Biomedical subjects

A H Zwinderman

Publications and source records attributed to A H Zwinderman.

At least 37 records · Page 2Linked to original sources

PubMed2004

Idiopathic impaired spermatogenesis: genetic epidemiology is unlikely to provide a short-cut to better understanding.

The aetiology of impaired spermatogenesis is unknown in the majority of subfertile men. From several studies of concordance for involuntary childlessness among men, we can conclude that there is a substantial familial component in male subfertility and that shared loci segregating through families can be assumed. We now know that deletions on the Y chromosome, which do not penetrate fully, account for some of these cases. There are good reasons to suspect that other cases result from mutations in genes located elsewhere in the genome. In this article, we discuss different approaches to unravelling the molecular basis of impaired spermatogenesis originating from genetic abnormalities in chromosomes other than the Y chromosome. Genetic mapping studies are in general a good approach to detect disease-causing genes that are segregating through a population; they can provide a shortcut to unravelling the biochemistry of a disease. In this paper, we explain our reasons for arguing that linkage and association studies are no promising means to identify the genes causing impaired spermatogenesis. We conclude that direct screening of candidate genes for mutations will be necessary to detect genes involved in impaired spermatogenesis. However, this approach requires studies of the biochemical pathways of normal and abnormal spermatogenesis. Since we have a poor understanding of these pathways, more research is needed into the biochemistry of spermatogenesis.

Chromosomes, Human, Y↗

PubMed2004

Pharmacokinetic/pharmacodynamic modelling of effects of dexamethasone and prednisolone in combination with endogenous cortisol on lymphocyte counts and systemic markers of bone turn over and inflammation in healthy and asthmatic men.

OBJECTIVE: To compare potency and efficacy of dexamethasone (DEXA) and prednisolone (PRED) in assumed equipotent doses in combination with endogenous cortisol, using lymphocyte counts, plasma osteocalcin (OC), and eosinophilic cationic protein (ECP) as effect variables and to evaluate potential differences between healthy subjects and asthmatic patients. METHODS: Eight healthy subjects and six asthmatic patients who had stopped taking their regular inhaled glucocorticosteroid treatment (ICS) for 1 week, were given an IV bolus of DEXA and PRED in assumed equipotent doses of 2.0 mg and 12.5 mg, respectively, on separate occasions, in combination with subcutaneously injected granulocyte-colony-stimulating factor (G-CSF) as a stimulant for ECP production. Plasma levels of DEXA, PRED, cortisol and effect variables were determined over 25 h and pharmacokinetic-pharmacodynamic (PK-PD) modelling was performed. RESULTS: Baseline cortisol concentration was lower in patients than in healthy subjects. Both of the exogenous glucocorticoids (GCs) diminished cortisol production. In the healthy subjects, the cortisol production remained suppressed for the full duration of the study day after DEXA but not after PRED. In the asthmatic patients though, the reappearance of the endogenous production of cortisol was seen after both DEXA and PRED. The E(max) values for lymphocyte counts and OC showed that cortisol acted as partial, and DEXA and PRED as full agonists. The observed responses of DEXA and PRED suppressing cortisol, OC and lymphocyte counts were all of the same relative order of magnitude, in accordance with the estimated PD parameters. However, cortisol was estimated to have very little effect on ECP and modelling further predicted that DEXA and PRED were only partial agonists for this effect, without a difference between healthy and asthmatic subjects. Yet, in healthy subjects, the area under the concentration-time curves (AUCs) indicated unexpectedly that ECP was only suppressed after PRED and not after DEXA, while in patients it was suppressed after both GCs. The rank order of potency on lymphocyte counts, OC and ECP was DEXA>PRED>cortisol, although the different relative potencies of the three GCs involved were not the same for all of the three effect variables and differences were also found between healthy and asthmatic subjects. CONCLUSION: PK-PD modelling studies of GCs demonstrated not only differences in potency of DEXA and PRED on the measured systemic markers, but also different potencies per target tissue and differences between healthy and asthmatic men. The effects caused by the achieved blood concentrations of DEXA and PRED, expressed as AUCs of the effect variables, were in accordance with their respective E(max) values in case of the lymphocytes and OC but not for ECP.

Adult↗

PubMed2004

[Community-acquired pneumonia: pathogens and course in patients admitted to a general hospital].

