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.

Phase II study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first-line therapy in patients with non-resectable gastric cancer.

Epirubicin, cisplatin and continuous infusion of 5-FU is a widely used palliative regimen in patients with gastric cancer. If cisplatin is substituted by oxaliplatin and 5-FU by capecitabine this regimen can be administered in the outpatient setting. Dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy and it is recommended to give oxaliplatin as a 120 min infusion. However, in patients with colorectal cancer a 30 min infusion of oxaliplatin can safely be administered without increasing neurotoxicity, standard infusion time is 30 min at our departments. In our phase I study the recommended doses of EXE was established (Dupont et al, 2006). Patients with non-resectable gastric adenocarcinoma were eligible. Patients received EXE (epirubicin 50 mg m(-2) day 1; capecitabine 1000 mg m(-2) day(-1) continuously and oxaliplatin 130 mg m(-2) day 1) as outpatient therapy every third week for a maximum of 8 cycles. From June 2004 to September 2005, we enroled 54 patients. Median age was 60 years (31-74 years) Median number of courses was 6 (1-8). Response rate was 45%. Median PFS was 6.8 (5.2-7.9) months and median survival was 10.1 (7.9-1.1) months. Most important grade 3 toxicities were as follows: nausea, vomiting, and diarrhoea (6%). Neurotoxicity grade 2 was seen in 36.5%. We therefore conclude, that EXE every third week is a convenient regimen that easily can be administrated in the outpatient setting but the regimen needs further evaluation in a phase III study.

Resectability of rectal cancers still fixed after radio-chemotherapy: evaluation by digital rectal examination, MRI, and intraoperative examination.

Eighteen patients with primary fixed rectal cancer as judged by digital rectal examination (DRE) were included. They all had radiation therapy with 60 Gy in 30 fractions combined with oral UFT and Isovorin. All patients were evaluated by DRE and magnetic resonance imaging (MRI) before and after treatment. After 5-7 weeks, eight tumors were mobile on DRE. All eight patients had an R0 resection. Of the remaining ten patients with fixed rectal cancer, eight had an R0 resection. One patient had an R1 resection and one patient was not operated. Intraoperative bimanual rectal examination was performed with one finger through the anus and one hand in the rectovaginal/rectovesical fossa before resection was performed. After chemo-radiation DRE correctly predicted the tumor to be advanced or not in 12/17 patients, MRI in 14/17, and bimanual rectal examination in 17/17 patients.

No evidence of gemcitabine accumulation during weekly administration.

Some anticancer agents tend to accumulate during repeated administration. We determined whether gemcitabine or its metabolites would accumulate during repeated administration. Gemcitabine was administered over two courses with each course consisting of a 30-min infusion at 1000 mg/m(2) weekly for 3 weeks followed by 1 week of rest. In 14 patients we evaluated eventual accumulation by comparing the concentrations in blood samples taken before, and at 30 and 60 min after the start of infusion on days 1, 8 and 15, in both cycles. At the end of the infusion gemcitabine concentrations at day 1 of both courses varied between 18 and 77 microM and at day 15 between 13 and 90 microM. The mean ratios day 8/day 1 and day 15/day 1 varied from 0.94 to 1.18. For the inactive metabolite 2',2'-difluoro-2'-deoxyuridine (dFdU) these values varied between 54 and 152 microM and 55 and 157, respectively, and the ratios from 0.96 to 1.08. The concentration of the active metabolite of gemcitabine, gemcitabine triphosphate (dFdCTP) in peripheral white blood cells, ranged between 37 and 283 pmol/10(6) cells at the end of infusion on day 1 and 35 and 115 pmol/10(6) cells on day 15. Potential accumulation was evaluated using a mixed effects model and no evidence was observed of accumulation for either gemcitabine or its metabolites. Gemcitabine can be administered safely without the risk that the drug will accumulate.

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.

Blood pressure level and relation to other cardiovascular risk factors in male hypertensive patients without clinical evidence of ischemic heart disease.

