Biomedical subjects

A H Zwinderman

Publications and source records attributed to A H Zwinderman.

At least 127 records · Page 7Linked to original sources

PubMed2000

Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature.

PURPOSE: To evaluate the risk of major thromboembolic complications in male germ cell cancer patients receiving cisplatin-based chemotherapy and to review the literature on this subject. PATIENTS AND METHODS: One hundred seventy-nine germ cell cancer patients treated between January 1979 and May 1997 in our hospital were analyzed with respect to risk factors for developing thromboembolic events, such as baseline tumor characteristics, prior tumor therapy, administration of cytostatic agents, and the use of antiemetic drugs. The patients were treated with a variety of combination chemotherapy regimens, primarily cisplatin-containing combination regimens. RESULTS: Of the 179 patients, 15 patients (8.4%) were identified who developed a total of 18 major thromboembolic complications in the time period between the start of chemotherapy and 6 weeks after administration of the last cytostatic drug in first-line treatment. Of these 18 events, three (16.7%) were arterial events, including two cerebral ischemic strokes, and 15 (83. 3%) were venous thromboembolic events, including 11 pulmonary embolisms. One (5.6%) of the 18 events was fatal. Liver metastases (odds ratio, 4.9; 95% confidence interval, 1.1 to 20.8) and the administration of high doses of corticosteroids (>/= 80 mg dexamethasone per cycle; odds ratio, 3.5; 95% confidence interval, 1. 2 to 10.3) as antiemetic therapy were identified as risk factors for the development of major thromboembolic complications. CONCLUSION: Germ cell cancer patients who receive chemotherapy, in particular those who have liver metastases or receive high doses of corticosteroids, are at considerable risk of developing thromboembolic complications.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Limitations of randomized clinical trials. Proposed alternative designs.

BACKGROUND: The classical two-period crossover and two-parallel-groups designs for clinical drug trials are unable to answer many current scientific questions, and are sometimes ethically or financially difficult. For example, the classical designs do not allow the study of the effects of combined treatments and their interactions. Also, the generation of parallel data that are no more than a repetition of previous research is ethically debatable and in a sense a waste of money. Objectives are to identify what a classical clinical trial cannot manage, to summarize and discuss alternative trial designs that are helpful for such purposes. RESULTS: A classical clinical trial cannot: (i) assess combined therapies, (ii) take historical data into account, (iii) safeguard ethics and efficacy during the course of long-term trials, (iv) study drugs, before well-established toxicity information is available, (v) account for the possibility of therapeutic equivalence between test and reference treatment, (vi) study multiple treatments in one trial, and (vii) adjust change scores for baseline levels. Alternative designs helpful for such purposes are respectively: (i) factorial designs, (ii) historical controls designs, (iii) group-sequential interim analysis designs, (iv) sequential designs for continuous monitoring, (v) therapeutic equivalence designs, (vi) multiple crossover-periods/multiple parallel-groups design, and (vii) increased precision designs through multivariate adjustment. Main problems include the increased risks of type I and type II errors and the loss of validity criteria. CONCLUSIONS: Non-classical trial designs are reviewed. They offer relevant scientific, ethical, and financial advantages. The increased risks of type I and type II errors should be accounted for in the design stage of the trial.

Clinical Trials as Topic↗

PubMed2000

Independent determinants of the efficacy of nitrate therapy.