OBJECTIVE: To determine prognostic factors and the significance of (non-invasive) microbiological tests for the clinical course of patients admitted to one general hospital with community-acquired pneumonia (CAP). DESIGN: Prospective observational study. METHOD: Patients admitted to one location of a general hospital with symptoms of CAP during the period January 1998-December 1999 were included. Data from the anamnesis, physical examination and laboratory tests were recorded and samples were taken for diagnosis of the possible pathogens. Cultures were made of sputum and blood, serum and sputum were examined for infection with viral and atypical microorganisms, and the urine was screened for Streptococcus pneumoniae and Legionella antigens. RESULTS: Of the 157 patients studied, 28 (18%) died as a direct result of CAP. In a stepwise multivariate analysis, age > or = 65 years, increased serum-creatinine levels and hypercapnia were independent predictors of mortality. Streptococcus pneumoniae and Haemophilus influenzae were detected 53 and 19 times, respectively, and were the bacterial pathogens most frequently found. Among the nonbacterial pathogens, Mycoplasma pneumoniae was found 37 times and serologic tests for influenza A or B virus were positive in 34 cases. In 62 patients (39%), extensive microbiological tests revealed signs of a combined infection and in 20 patients (13%) no microorganism could be detected. An elevated serum-procalcitonin level was associated with bacterial infections. As a consequence of their retrospective nature, the results of the extensive serological tests did not contribute to reaching a diagnosis in daily clinical practice. In comparison with the literature, there was a markedly high number of subclinical or atypical infections with Legionella (8%) and Bordetella (18%) and a high incidence of viral and atypical microorganisms as the cause of CAP.

Adult↗

PubMed2004

A prospective longitudinal study comparing the impact of external radiation therapy with radical prostatectomy on health related quality of life (HRQOL) in prostate cancer patients.

BACKGROUND: The objective of the present study is to compare the impact on the general and disease-specific health related quality of life (HRQOL) of external radiation therapy (ERT) with radical prostatectomy (RP) in patients with localized prostate cancer, and to explore which factors, and to what extent, contribute to the assessed changes in HRQOL. METHODS: One hundred and thirty eight patients participated in this prospective longitudinal study. They completed before treatment (T0) and after 12 months (T1) a questionnaire constructed of validated instruments, measuring HRQOL and several psychosocial factors (PF). Among other things, multiple regression analyses including all baseline characteristics, HRQOL and PF were executed in order to meet the objectives. RESULTS: RP patients showed significantly more improvement in their emotional function, while they reported more incontinence and a worse sexual function. There was significantly more improvement in the overall HRQOL of ERT patients, while the changes in the gastrointestinal function of these patients were significantly worse. Only the differences with respect to incontinence can be attributed to the treatment itself. Almost all HRQOL change scores are primarily influenced by their own baseline score. The influence of other factors, like age, socioeconomic status, and several PF, is limited. CONCLUSIONS: The impact on HRQOL of ERT is similar to that of RP, except for incontinence. RP patients suffer more from incontinence than ERT patients. Changes in the assessed HRQOL are mainly influenced by the pre-treatment HRQOL scores.

Adaptation, Psychological↗

PubMed2004

Familial Paget's disease in The Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations.

OBJECTIVE: To estimate the occurrence of familial Paget's disease of bone in The Netherlands, to examine the prevalence of mutations of the sequestosome 1 gene (SQSTM1) in identified families, and to assess potential genotype-phenotype associations. METHODS: We performed a case-control study of patients with Paget's disease and a mutation analysis of the SQSTM1 gene of index patients with familial disease and of the relatives of those with a mutation. Serum alkaline phosphatase (AP) activity was assessed, and bone scintigraphy was performed. RESULTS: Five percent of patients had at least 1 first-degree relative with the disease, compared with 0.5% of the controls (relative risk 10; 95% confidence interval 1.3-75.6). In 38.9% of patients with familial disease, heterozygous mutations in the SQSTM1 gene were identified. These were the previously described P392L mutation, which was present in 22.2% of patients, and 3 new mutations, S399P, G425R, M404T, 9 of which were present in 3 different families. All mutations were located in the ubiquitin-associated domain of the gene. There was a relationship between serum AP activity, as a marker of the disease, and the presence or absence of the G425R and P392L mutations, the subject's age, and the presence of Paget's disease. CONCLUSION: Our data provide further evidence of a causal role of SQSTM1 gene mutations in the pathogenesis of Paget's disease and allow the design of a strategy based on measurements of serum AP activity and age for investigating asymptomatic relatives of patients with familial Paget's disease of bone.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Effects of oral prednisolone on biomarkers in synovial tissue and clinical improvement in rheumatoid arthritis.