Arterial hypertension is accompanied by increased morbidity and mortality and constitutes a substantial part of medical care. Antihypertensive intervention reduces the cardiovascular morbidity and mortality. The aims of the study were to evaluate the relationship between cardiovascular risk factors and the blood pressure (BP), and to evaluate the percentage of patients who had achieved a BP level as recommended by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). BP was evaluated in relation to age, body mass index, duration of hypertension, cholesterol and triglyceride level, smoking status, information of regular exercise, a family history of ischemic heart disease (IHD) and drug treatment, in 220 men treated for arterial hypertension. In the univariate analyses we found a higher systolic blood pressure (SBP) with older age, higher SBP in smoking patients and lower SBP in patients with regular exercise. In a multivariate model age (p = 0.0004), smoking status (p = 0.01) and regular exercise (p= 0.06) were independently associated with SBP. There was a lower diastolic blood pressure (DBP) with older age, and age was independently associated with DBP. Office SBP was above 140 mmHg in 83% and above 160 mmHg in 44% of patients. During ambulatory blood pressure monitoring (AMBP), SBP was above 135 mmHg in 40% and above 155 mmHg in 15% of patients. In addition to male sex and hypertension there was a high percentage of other cardiovascular risk factors--43% was smoking, 21% had a family history of IHD, 77% had a se-cholesterol above 5.5 mmol/l and 48% had a se-triglyceride above 1.6 mmol/l. In a consecutive group of asymptomatic male treated hypertensive patients SBP is independently associated with age and smoking status, and DBP with age. A high percentage of the patients do not have a well controlled BP, and a high percentage have additional risk factors such as smoking, hypercholesterolaemia, hypertriglyceridaemia and a family history of IHD. This means that there is room for much improvement in the control of hypertension.

Efficacy of Ki-67 antigen staining in Papanicolaou (Pap) smears in post-menopausal women with atypia--an audit.

In cervical smears from post-menopausal women with mucosal atrophy it can be difficult to distinguish atrophic epithelial cell groups from neoplastic cell groups on cytomorphological criteria only. The consequence of post-menopausal atypia is that the woman is referred for a repeat smear after local oestrogen treatment or for colposcopy. We investigated whether immunocytochemical expression of Ki-67 (MIB-1) on the primary Papanicolaou-stained smear could be of any diagnostic help. Our data showed that negative Ki-67 expression is a very reliable indicator of a normal atrophic cell pattern, and by using this method on the original smear we were able to reduce the false-positive cytologic diagnoses by 86%.

Assessment of pH and oxygen status during hemodialysis using the arterial blood line in patients with an arteriovenous fistula.

BACKGROUND: In patients with arteriovenous fistulas, assessment of pH and oxygen status during hemodialysis (HD) using the extracorporeal dialysis arterial blood line is widely used both in daily routine and in most studies investigating hypoxia during HD. We designed this study to evaluate whether results of blood gas samples drawn from the extracorporeal arterial line were clinically acceptable in assessing oxygen status. METHODS: We compared samples drawn from the extracorporeal arterial line with conventionally arterial punctures during 18 routine HD sessions. The samples were drawn simultaneously and analyzed immediately for blood gases, pH and hemoximetry values. RESULTS: No significant difference was found between the values from the radial artery and the extracorporeal arterial blood line except for FMetHb. CONCLUSION: Thus, obtaining samples from the extracorporeal dialysis arterial blood line to evaluate the parameters of the oxygen status (pH, pO(2), pCO(2), ctHb, sO(2), FCOHb and ctO(2)) during routine HD is a clinically convenient and accurate sampling approach.

Glomerular filtration rate estimated from the uptake phase of 99mTc-DTPA renography in chronic renal failure.

BACKGROUND: The purpose of the study was to compare the estimation of glomerular filtration rate (GFR) from 99mTc-DTPA renography with that estimated from the renal clearance of 51Cr-EDTA, creatinine and urea. METHODS: Fifty patients with reduced renal function (serum creatinine between 150 and 600 micromol/l) were enrolled in the study. GFR was estimated from the uptake phase of 99mTc-DTPA renography (GFR(DTPA)). The renal clearance of 51Cr-EDTA (GFR(EDTA)) was used as the reference method. Creatinine clearance (C(Cr)), urea clearance (C(Ur)) and the mean of urea and creatinine clearance (C(Cr+Ur)/2) were also calculated from urine collected during a period of 24 h. Limits of agreement were used for method comparison. RESULTS: The limit of agreement between GFR(DTPA) and GFR(EDTA) was 2 +/- 17 ml/min. The mean difference did not deviate significantly from zero. The other clearance techniques had larger limits of agreement and a mean difference significantly different from zero. Furthermore, C(Ur) and C(Cr+Ur)/2 had systematic deviations of the differences, indicating that C(Ur) and C(Cr+Ur)/2 are poor estimates of GFR. CONCLUSION: The limit of agreement between GFR(DTPA) and GFR(EDTA) are acceptable and, therefore, GFR estimated from 99mTc-DTPA renography is acceptable for clinical use in patients with reduced renal function. Furthermore, the method is simple and less time consuming compared with renal clearance techniques.