BACKGROUND: Asymmetric dosage regimens of isosorbide mononitrate provide better antianginal efficacy and quality of life in patients with stable angina pectoris than the daily administration of multiple small doses of the compound. It is not known whether certain patient characteristics contribute to this improved benefit. OBJECTIVE: To determine independent factors contributing to this improved benefit. Multiple linear regression analysis was performed with a self assessment study in 1350 patients with stable angina pectoris. Quality of life was assessed by the Marquis questionnaire for patients with angina and included the assessment of immobility, pain and psychological distress. Individual scores were calculated as the pooled sums of the assessment scores and were expressed on an ordinal scale of 10. RESULTS: Age did not influence the improvement in benefit. Gender, rhythmic disturbances, peripheral artery disease and the concomitant use of calcium channel blockers or beta-blockers were without effect. New York Heart Association angina classification was an independent variable: patients with a class I or II showed less benefit than did patients with class III or IV (p = 0.02). Obese patients as well as hypertensive patients (p = 0.04 and 0.02), and smokers also tended to benefit less (p = 0.08). In contrast, the presence of cholesterolemia and diabetes mellitus were associated with increase in the beneficial effect of nitrates on quality of life (p = 0.03 and 0.05). CONCLUSIONS: Patients with severe angina pectoris benefit better from nitrate therapy than do patients with New York Heart Association class I - II. Also, patients with coronary artery disease and concomitant diabetes mellitus or cholesterolemia may benefit better from nitric oxide donor therapy than patients without such condition. In contrast, patients with concomitant obesity, hypertension, or who are smokers may show less benefit.

Aged↗

PubMed2000

Expression of epidermal growth factor receptor: risk factor in uveal melanoma.

PURPOSE: To investigate the prognostic significance of the expression of epidermal growth factor receptor (EGFR) in uveal melanoma. EGFR is a transmembrane glycoprotein, and its expression has been correlated with the development of metastases in various malignancies. METHODS: Frozen sections from 22 primary uveal melanomas were examined for EGFR expression by a three-step immunoperoxidase staining, using a mouse anti-human EGFR IgG2b monoclonal antibody. The results were compared with patient survival and clinical and histopathologic parameters. RESULTS: EGFR expression could not be determined on one tumor due to excessive pigmentation. Two patients died of causes unrelated to melanoma, and two patients were lost to follow-up. Out of 21 tumors, six tumors showed immunoreactivity for EGFR. Five of these six patients (83%) died due to metastases, compared with 2 (17%) of 12 patients with no EGFR expression (Kaplan-Meier analysis P = 0.0004). EGFR-positive tumors tended to have a greater tumor prominence and a higher mitotic rate. CONCLUSIONS: The expression of EGFR was significantly correlated with death due to metastatic disease and therefore can be regarded as an important prognostic factor in human uveal melanoma.

Adult↗

PubMed2000

Isosorbide mononitrate 30% immediate-release 70% sustained-release formulation: a review. DUMQOL (DUtch Mononitrate Quality of Life) Study Group.

Since the first publication of isosorbide mononitrate 30% immediate-release 70% sustained-release (IR-SR) formulation in 1985, a considerable body of literature concerning its clinical efficacy and safety has become available. Theoretically, the formulation has the advantage over conventional isosorbide mononitrate or dinitrate (ISMN/ISDN) that it has a simpler and more predictable pharmacokinetic profile. The objectives of this paper are to review published data so far and to see whether the theoretical advantages translate into better clinical effectiveness. 1. After oral administration, isosorbide mononitrate IR-SR has a rapid onset of action (30 minutes), and effects are evident for up to 17 hours. 2. The antianginal effects of once-daily isosorbide mononitrate IR-SR increased with increasing dosages, were generally larger than those of either placebo or equipotent doses of conventional ISMN/ISDN, and were somewhat larger than those of the beta blocker bupranolol. The effects were generally similar to those of sustained release nifedipine. 3. Patients showed significantly greater improvement in some quality-of-life indices with once-daily isosorbide mononitrate IR-SR than with twice or three times daily regimens of conventional ISMN/ISDN. This was particularly so with mobility, psychological distress, and life satisfaction indices. 4. Tolerance did not develop after 13 months of once daily isosorbide dinitrate IR-SR. No rebound increase in incidence of ischemic episodes was observed after discontinuation of treatment. 5. Long-term efficacy data both of isosorbide mononitrate IR-SR and of conventional ISMN/ISDN are limited so far. Large studies in patients with angina pectoris and patients with heart failure addressing long-term effects are ongoing, and some of the data will be completed within the next months. Isosorbide mononitrate IR-SR has a rapid onset of action and has been shown to be clinically efficient and, in addition, to be more so than conventional ISMN / ISDN. Nitrate tolerance with continued use of the formulation has not yet been reported. Long-term effects on morbidity and mortality are currently being assessed.