OBJECTIVE: To create greater understanding of the changes in synovial tissue parameters that occur in conjunction with clinical response by using an effective therapy, in order to facilitate the planning of future studies with therapeutic agents for rheumatoid arthritis (RA). METHODS: Twenty-one patients with active RA were randomized to receive either oral prednisolone (n = 10) or placebo (n = 11) for 2 weeks. In all patients, synovial tissue biopsy specimens were obtained by arthroscopy directly before treatment and after 14 days of treatment. Immunohistochemical analysis was performed to characterize the cell infiltrate and vascularity. Stained tissue sections were analyzed by digital imaging. Statistical analysis was performed using an analysis of covariance model. RESULTS: After treatment, the mean Disease Activity Score in 28 joints (DAS28) was 2.0 units lower (95% confidence interval [95% CI] 1.0-3.0) in patients who received prednisolone than in those who received placebo. In the prednisolone group, the mean (+/-SD) DAS28 decreased from 6.27 +/- 0.95 to 4.11 +/- 1.43 after therapy; minimal change was observed in the placebo group. For macrophages, the estimated effect of prednisolone was large. Patients receiving active treatment had fewer (mean 628 cells/mm(2) [95% CI 328-927]) macrophages after therapy compared with those receiving placebo. A reduction in the total number of CD68+ macrophages, from 1,038 +/- 283 cells/mm(2) before treatment to 533 +/- 248 cells/mm(2) after treatment, was observed in the prednisolone group. There were clear trends toward decreased infiltration by T cells, plasma cells, and fibroblast-like synoviocytes after active treatment. We observed a trend toward a reduction in alphavbeta3+ newly formed blood vessels and expression of vascular growth factors after prednisolone therapy. CONCLUSION: Prednisolone therapy in RA is associated with a marked reduction in macrophage infiltration in synovial tissue, suggesting that synovial macrophage numbers could be used as a biomarker for clinical efficacy.

Administration, Oral↗

PubMed2004

Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind, placebo-controlled study.

Cisplatin-induced toxicities are mainly caused by the formation of free radicals, leading to oxidative organ damage. Plasma concentrations of antioxidants decrease significantly during cisplatin chemotherapy for cancer. Forty-eight cancer patients treated with cisplatin-based chemotherapy were randomised in a double-blind manner to receive either supplementation with vitamin C, vitamin E and selenium dissolved in a beverage or to receive a placebo beverage. Primary outcome measures were the amount of nephrotoxicity and ototoxicity induced by cisplatin. No significant differences were found between the two study groups with respect to these primary outcome measures. However, patients who achieved the highest plasma concentrations of the three antioxidant micronutrients had significantly less loss of high-tone hearing. In addition, significant correlations were found between the reduced/oxidised vitamin C ratio and malondialdehyde (MDA), markers of oxidative stress, and cisplatin-induced ototoxicity and nephrotoxicity. The lack of protection against cisplatin-induced toxicities in patients in the intervention arm may be related to poor compliance and/or inadequate supplementation. Supplementation with a higher dose (intensity) and in combination with other antioxidants should be investigated further.

Adolescent↗

PubMed2004

Validity of conjoint analysis to study clinical decision making in elderly patients with aortic stenosis.

OBJECTIVE: Written case simulations are increasingly being used to investigate clinical decision making. Our study was designed to determine the validity of written case simulations within a conjoint analysis approach. STUDY DESIGN AND SETTING: We developed a series of 32 written case simulations that differed with respect to nine clinical characteristics. These case simulations represented elderly patients with aortic stenosis. The clinical characteristics varied according to a fractional factorial design. We analyzed retrospectively all consecutive patients of 70 years of age or older with an aortic stenosis in three university hospitals. RESULTS: 34 cardiologists from three Dutch hospitals gave their treatment advice to each of these case simulations on a six-point scale (ranging from 'certainly no' to 'certainly yes' to surgical treatment). We compared the influence that the clinical characteristics had on the responses to these case simulations with their influence on the actual treatment decision for 147 actual patients in the same three hospitals. We found a strong agreement. This agreement was only slightly affected by the cut-off value used to dichotomize the treatment advice into a recommendation in favor of or against surgical treatment. CONCLUSION: Written case simulations reflect well how clinicians are influenced by specific clinical characteristics of their patients.