Oxygen and 2,3 biphosphoglycerate (2,3-BPG) during haemodialysis.

Eleven patients with chronic renal failure who were being treated with haemodialysis three times a week were monitored for a total of 34 haemodialysis sessions. Erythrocyte 2,3-biphosphoglycerate (2,3-BPG) concentration was analysed immediately before initiation of bicarbonate haemodialysis and 1 h afterwards. The 2,3-BPG concentration was expressed relative to the haemoglobin tetramer (Hb4) concentration as the 2,3-BPG/Hb4 ratio and compared with blood gas analyses and biochemical variables important for characterizing uraemia. During the first hour of haemodialysis the 2,3-BPG/Hb4 ratio decreased (p < 0.002), but the magnitude of the decrease did not significantly correlate with the 2,3-BPG/Hb4 ratio measured before haemodialysis (p=0.104). The decrease is most likely to be caused by the haemodialysis procedure itself. Mechanical stress on the erythrocytes is believed to cause the 2,3-BPG to escape; it is then removed by haemodialysis. Physiologically, an increase in 2,3-BPG would be expected to counteract the hypoxia which is frequently observed during haemodialysis. However, the present results show the opposite, a decrease in 2,3-BPG. No significant correlation was shown between the haemoglobin concentration and the 2,3-BPG/Hb4 ratio before dialysis (p=0.414). The pH showed a significant positive correlation with the 2,3-BPG/Hb4 ratio before dialysis, whereas the arterial pO2 and the 2,3-BPG/Hb4 ratio before dialysis were insignificantly negatively correlated. The concentrations of calcium, phosphate, creatinine, urea and albumin did not correlate significantly with the change in 2,3-BPG/Hb4-ratio after 1 h. The 2,3-BPG/Hb4 ratio (p=0.03) sampled just before dialysis correlated significantly and positively with the total weekly dosage of erythropoietin given to the patients.

The pulsatility index and the resistive index in renal arteries. Associations with long-term progression in chronic renal failure.

BACKGROUND: The pulsatility index (PI) and the resistive index (RI) are used as pulsed-wave Doppler measurements of downstream renal artery resistance. PI and RI have been found to correlate with renal vascular resistance, filtration fraction and effective renal plasma flow in chronic renal failure. The aim of the present study was to evaluate the potential relationship between these indices and the rate of decline in renal function, as reflected by changes in different parameters of renal function in patients with chronic renal failure. METHODS: Twenty-one patients (8 females; 13 males, mean age 58 years (36-75)) with chronic renal failure were enrolled in the study. Doppler examinations were performed in the segmental arteries by an Acuson 128XP. The PI and the RI was calculated from the blood flow velocities. Parameters of renal function were measured every 3 1/2 months, and all patients were followed for 18-21 months. Progression of renal dysfunction was estimated by linear regression of parameters of renal function versus time. RESULTS: In a multiple regression analysis both PI and RI correlated significantly to the rate of decline in reciprocal serum creatinine (PI: r = -0.48, P = 0.03; RI: r = -0.52, P = 0.02). Furthermore, when separating the patients in two groups by the median RI value, there was a significant difference between the groups in rate of decline in reciprocal serum creatinine (P = 0.02). For PI this distinction was also present (P = 0.04). CONCLUSION: PI and RI correlated to the severity of the renal disease, as reflected by the rate of decline in reciprocal serum creatinine during antihypertensive treatment. The median RI or PI value could separate the patients into groups one of slow and another of fast progression.

[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.

Losartan reduces albuminuria in patients with essential hypertension. An enalapril controlled 3 months study.

BACKGROUND: Elevated urinary albumin excretion is a common feature of essential hypertension which may be reduced by ACE-inhibition through independent reductions of both systemic and intraglomerular pressure. A concurrent inhibition of bradykinin breakdown may be involved. METHODS: A double-blind, randomized, 12 weeks study of the effects on enalapril 20 mg (n = 46) vs losartan 50 mg daily (n = 47) on blood pressure, albuminuria, fasting blood glucose, and lipids in 57 male and 36 female patients with essential hypertension. RESULTS: Blood pressure was similarly reduced during both treatments: enalapril 156/102 (15/5) (mean [SD] to 142/92 [14/7]) mmHg, losartan: 159/103 (17/6) to 149/94 (21/9) mmHg, both P < 0.001. Urinary albumin to creatinine ratio was significantly reduced during losartan (from 1.14(x/divided by 2.48) (geometric mean (x/divided by antilog SD) to 0.81 (x/divided by 2.43) mg/mmol, P < 0.01), as well as during enalapril (from 0.95 (x/divided by 2.45) to 0.73 (x/divided by 2.00) mg/mmol, both P < 0.05). The effect on albuminuria was especially evident in patients with microalbuminuria. Fasting blood glucose, total cholesterol, HDL-cholesterol and triglycerides were unchanged during losartan, whereas minor reductions were found in all lipids during enalapril. No difference was observed between the groups. CONCLUSION: Enalapril 20 mg and losartan 50 mg daily reduce blood pressure equally in essential hypertensive patients. No adverse effects were seen on glucose and lipid concentrations. Losartan treatment reduces albuminuria at least as effectively as enalapril, suggesting that glomerular leakage of albumin is profoundly affected by the effects angiotensin II.