Administration, Oral↗

PubMed1999

Measurement of HPRT mutations in splenic lymphocytes and haemoglobin adducts in erythrocytes of Lewis rats exposed to ethylene oxide.

Young adult male Lewis rats were exposed to ethylene oxide (EO) via single intraperitoneal (i.p.) injections (10-80 mg kg-1) or drinking water (4 weeks at concentrations of 2, 5, and 10 mM) or inhalation (50, 100 or 200 ppm for 4 weeks, 5 days week-1, 6 h day-1) to measure induction of HPRT mutations in lymphocytes from spleen by means of a cloning assay. N-ethyl-N-nitrosourea (ENU) and N-(2-hydroxyethyl)-N-nitrosourea (HOENU) were used as positive controls. Levels of N-(2-hydroxyethyl)valine (HOEtVal) adducts in haemoglobin (expressed in nmol g-1 globin) were measured to determine blood doses of EO (mmol kg-1 h, mM h). Blood doses were used as a common denominator for comparison of mutagenic effects of EO administered via the three routes. The mean HPRT mutant frequency (MF) of the historical control was 4.3 x 10(-6). Maximal mean MFs for ENU (100 mg kg-1) and HOENU (75 mg kg-1) were 243 x 10(-6) and 93 x 10(-6), respectively. In two independent experiments, EO injections led to a statistically significant dose-dependent induction of mutations, with a maximal increase in MF by 2.3-fold over the background. Administration of EO via drinking water gave statistically significant increases of MFs in two independent experiments. Effects were, at most, 2.5-fold above the concurrent control. Finally, inhalation exposure also caused a statistically significant maximal increase in MF by 1.4-fold over the background. Plotting of mutagenicity data (i.e., selected data pertaining to expression times where maximal mutagenic effects were found) for the three exposure routes against blood dose as common denominator indicated that, at equal blood doses, acute i.p. exposure led to higher observed MFs than drinking water treatment, which was more mutagenic than exposure via inhalation. In the injection experiments, there was evidence for a saturation of detoxification processes at the highest doses. This was not seen after subchronic administration of EO. The resulting HPRT mutagenicity data suggest that EO is a relatively weak mutagen in T-lymphocytes of rats following exposure(s) by i.p. injection, in drinking water or by inhalation.

Administration, Inhalation↗

PubMed1999

Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis.

It has proved difficult to identify high-risk patients for atherosclerosis and to determine how they might respond to medication. Recently, a common promoter variant of the human stromelysin-1 gene has been reported, which has been shown to affect the transcription. We investigated whether this polymorphism had any impact on the risk of events, especially restenosis and progression of coronary artery disease and whether the effect was modulated by treatment with pravastatin. The stromelysin-1 genotype was determined for 496 men with coronary artery disease and cholesterol levels between 4.0 and 8.0 mmol/L, participating in the Regression Growth Evaluation Statin Study (REGRESS) study, a clinical trial assessing the effect of the lipid-lowering drug pravastatin on the progression of atherosclerosis. Patients in the placebo group with 5A6A or 6A6A genotypes had more clinical events than patients with the 5A5A genotype (26% and 12%, respectively, p = 0.03). In the pravastatin group, the risk of clinical events in patients with 5A6A or 6A6A genotypes was lower, compared with placebo, whereas it was unchanged in those with a 5A5A genotype (p value for interaction: 0.038). Also, the incidence of repeat angioplasty in the placebo group was greater in patients with the 6A6A or 5A6A genotypes, compared with 5A homozygotes (38% and 40%, respectively, vs 11%, p = 0.09). Again, treatment substantially reduced the incidence in heterozygotes and 6A homozygotes (0% and 15%, respectively), whereas it was unchanged in 5A homozygotes (28%, p for interaction: 0.002). These effects were independent of the effects of pravastatin on the lipid levels. Thus, this study suggests that the stomelysin-1 promoter polymorphism confers a genotype-specific response to medication in determining clinical event-free survival and the risk for symptom-driven repeat angioplasty. This variant may therefore act as a predictor, not only of disease progression, but also of response to therapy and risk of restenosis.