Aged↗

PubMed2004

Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis.

The aim of this systematic review and meta-analysis is to evaluate whether the design and methodology of drug-treatment studies of premature ejaculation affect the efficacy outcome differently. Therefore, methodological, design and efficacy data from 79 studies (3034 males), published between 1943 and 2003, are reviewed. A meta-analysis is performed on 43 selective serotonin reuptake inhibitors (SSRIs) and clomipramine studies (1514 males), published between 1973 and 2003; these studies were pooled to provide a summary variance-weighted effect size. The antidepressant-induced percentage increase of the intravaginal ejaculation latency time (IELT) was calculated and examined against various methodological items. A significant difference in efficacy between SSRIs was observed. Using daily treatment, paroxetine appeared more effective than the other SSRIs. Retrospective use of a questionnaire, subjective reports, single-blind and open study designs generate far greater variability of ejaculation time both at baseline and during active drug treatment than real time assessment by stopwatch. In conclusion, at daily treatment, the overall efficacy of paroxetine, clomipramine, sertraline and fluoxetine is comparable, but paroxetine exerts the strongest ejaculation delay. Only eight (18.5%) studies on antidepressant treatment fulfilled all criteria used in evidence-based medicine, for example, randomised, double-blind studies with prospective real time (stopwatch) assessment of the IELT at each intercourse. Single-blind studies, open designs, retrospective reporting, or the use of a questionnaire to assess ejaculation time should be avoided.

Adult↗

PubMed2004

A study into predictors for the speed of response to electroconvulsive therapy.

The efficacy of electroconvulsive therapy (ECT) has been firmly established in the treatment of depression. However, prediction of the speed of response to ECT is an issue that needs to be further explored. This study aims to examine the presence of predictors for the speed of response. In a retrospective chart review using 57 patients suffering from major depression who received ECT, the relation of several patient and ECT variables with the speed of response was explored. Response was defined as a drop of at least 35% in Hamilton rating scale of depression (HRSD) score from baseline after 3 or 4 ECT sessions. Patients received ECT with an aged-based stimulus dosage in a clinical setting. Multiple regression analysis showed that high baseline HRSD score and high seizure energy index (SEI) were significantly and independently associated with a rapid response. In a regression model, baseline HRSD score and SEI can be used to predict the speed of response to ECT. Rapid responders to ECT achieved remission significantly more often than slow responders did. SEI can be modified by the clinician. This offers the possibility to optimize ECT treatment.

Major Depressive Disorder↗

PubMed2004

Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS).

BACKGROUND: The TaqIB polymorphism in the cholesteryl ester transfer protein (CETP) gene is associated with HDL-C, progression of coronary artery disease (CAD) and response to pravastatin treatment in men with angiographically proven CAD (REGRESS). We hypothesized that differences in CETP concentration could explain these associations and now investigated whether CETP concentration is an independent determinant of these parameters. MATERIALS AND METHODS: Plasma CETP concentrations at baseline and after 2 years' treatment with pravastatin or placebo were measured (n=674), and correlations with lipid and angiographic parameters (mean segment- and obstruction-diameter; MSD and MOD), and TaqIB genotype were studied. RESULTS: After segregation into three groups (baseline CETP<1.58, 1.58-2.21, >2.21 mg L(-1)), subjects with the highest CETP had significantly higher baseline total cholesterol, LDL-C and triglycerides (P<0.01), while HDL-C, MSD and MOD were not different among these groups. After 2 years of placebo, the MSD decreased threefold (P<0.001) and the MOD decreased 2.4-fold (P=0.042) more in the highest compared with the lowest CETP quartile. Pravastatin treatment reduced total cholesterol LDL-C and triglycerides significantly more in the highest CETP quartile. Moreover, only in the highest CETP quartile, pravastatin significantly reduced the MSD- (P=0.003) and MOD-decrease (P=0.014) compared with placebo, and, notably, this was independent of baseline lipids and differential lipid changes in these quartiles. Strikingly, baseline associations and treatment responses according to baseline CETP were independent of TaqIB genotype. CONCLUSIONS: High CETP concentration is associated with faster progression of coronary atherosclerosis in men with proven CAD. Second, pravastatin yielded the highest improvement of lipid and angiographic parameters in patients with high baseline CETP independent of baseline lipids, lipid changes and TaqIB genotype, indicating that the plasma CETP level itself is an important determinant of the response to statins.