The pulsatility index and the resistive index in renal arteries in patients with hypertension and chronic renal failure.

BACKGROUND: The pulsatility index (PI) and the resistive index (RI) are used as pulsed-wave Doppler measurement of downstream renal artery resistance. Little information is available on their value in chronic renal failure and their correlation to parameters of renal function and haemodynamics. The aim was to compare PI and RI of renal arteries in healthy volunteers and in patients with hypertension and chronic renal failure, and furthermore to study the correlation of these indices to measurements of renal haemodynamics and function by standard methods in patients with renal failure and hypertension. METHODS: Twenty-five hypertensive patients (10 females, 15 males, mean age 52 years (24-74) with a glomerular filtration rate (GFR) less than 50 ml/min and an arterial blood pressure above 140 mmHg systolic and 95 mmHg diastolic were included in the study. Ten healthy, normotensive volunteers (4 females and 6 males, mean age 43 years (30-62)) served as controls in the Doppler examinations. Doppler examinations were performed in segmental arteries by an Acuson 128. The PI and the RI was calculated from the blood flow velocities. RESULTS: Both the PI and the RI were significantly higher in the patient group (P) than in the control group (C) (PI, P 1.65 (1.31-1.86), C 1.19 (0.93-1.25), P = 0.003; RI, P 0.76 (0.69-0.81), C 0.67 (0.64-0.70), P = 0.003). Both PI and RI correlated significantly with effective renal plasma flow (PI: r = -0.5, P = 0.02; RI: r = -0.5, P = 0.006), renal vascular resistance (PI: r = 0.4, P = 0.05; r = 0.5, P = 0.02), filtration fraction (PI: r = 0.6, P = 0.005; RI: r = 0.5, P = 0.01) and clearance of creatinine (PI: r = -0.6, P = 0.008; RI: r = -0.6, P = 0.006). Only RI correlated significantly to GFR (r = -0.5, P = 0.02). The indices did not correlate to serum creatinine, or mean arterial blood pressure. CONCLUSION: PI and RI seems to be closely related to parameters of renal haemodynamics and clearance of creatinine in patients with chronic renal failure and hypertension.

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.

Carbon monoxide in chronic uraemia related to erythropoietin treatment and smoking habits.

In 69 patients on chronic haemodialysis, blood sampled randomly during dialysis was analyzed for carboxyhaemoglobin (COHb). The median value was 1.40% (range 0.9-2.3) in non-smoking patients and (1.4-7.5) in smokers. In non-smokers treated with erythropoietin (EPO) correlation was found between COHb and the weekly EPO dose (r = 0.57, p = 0.007). In smoking patients not given EPO, the COHb correlated well with the number of cigarettes smoked (r = 0.84, p = 0.003). The COHb values did not correlate to the haemoglobin values. It is concluded that COHb levels in uraemic non-smokers are elevated because of increased endogenous CO production from the enhanced erythrocyte turnover. As even low COHb levels may negatively influence the oxygen status of the uraemic patient, the addition of exogenous CO from cigarette smoking should be avoided.

Oxygen status during haemodialysis. The Cord-Group.

Hypoxia during haemodialysis, mainly acetate, has been reported several times. In our study we have monitored oxygen status during 258 bicarbonate haemodialyses. A significant drop below 80 mmHg in mean oxygen tension occurred. Mean oxygen saturation reflected this drop but did not reach levels below 90%. The mean oxygen concentration was on the whole critical low, though slightly increasing during each haemodialysis session due to ultrafiltration. It is concluded that both hypoxia and hypoxaemia do occur during bicarbonate haemodialysis. To a group of patients generally having limited cardiac reserves, a poor oxygen status is a potentially serious complication to haemodialysis. Monitoring oxygen status is thus advisable.