Anticholesteremic Agents↗

PubMed1999

Long-term course and outcome of functional capacity in rheumatoid arthritis: the effect of disease activity and radiologic damage over time.

OBJECTIVE: To investigate the evolution of functional capacity, disease activity, and joint destruction over time in a 12-year prospective cohort of rheumatoid arthritis (RA) patients, and to study the relative contribution of disease activity and joint destruction to the loss of functional capacity. METHODS: One hundred thirty-two female patients with recent-onset RA were assessed at 0, 3, 6, and 12 years of followup for functional capacity (Health Assessment Questionnaire [HAQ] score), disease activity (Disease Activity Score [DAS]), and joint destruction (Sharp score of radiologic damage). RESULTS: The Sharp score deteriorated steadily over time, while the HAQ score and DAS showed a variable course. The DAS correlated strongly with the HAQ score throughout the disease course. The correlation between the Sharp score and the HAQ score was weak at study start, but became strong after 12 years. After 12 years of followup, disease activity was the main determinant of the HAQ score when entered in a multivariate analysis. CONCLUSION: Functional capacity is strongly influenced by disease activity throughout the course of RA. Even in longstanding RA, disease activity proves to be the main determinant of the HAQ score for functional capacity.

Adult↗

PubMed1999

Presence of an eosinophilic infiltrate in cervical squamous carcinoma results from a type 2 immune response.

OBJECTIVES: The presence of an eosinophilic infiltrate in patients with cervical squamous carcinoma has been shown to correlate with a worse overall survival, suggesting a less effective immune response in these cases. Since type 2 cytokines such as IL-4 and IL-5 are known to attract eosinophilic granulocytes, an immunohistochemical study was performed to gain further insight as to whether a type 1 or type 2 immune response is involved in eliciting an eosinophilic infiltrate. MATERIAL AND METHODS: Frozen tissue sections of 9 normal cervical tissues, 23 premalignant cervical lesions, and 23 cervical squamous carcinomas were stained by immunohistochemistry with monoclonal antibodies directed against IFN-gamma and IL-4 as representatives of a type 1 or a type 2 response, respectively. RESULTS: Normal tissues and premalignant lesions of the cervix did not contain eosinophilic granulocytes and showed very few IL-4- and IFN-gamma-positive cells. In cervical carcinoma the presence of IL-4 on tumor infiltrating cells correlated with the presence of eosinophilic granulocytes in the tumor (P value <0.01) and stroma (P value <0.05). IFN-gamma-positive cells did not show any such correlation. In addition, colocalization was observed of CD3- and IL-4-positive T lymphocytes indicating that IL-4 production is mediated by T lymphocytes. CONCLUSION: The relative increase of IL-4-positive cells in the presence of an eosinophilic infiltrate might thus reflect an imbalance between a type 1 and type 2 response, in favor of the latter. Since a type 1 response stimulates an adequate cellular response which is negatively regulated by type 2 cytokines, these findings might explain the worse clinical outcome seen in cervical cancer patients with an eosinophilic tumor infiltrate. These results may have implications when developing immunotherapeutical strategies for cervical cancer.

Carcinoma, Squamous Cell↗

PubMed1999

E-cadherin expression in oesophageal carcinoma treated with high-dose radiotherapy; correlation with pretreatment parameters and treatment outcome.