Carrier Proteins↗

PubMed2004

High intensity exercise or conventional exercise for patients with rheumatoid arthritis? Outcome expectations of patients, rheumatologists, and physiotherapists.

OBJECTIVE: To examine the outcome expectations of RA patients, rheumatologists, and physiotherapists regarding high intensity exercise programmes compared with conventional exercise programmes. METHODS: An exercise outcome expectations questionnaire was administered to 807 RA patients, 153 rheumatologists, and 624 physiotherapists. The questionnaire consisted of four statements regarding positive and negative outcomes of high intensity exercise programmes and four similar statements for conventional exercise programmes. A total expectation score for both conventional and high intensity exercise was calculated, ranging from -2 (very negative expectation) to 2 (very positive expectation). RESULTS: The questionnaire was returned by 662 RA patients (82%), 132 rheumatologists (86%), and 467 physiotherapists (75%). The mean (95% confidence interval) scores for high intensity exercise programmes were 0.30 (0.25 to 0.34), 0.68 (0.62 to 0.74), and -0.06 (-0.15 to 0.02), and for conventional exercise programmes were 0.99 (0.96 to 1.02), 1.13 (1.09 to 1.17), and 1.27 (1.21 to 1.34) for RA patients, rheumatologists, and physiotherapists, respectively. In all three respondent groups, the outcome expectations of high intensity exercise were significantly less positive than those of conventional exercise programme. CONCLUSIONS: Despite the existing evidence regarding the effectiveness and safety of high intensity exercise programmes, RA patients, rheumatologists, and physiotherapists have more positive expectations of conventional exercise programmes than of high intensity exercise programmes. Physiotherapists were the least positive about outcomes of high intensity exercise programmes while rheumatologists were the most positive. To help the implementation of new insights in the effectiveness of physical therapy modalities in rheumatology, the need for continuous education of patients, rheumatologists and physiotherapists is emphasised.

Arthritis, Rheumatoid↗

PubMed2004

Long term high intensity exercise and damage of small joints in rheumatoid arthritis.

OBJECTIVE: To investigate the effect of long term high intensity weightbearing exercises on radiological damage of the joints of the hands and feet in patients with rheumatoid arthritis (RA). METHODS: Data of the 281 completers of a 2 year randomised controlled trial comparing the effects of usual care physical therapy (UC) with high intensity weightbearing exercises were analysed for the rate of radiological joint damage (Larsen score) of the hands and feet. Potential determinants of outcome were defined: disease activity, use of drugs, change in physical capacity and in bone mineral density, and attendance rate at exercise sessions. RESULTS: After 2 years, the 136 participants in high intensity weightbearing exercises developed significantly less radiological damage than the 145 participants in UC. The mean (SD) increase in damage was 3.5 (7.9) in the exercise group and 5.7 (10.2) in the UC group, p = 0.045. Separate analysis of the damage to the hands and feet suggests that this difference in rate of increase of damage is more pronounced in the joints of the feet than in the hands. The rate of damage was independently associated with less disease activity, less frequent use of glucocorticoids, and with an improvement in aerobic fitness. CONCLUSION: The progression of radiological joint damage of the hands and feet in patients with RA is not increased by long term high intensity weightbearing exercises. These exercises may have a protective effect on the joints of the feet.

Adult↗

PubMed2003

Distinct actions of prednisolone and dexamethasone towards osteocalcin and eosinophilic cationic protein in assumed clinically equivalent doses: a study in healthy men.

