate the safety and the efficacy of a new angiotensin-converting enzyme inhibitor cilazapril in patients with both hypertension and renal impairment defined as endogenous creatinine clearance below 50 ml/minute. Twenty-five patients with a diastolic blood pressure from 95 to 115 mm Hg completed the trial. Blood pressure was measured pre-dose sitting and standing every week during placebo and every second week during active therapy, as well as two hours post-dose after placebo and at the end of active therapy. The dose of cilazapril was from 0.5 to 5.0 mg daily. After eight weeks of active therapy, a reduction in both pre-dose systolic and diastolic blood pressure was seen. No orthostatic effect on blood pressure was observed. The systolic blood pressure was better controlled as measured two hours post-dose compared with pre-dose, whereas no difference was found in diastolic blood pressure. No deterioration in kidney function occurred. Some cases of moderately increased serum-potassium were observed, especially in acidotic patients. No serious adverse reactions were observed.

Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension.

OBJECTIVE: To evaluate the blood pressure lowering efficacy as well as tolerability and safety of the angiotensin II antagonist losartan compared with that of the angiotensin converting enzyme inhibitor enalapril in patients with mild-to-moderate essential hypertension. DESIGN AND METHODS: The study was a multicentre, double-blind, double-dummy, randomized, parallel study. Patients (n = 407) with diastolic blood pressure > or = 95 and < or = 120 mmHg at the end of a 2-week baseline placebo period were randomly allocated to receive either 50 mg losartan once a day or 20 mg enalapril once a day for 12 weeks. Blood pressure, clinical and laboratory safety, specific symptoms including coughing determined using a symptoms questionnaire and metabolic variables were examined at baseline and at weeks 6 and 12. RESULTS: Both losartan and enalapril decreased systolic and diastolic blood pressure from baseline at weeks 6 and 12. Blood pressure changes from baseline at trough (22-26 h after the dose) did not differ between the two groups in the per-protocol analysis. Response to treatment at trough was excellent or good (diastolic blood pressure < 90 mmHg or reduction in diastolic blood pressure of 10 mmHg) in 51 and 53% of the patients in the losartan and enalapril groups, respectively. Enalapril administration increased dry coughing symptoms whereas losartan did not. The incidence of dry coughing was 1.0 and 12.2% as a spontaneously reported discomfort at week 12 and 3.0 and 15.1% as a clinical adverse experience in the losartan and enalapril groups, respectively. The difference from baseline at week 12 in the incidence of dry coughing between the two groups was 14.9% as a specific symptom in the symptoms questionnaire. Losartan reduced serum uric acid concentration, whereas effects on other metabolic parameters did not differ between the groups. CONCLUSIONS: Losartan is an effective and well-tolerated antihypertensive drug showing similar blood-pressure-lowering efficacy to that of enalapril at trough. However, in contrast to enalapril, losartan does not increase the incidence of dry coughing. Thus, the angiotensin II antagonist losartan provides a promising new approach to treatment of hypertension.

Long term haemodynamic effects of pinacidil and hydralazine in arterial hypertension.

Eight patients with a diastolic blood pressure greater than or equal to 100mm Hg when treated with a diuretic and a beta-blocker participated in a randomised crossover study comparing the haemodynamic effects of adjunctive therapy with pinacidil or hydralazine. The vasodilator dose was increased until the diastolic blood pressure was less than 90mm Hg or the maximum dosage, hydralazine 100mg twice daily, or pinacidil 50mg twice daily, was reached. Treatment continued for 3 to 6 months and a haemodynamic study was performed. After washout, the patients received the alternative treatment. In the upright position, during supine rest and during isometric as well as dynamic exercise, pinacidil lowered blood pressure more effectively than hydralazine. No differences between the 2 treatments were found in heart rate, stroke index, cardiac index, end systolic wall stress or glomerular filtration rate. Pulmonary mean and wedge pressure were lower during treatment with pinacidil. Forearm blood flow was higher and forearm vascular resistance lower during treatment with pinacidil. Cardiac contractility, judged from the systolic time interval ratio PEP: LVET, was lower during treatment with pinacidil compared with hydralazine. The median daily dose of pinacidil was 50mg and that of hydralazine 200mg. It was also noted that during long term treatment, pinacidil seemed more effective in reducing blood pressure than hydralazine.

Inter-laboratory comparison of acid-base variable in human blood and in quality control materials.

Routine results, pH, partial pressure of carbon dioxide (pCO2) and of oxygen (pO2), and standard hydrogen carbonate ion concentration (SBC) in identical specimens of arterial blood from patients deviate substantially. The results from seven laboratories (each laboratory examining the same 12 patients and the same five types of quality control materials) and evaluation in terms of accuracy and precision suggest the variations between days (delta 2) and single measurements (sigma 2) to be the main factors for these deviations. A reduction of these variations must have the highest priority in quality control programmes, since the variations mask possible true level deviations between laboratories. The five control materials (Qualicheck, Quantra whole blood level I-II-III and hemolyzed donor blood) are not fully optimal as substitutes for patient blood in such quality control programmes.

A randomized and double-blind comparison of isradipine and spirapril as monotherapy and in combination on the decline in renal function in patients with chronic renal failure and hypertension.