BACKGROUND AND PURPOSE: E-cadherin plays an important role in the cell-cell contact of normal epithelium. Loss of E-cadherin expression may be related to tumour invasiveness and metastatic potential. In a group of patients treated for oesophageal carcinoma by radiotherapy only, we found that immunohistochemically detected p53 expression correlated with reduced survival, mainly because of the occurrence of distant metastases. We questioned whether, in this group of patients, E-cadherin expression was concomitantly altered and served as a predictive factor for the development of distant metastases. MATERIALS AND METHODS: Immunostaining for E-cadherin was performed on paraffin- embedded biopsy specimens from patients with adenocarcinoma and squamous cell carcinoma of the oesophagus. E-cadherin status and its correlation with regard to pretreatment parameters and treatment outcome were determined. RESULTS: An aberrant staining pattern of E-cadherin did not correlate with any of the pretreatment parameters. In a univariate analysis, a significantly reduced metastatic potential was found for tumours that had an aberrant cellular staining pattern for E-cadherin, which was strongest for squamous cell carcinomas. However, in a multivariate analysis only p53 status correlated significantly with the occurrence of distant metastases. CONCLUSION: Although, in univariate analysis, aberrant E-cadherin expression served as a better, rather than a worse prognostic factor, p53 status remained the only significant parameter in multivariate analysis, in this group of patients with oesophageal carcinoma. No relationship between p53 status and E-cadherin expression was found.

Adenocarcinoma↗

PubMed1999

Adjuvant radiotherapy following radical hysterectomy for patients with early-stage cervical carcinoma (1984-1996).

BACKGROUND AND PURPOSE: The aim of this study was to assess the results of treatment (surgery alone or surgery and postoperative radiotherapy) for early-stage cervical carcinoma and to determine the morbidity associated with adjuvant radiotherapy. A subset of these patients (n = 10) was irradiated postoperatively for tumor related negative prognostic factors only and this retrospective analysis was also performed to determine if this decision was right and if the selection for this treatment was based on the right criteria. MATERIAL AND METHODS: From 1984 to 1996, 233 women underwent radical hysterectomy as primary treatment of stage I or IIA cervical carcinoma. One hundred and fifty-six patients were treated with surgery alone (67%) and 77 patients (33%) received adjuvant radiotherapy for a, tumor related negative prognostic factors: the combination CLS(+), tumor size > or = 40 mm and poor differentiation grade or the combination tumor size > or = 40 mm and depth of invasion > or = 15 mm (n = 10), or b, positive surgical margins (n = 17), and/or c. lymphnode metastases (n = 42) and/ or d. parametrial involvement (n = 6). RESULTS: For the entire group the most important prognostic factor for survival and disease free survival was node positivity. Additional factors were depth of invasion and positive surgical margins. Thirty-five patients recurred of which 12 after surgery alone. In all these cases the relapse was in the pelvis (100%). Of the 23 recurrences after surgery and adjuvant radiotherapy 13 were seen in the pelvis (56%) (P = 0.003). All patients with negative prognostic factors and N0, received adjuvant radiotherapy (n = 10) and none of these patients recurred. The incidence of severe gastrointestinal radiation related side effects was low (2%). The incidence of lymphedema of the leg was 11% which was similar in the surgery alone group. CONCLUSIONS: The relatively low percentage of radiation related side effects together with 0% recurrence in a subgroup of node negative patients with high risk of recurrence, and a relatively low percentage of recurrence in the surgery alone group lead us to the conclusion that postoperative radiotherapy in special subsets of node negative patients is justified.

Adult↗

PubMed1999

Parenteral nutrition following intensive cytotoxic therapy: an exploratory study on the need for parenteral nutrition after various treatment approaches for haematological malignancies.