OBJECTIVE: To study the effects of prednisolone (PRED) and dexamethasone (DEXA) in assumed clinically equivalent doses towards the lowering of cortisol, osteocalcin (OC) and the stimulated rise of eosinophilic cationic protein (ECP) by granulocyte colony stimulating factor (G-CSF). METHODS: At four separate sessions of 25 h each, saline i.v. alone, G-CSF s.c. alone or in combination with either 12.5 mg PRED i.v. or 2.0 mg DEXA i.v., were randomly administered in eight healthy male subjects. RESULTS: All subjects had equal lowering of cortisol after DEXA and PRED at 10 h, whereas a sustained suppression at 25 h persisted only after administration of DEXA. Between 4 h and 10 h after administration of DEXA and PRED, the change in the area under the concentration-time curve (DeltaAUC4-10) of OC became 24.4% and 2.3% lower, respectively ( p<0.0001). After 25 h, this effect persisted for DEXA. DeltaAUC4-10 of the G-CSF-stimulated ECP response decreased by a mean of 76.8% after PRED compared with DEXA and to controls ( p<0.02), and this difference had disappeared at 25 h. DEXA did not elicit any effect towards the G-CSF-stimulated ECP response. CONCLUSION: PRED and DEXA in formerly assumed clinically equivalent doses induced a similar suppression towards cortisol within the first 10 h, but had different actions towards blood concentrations of OC and ECP following G-CSF stimulation in healthy male subjects.

Adult↗

PubMed2003

Lack of relationships between cumulative methylprednisolone dose and bone mineral density in healthy men and postmenopausal women with chronic low back pain.

The medical use of glucocorticoids (GCs) is related to low bone mineral density (BMD). In this study we tested the hypothesis that the cumulative dose of GC is not related to BMD outcome. The study was cross-sectional in design and included healthy individuals with chronic low back pain resistant to conventional treatments. In two steroid-naive subjects cortisol and methylprednisolone (MP) concentrations were serially assessed after a single MP depot injection (160 mg epidurally). Furthermore, in 14 men and 14 postmenopausal women, previously treated with multiple epidural MP depots, endocrine parameters were analysed in relation to BMD outcomes. The minimal cumulative MP dose received by all 28 subjects was 3 g. In the two steroid-naive subjects, cortisol concentrations were completely suppressed for at least 6 days and partly recovered over the course of 30 days. During this period, MP concentrations remained detectable in plasma. In the 28 subjects, the cumulative MP dose received was 7.76+/-4.23 g in the men and 8.50+/-3.13 g in the women (mean+/-1SD). None of the men had osteoporosis, but osteopenia was prevalent in 78.5% according to WHO criteria extrapolated to men. Half of the women had osteoporosis and half of them had osteopenia. The body mass index (BMI) and endogenous oestradiol levels of the men were not related to BMD outcomes. Univariate linear relationships in women were found between BMI and spinal ( r 0.62; P=0.02) and total hip BMD ( r 0.61; P=0.03), but not femoral neck BMD. In women, relationships were also found between the total and, for protein binding-corrected oestradiol levels, and spinal BMD ( r 0.70; P=0.01 and r 0.72; P=0.01, respectively) and total hip BMD ( r 0.53; P=0.08 and r 0.56; P=0.05, respectively). No significance was observed between endogenous oestradiol levels and the BMD of the femoral neck. The administration of a single MP depot injection (160 mg) resembled a systemic low peak dose GC exposure. The administration of multiple MP depots in men and women with chronic low back pain revealed no relationship between cumulative GC dose and BMD. These findings support the hypothesis of a non-existent relationship between cumulative GC dose and BMD outcomes in healthy men and women with a prior GC administration of at least 3 g.

Aged↗

PubMed2003

Heterozygosity for ABCA1 gene mutations: effects on enzymes, apolipoproteins and lipoprotein particle size.