AIMS: Treatment of hypertension in patients with chronic renal failure has been shown to postpone the decline in renal function. Treatment with an ACE inhibitor has been shown to be superior to conventional antihypertensive treatment, but it is not known how an ACE inhibitor compares to treatment with a calcium channel blocker or to treatment with a combination of these drugs. The aim of the study was to evaluate the rate of decline in GFR in patients with chronic renal failure and hypertension treated with isradipine and spirapril as monotherapy and in combination. METHODS: Sixty patients with chronic renal failure and hypertension were enrolled in the study. After enrollment, patients were followed prospectively for 6 months in the outpatient clinic on their usual antihypertensive medication, and then randomized to a double-blinded comparison of either spirapril 6 mg daily, isradipine 5 mg daily or spirapril 3 mg and isradipine 2.5 mg daily. After randomization, patients were followed for 21 months or until the need for dialysis. Every 3 months before and 3.5 months after randomization the glomerular filtration rate was measured by 51Cr-EDTA clearance and the effective renal plasma flow evaluated using the renal clearance of paraaminohippuric acid. RESULTS: Blood pressure and the decline in glomerular filtration rate did not differ between the groups before randomization. After randomization, the mean decline in the glomerular filtration rate was -0.32 ml/(min x month x 1.73 m2) in the spirapril group, -0.58 ml/(min x month x 1.73 m2) in the isradipine group and -0.14 ml/(min x month x 1.73 m2) in the combination group (p = 0.38). Twelve patients, 4 in each group, reached end-stage renal failure. No significant difference was found with respect to diastolic (p = 0.10) or systolic blood pressure (p = 0.08) during the treatment period, but a trend towards a better blood pressure control in the combination group was present. During treatment, the rate of decline in renal plasma flow did not differ significantly between the groups (p = 0.09), neither did the changes in filtration fraction (FF) (p = 0.58) nor the mean FF (p = 0.22) during the treatment. CONCLUSIONS: Our study indicated differences between the 3 treatment modalities in favor of combined therapy with respect to both the rate of decline in GFR and blood pressure control, but the differences where insignificant. Thus, the treatments might differ, but we were unable to confirm this because of large variation in GFR and small sample size.

Therapeutic serum concentrations of primidone and its metabolites, phenobarbital and phenylethylmalonamide in epileptic dogs.

Fifteen dogs with idiopathic epilepsy were included in a 9-month clinical trial to determine the therapeutic serum concentrations of primidone and its active metabolites, phenobarbital and phenylethylmalonamide. Dogs with a seizure frequency greater than 1/mo or with a record of multiple seizures greater than 1/day were chosen for the study. Each dog was given primidone 3 times daily at dosages intended to maximize seizure control and to minimize undesired side effects. Maintenance period blood samples were taken from fasted dogs 7 hours after dosing in the 3rd, 5th, 7th, and 9th months of the trial to determine therapeutic serum concentrations of primidone and its metabolites. Two blood samples also were taken from all dogs 7 hours after dosing, during an enforced drowsy period, to establish upper limits of desirable serum concentrations of the drug. Seizure frequencies during the trial were controlled in 13 dogs, 7 of which had no seizures during the 9-month trial. The mean percentage reduction in seizure frequency from pretrial frequency was 85%. Two dogs appeared refractory to primidone therapy. Serum phenobarbital was the best metabolite of primidone to use to assess therapeutic serum concentrations. The therapeutic antiepileptic serum concentration of phenobarbital was found to be between 25 and 40 micrograms/ml of serum. Serum phenobarbital concentrations greater than 40 micrograms/ml resulted in side effects in most dogs.

[The influence of antihypertensive treatment on progression of chronic nepropathy]. / Antihypertensiv behandlings indflydelse på progressionen af kronisk nefropati.

This article describes the influence of antihypertensive treatment on the kidneys, both the acute and the long-term effects, especially with regard to the progression of chronic non-diabetic renal failure. Our knowledge about the different antihypertensive drugs is still limited, but some studies indicate that especially ACE-inhibition and perhaps calcium antagonism may have the potential to postpone renal failure.

[Treatment of hypertension in general practice, consequences of therapeutic changes. A multipractice study of the therapeutic patterns, blood pressure control, drug administration schedule and incidence of side effects]. / Behandlingen af hypertension i almen praksis, konsekvenser af behandlingsskift. En multipraksisundersøgelse over behandlingsmønstre, blodtrykskontrol, doseringshyppighed og bivirkningsforekomst.

The antihypertensive treatment schedules were investigated in 1,153 consecutive patients in 65 general practices. Treatment consisted mainly of diuretics or betablockers singly or combined. In a sample of 303 of these patients, treatment was altered in a randomised, single-blind, cross-over design to consist of a single daily dose of metoprolol, or a single daily dose of metoprolol plus a single dose of a placebo. The effect of multiple dosages on the quality of life was investigated simultaneously with investigation of the efficacy of single drug treatment with a beta-blocker on blood-pressure control as compared with the previous treatment. A slight increase in side-effects was observed which might be ascribed to increased awareness by the patient and also by the doctor. The more simplified regimen with a single daily dose of the betablocker showed the same blood-pressure levels as in the previous more complicated regimen.