Patients receiving intensive cytotoxic therapy are traditionally supported with parenteral nutrition (PN), although it is unclear whether all patients benefit from PN. This study aimed to identify regimen-associated differences in PN requirements, to reveal discrepancies between the number of PN indications and the frequency with which PN was actually given, and to describe characteristics of patients who met nutritional goals without PN. PN indications were defined as: (1) severe malnutrition at admission; (2) a prolonged period (7-10 days) of minimal oral intake; or (3) clinical weight loss >10%. PN was found to be needed in only 35% of consolidation courses, compared with 80% during remission induction and 55% during BMT. Significant differences were also seen between BMT protocols: PN was required in only 37% of autologous BMT recipients conditioned without total body irradiation (for lymphoma) vs 92% of recipients of a mismatched graft. A high body mass index was the only significant characteristic of patients who could do without PN. In conclusion, PN is not required for all patients undergoing intensive cytotoxic therapy. Screening of nutritional status at the start of therapy and monitoring oral intake following cytotoxic treatment may allow more appropriate identification of patients requiring PN.

Adult↗

PubMed1999

Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis.

Multiple genetic factors contribute to susceptibility to rheumatoid arthritis (RA). The extent of variability in disease presentation in RA may be related to genetic heterogeneity. In this study we investigated the association of the TNF gene polymorphism at position +489 with susceptibility to and severity of RA. Analysis of the frequency of the +489 A and G alleles in a group of 293 consecutive RA patients and 138 healthy controls revealed a significant decrease of the A allele. The +489 GA patients had a 3.9 times decreased chance of having erosive disease than +489 GG patients. These results were confirmed in a prospective study using a cohort of 112 patients who were followed for 12 years. The progression rate of the erosion score over 12 years expressed as Sharp score for X-rays of hands and feet was 3.4 per year for the GA-genotyped patients and 12.1 for the GG-genotyped patients. These associations were independent of rheumatoid factor and HLA-shared epitope positivity. In conclusion, these data suggest that the intron TNF +489 polymorphism is associated with susceptibility to and disease severity of RA independently of HLA-shared epitope-positive alleles.

Adult↗

PubMed1999

The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma.

BACKGROUND: Cysteinyl leukotrienes are capable of inducing chemotaxis of eosinophils in vitro and within the airways of animals and humans in vivo. OBJECTIVE: We hypothesized that montelukast (MK-0476), a potent cysLT1 receptor antagonist, would protect against allergen-induced early (EAR) and late (LAR) asthmatic responses by virtue of anti-inflammatory properties. Hence, we studied the effect of pretreatment with oral montelukast on allergen-induced airway responses. As an exploratory endpoint, changes in inflammatory cell differentials and eosinophil cationic protein (ECP) were evaluated in hypertonic saline-induced sputum. METHODS: Twelve asthmatic men (20-34 years, FEV1 79-109% predicted, histamine PC20FEV1 <4 mg/mL) with dual responses to inhaled house dust mite extract participated in a two-period, double-blind, placebo-controlled, crossover study. Three oral doses of montelukast (10 mg) or matching placebo were administered 36 and 12 h before, and 12 h post-allergen. The airway response to allergen was measured by FEV1, and the EAR and LAR were expressed as the corresponding areas under the time-response curves (AUC0-3 h and AUC3-8h, respectively). During each study period, sputum was induced with 4.5% NaCl 24 h before and 24 h after a standardized allergen challenge. Processed whole sputum cytospins were stained with Giemsa, and cell counts expressed as percentage nonsquamous cells. ECP was measured by FEIA in sputum supernatants. RESULTS: All subjects completed the study. The changes in baseline FEV1 were not significantly different between the two pretreatments (P = 0.183). Montelukast significantly inhibited the EAR and LAR, reducing the AUC0-3h by 75.4% (P<0.001) and the AUC3-8h by 56.9% (P = 0.003) as compared with placebo. Sputa of nine subjects could be included in the analysis (<80% squamous cells). Allergen challenge significantly increased sputum eosinophils after placebo (mean change +/- SD: 4.8 +/- 5.8%, P = 0.038), with a similar trend after montelukast (mean change +/- SD: 4.1 +/- 5.4%; P = 0.056). The allergen-induced changes in sputum eosinophils and ECP, however, were not significantly different between the two pretreatments (P = 0.652 and P = 0.506, respectively). CONCLUSION: We conclude that oral montelukast protects against allergen-induced early and late airway responses in asthma. However, using the present dosing and sample size, this protection was not accompanied with changes in sputum eosinophil percentage or activity, which may require more prolonged pretreatment with cysLT1 receptor antagonists.