A cohort of 13 female and 14 male heterozygotes for ATP binding cassette A1 (ABCA1) gene defects was directly compared with 13 and 14 unaffected female and male family members of almost exact same age. The activities of three proteins that play key roles in HDL metabolism were measured in addition to extensive lipid and (apo) lipoprotein subfraction analysis. Compared to controls, LCAT activity was reduced by 15% in affected subjects (P < 0.001) while PLTP activity was unaffected. Interestingly, CETP activity was elevated by 50% in the heterozygote siblings of one kindred but was unaffected in heterozygotes of the three other families. With respect to lipids, the heterozygotes had normal total cholesterol (TC), and LDL-cholesterol concentrations but presented with a trend towards increased triglyceride levels (13%; P = 0.08). HDL metabolism, by contrast, was severely affected as illustrated by 40% reductions in HDL-cholesterol (P < 0.001) with concomitant reductions in apoAI (25%; P < 0.001) levels and in lipoprotein subfraction LpAI (28%; P < 0.001), LpAI:AII (24%; P=0.014), and LpCIII:nonB (34%; P < 0.001) concentrations. We furthermore observed reduced average HDL particle size (5%; P = 0.004; 16% in female and 3.6% in male) and reduced plasma apoCIII concentration (15%; P = 0.006) while apoAII, apoAIV, apoE and apoB levels were unchanged. In conclusion, heterozygosity for ABCA1 defects was associated with reduced LCAT activity in absence of effects on PLTP activity. Of special interest was our finding that the effects of compromised ABCA1 function on HDL were more pronounced in women than in men.

ATP Binding Cassette Transporter 1↗

PubMed2003

Is hypotension a major risk factor for neurological morbidity at term age in very preterm infants?

OBJECTIVE: To investigate the influence of perinatal risk factors, especially hypotension, on neuromotor status at term in surviving preterm infants born before 32 weeks of gestation. METHODS: This study is part of the Leiden Follow-Up Project on Prematurity: a prospective, regional study of 266 live born infants with a gestational age (GA) < 32 weeks born in 1996-1997. Twenty-eight infants died before term age. Two hundred and eleven infants were examined neurologically at term according to Prechtl. The findings were classified as normal (N), mildly abnormal (MA) or definitely abnormal (DA). Hypotension was defined as a mean arterial blood pressure (MABP) < 30 mm Hg on at least two occasions. RESULTS: One hundred and six (50%) infants were classified as neurologically N, 92 (44%) infants were classified as MA and 13 (6%) infants as DA. Hypotension, bronchopulmonary dysplasia (BPD), flaring and cystic periventricular leucomalacia (PVL) were risk factors for neurological morbidity. Of the 68 infants with hypotension, 33 (49%) were classified as MA and 7 (10%) as DA. Of the 141 infants without hypotension, 58 (41%) were MA, and 5 (4%) were DA. The odds ratio of hypotension for neurological morbidity was 1.9 (95% CI 1.06-3.40), adjusted for gestational age, birth weight, small for gestational age (SGA) and gender, it was 1.96 (95% CI 1.02-3.77). The adjusted odds ratio of PVL was 18.6 (4.4-78.5), of flaring was 2.37 (1.18-4.74) and of BPD was 2.44 (1.08-5.5). CONCLUSIONS: Apart from gestational age, periventricular leucomalacia, and bronchopulmonary dysplasia, hypotension in preterm infants is a major risk factor for neurological morbidity at term.

Gestational Age↗

PubMed2003

Estimation of multilocus haplotype effects using weighted penalised log-likelihood: analysis of five sequence variations at the cholesteryl ester transfer protein gene locus.

Direct analyses of haplotype effects can be used to identify those specific combinations of alleles that are associated with a specific phenotype. We introduce a method for direct haplotype analysis that solves two problems that arise when haplotypes are analysed in populations of unrelated subjects. Instead of assigning a single, most likely, haplotype pair to multiple heterozygous subjects, all haplotype pairs compatible with their genotype were determined and the posterior probabilities of these pairs were calculated using Bayes' theorem and estimated haplotype frequencies. For the individual patients, all possible haplotype pairs were included in the statistical analysis using the posterior probabilities as weights, which were re-estimated in an iterative process together with the haplotype effects. The second problem of unstable haplotype effect estimates, due to the numerous haplotypes and the low frequency at which some occur, was solved by assuming that haplotypes sharing the same alleles show a similar effect and that the extent of this similarity relates to the number of alleles shared. These assumptions were incorporated in a weighted log-likelihood model by introducing a penalty, where differences in effects of similar haplotypes were penalised. Using CETP gene haplotypes, consisting of five closely linked polymorphisms, and baseline CETP and HDL-C concentrations from the REGRESS population, we demonstrated that the model resulted in more stable effects than estimates based on unambiguous patients only.

Alleles↗