Acetates↗

PubMed1999

Sharing cross-reactive groups of MHC class I improves long-term graft survival.

BACKGROUND: Renal transplant loss from chronic rejection remains substantial. To increase our understanding of this syndrome, we identified risk factors predicting late graft loss, with a special emphasis on the impact of human lymphocyte antigen (HLA) matching. METHODS: We studied all 654 cadaveric kidney transplants performed in our center between 1983 and 1996 that had survived for more than six months. Eighty-two transplants, lost because of chronic rejection, were used as the outcome variable. The influence of HLA mismatches and shares on long-term graft survival was evaluated at the level of private antigens and cross-reactive groups (CREG) of multiple histocompatibility complex (MHC) class I. HLA and other recipient, donors and transplant parameters were studied using univariate and multivariate Cox regression analysis. RESULTS: The cohort had a mean number of 1.9 HLA mismatches. Because of the homozygosity of HLA antigens, HLA mismatches were not reciprocal to shares. CREG and HLA-A-B mismatches had a relative risk for graft loss of 1.19 (95% CI, 0.97 to 1.45) and 1.05 (0.84 to 1.32) per mismatch. In contrast, the relative risk per shared CREG and broad HLA-A-B antigen was 0.76 (0.63 to 0.92) and 0.79 (0.61 to 1.03). Multivariate analysis revealed that individuals sharing less than four CREGs had a relative risk of 2.13 (1.29 to 3.75) for late graft loss. Other independent predictors were a recipient age of less than 50 years, relative risk 1.95 (1.02 to 3.71); a donor age of more than 50 years, relative risk 1.68 (1.01 to 2.80); acute rejection (vascular vs. no rejection), relative risk 3.52 (1.72 to 7.18); proteinuria (dipstick > 1+ vs. negative), relative risk 2.86 (1.29 to 6.35); and a serum creatinine concentration of more than 150 micromol/liter at six months, relative risk 3.41 (1.96 to 5.94). CONCLUSION: We identified several coexisting recipient-, donor-, and transplant-related risk factors for graft loss from chronic rejection. In this well-matched group of renal transplants, HLA mismatches and shares had a nonreciprocal relationship. Sharing of HLA antigens, especially CREG of MHC class I, was associated with improved long-term survival.

Adult↗

PubMed1999

Inflammatory status as a main determinant of outcome in patients with unstable angina, independent of coagulation activation and endothelial cell function.

AIMS: Inflammation, endothelial cell function and the coagulation system have been demonstrated to be involved in the onset and course of unstable angina. Whether a proinflammatory state independently determines outcome is unknown and has not been determined yet in a clinically well defined study population of consecutive patients admitted with unstable angina. METHODS AND RESULTS: Markers of inflammation, coagulation activation and endothelial cell function were determined on admission in blood of 211 consecutive patients with severe unstable angina and were related to the in-hospital course. Refractory unstable angina occurred in 76 patients (36%) during their hospital stay. In a univariate analysis, C-reactive protein (P = 0.03), fibrinogen (P < 0.001) and erythrocyte sedimentation rate (P = 0.001) levels were significantly higher in patients with refractory unstable angina, when compared with patients who had an uneventful clinical course. The odds ratios (95% CI) adjusted for age, sex, body mass index, smoking behaviour and cholesterol levels of the occurrence of refractory unstable angina for patients in the highest quartile compared with patients in the lowest quartile of inflammatory markers were 2.19 (0.94-5.11) for C-reactive protein, 2.83 (1.13-7.10) for fibrinogen and 4.72 (1.70-13.09) for the erythrocyte sedimentation rate. The findings were not affected by the presence or absence of myocardial necrosis or the interval between onset of angina and blood collection. No association was found between markers of coagulation activation or markers of endothelial cell function, and in-hospital outcome. CONCLUSION: We found that in a clinically well-defined study population of patients with severe unstable angina, a proinflammatory state is an important and independent determinant of short-term outcome. The data strengthen the importance of inflammation in this syndrome.

Adult↗

PubMed1999

The influence of a partially HLA-matched blood transfusion on the disease activity of rheumatoid arthritis.

OBJECTIVE: Based on the immunosuppressive effects of blood transfusions in organ transplantation, we determined the effect of a blood transfusion on disease activity of rheumatoid arthritis (RA). METHOD: In this double-blind pilot study, 40 patients with active RA were randomly assigned to receive a HLA-DRB1-matched blood transfusion (n = 30) or placebo (n = 10). Disease activity was scored according to the American College of Rheumatology response criteria during 6 months of follow-up. RESULTS: After 1 month and 6 months, respectively, 6 and 16% of patients fulfilled the response criteria in the blood transfusion group compared to none and 30%, respectively, in the placebo group. Following correction for the increase in haemoglobin levels, a majority of the response parameters in the blood transfusion group showed significant improvement compared to the placebo group. CONCLUSION: A DRB1-matched blood transfusion shows improvement of symptoms in several RA patients. Additional studies are required to identify blood transfusion regimens that enhance the potential for therapeutic responses.

Adult↗

PubMed1999

Replacement of angiotensin-converting enzyme inhibitors by angiotensin-II-receptor antagonists in hypertensive patients with type II diabetes mellitus: metabolic and hemodynamic consequences.

The main pharmacodynamic difference between angiotensin-converting enzyme-inhibitors (ACE-i) and angiotensin-II-receptor antagonists (AII-r) is that ACE-i increase levels of bradykinin, which, in addition to vasodilation, may cause a decrease in insulin resistance. Hypertensive patients with diabetes type II suffering from side effects from ACE-i are frequently changed over to AII-r. The objectives of this study were (1) to study whether this procedure reduces metabolic control, (2) to study effects on blood pressure and forearm blood flow (FLOW), and (3) to study possible associations between the variables hemoglobin A (1c) (HbA(1c)) and FLOW. A self-controlled sequential comparison is required to address such questions. Sixteen patients were treated with 10 mg enalapril or equipotent doses of other ACE-i for 6 months and subsequently with the AII-r losartan at 50 mg daily for 6 more months. Patients were examined at the outpatient clinic every 4 to 8 weeks during the trial. FLOW was measured by iridium strain gauge venous occlusion plethysmography. Mean arterial pressure (MAP) increased by 4 +/- 5 mm Hg (P <.05) after 6 months of losartan treatment as compared with the point of withdrawal of ACE-i. FLOW decreased by 5.4 +/- 5.0 mL/100 mL tissue/min (P <.001), and HbA (1c) increased by 0.6 +/- 0.8 mmol/L (P <.05). Other metabolic variables, including cholesterol, high-density lipoprotein cholesterol, and triglycerides, were not significantly influenced by the change in therapy. Multiple regression analysis revealed that after adjustment for difference in HbA (1c), the correlation between FLOW and MAP was unchanged, and after adjustment for difference in FLOW, the correlation between HbA (1c) and MAP was no longer significant. Replacement of ACE-i by AII-r in hypertensive patients with type II diabetes mellitus induced a significant increase in HbA (1c) and MAP and a decrease in FLOW. The associations of HbA (1c) and FLOW with MAP were at least partly independent of each other, suggesting that mechanisms other than the bradykinin system (eg, the angiotensin (2) -receptor system) are involved. Our study design did not control for placebo and time effects, and so the data are of a preliminary nature.

Adult↗