[Interaction of opioid analgesics at the level of biotransformation]. / Interaktionen der Opioidanalgetika auf Ebene der Biotransformation.

Opioids are an important component of the drug treatment of patients with acute and chronic pain. They differ in effectiveness, side effect profile and the risk of interactions. In this article the pharmacokinetic mechanisms of drug-drug interactions at the level of biotransformation are described and the clinical consequences which can arise are discussed. The relation of the active components to the two isoenzymes CYP2D6 and CYP3A4 is of major importance for assessing the potential drug-drug interactions of opioid analgesics at the level of the cytochrome P450 enzyme.

Population prevalence of Down's syndrome in the United Kingdom.

BACKGROUND: Aim was to estimate the age and sex-stratified prevalence of Down's syndrome (DS) in the United Kingdom (UK) general population using a large primary care database. METHOD: Data source was the Clinical Practice Research Datalink. We divided the number of individuals with a record of DS present on 01/07/2014 by the total number of individuals, and computed Wilson's confidence intervals. Prevalence by age and sex was represented using local linear smoothing plots. RESULTS: On July 1(st) 2014, 1159 females and 1317 males with DS were present in the data, corresponding to a prevalence of 5.9 per 10 000 (95% CI: 5.5; 6.2) in females and 6.8 (6.5; 7.2) per 10 000 in males. Prevalence of DS was increased in individuals aged 40 to 55 years compared to adjacent age groups. CONCLUSIONS: A relative peak prevalence of DS at age 40-55 years may be attributed to the combined effects of a rise in life expectancy and the still limited availability of selective abortion.

Frequency and Phenotype of Myotubular Myopathy Amongst Danish Patients with Congenital Myopathy Older than 5 Years.

BACKGROUND: Centronuclear myopathy (CNM) is one of four main subtypes of congenital myopathy. X-linked myotubular myopathy (XLMTM) is considered one of the most severe forms, but survivors past infancy have been described. However, detailed information on XLMTM phenotypes in patients who survive infancy is scarce. OBJECTIVE: The aim of the study was to report the genetic findings in patients with a predominant centronuclear finding on muscle biopsy and describe the prevalence, phenotypes and the course of the disease in patients with XLMTM in a Danish cohort of patients with congenital myopathies older than five years. METHODS: Ninety-four out of 119 invited patients older than five years were included in the study and assessed by muscle tests, functional tests, muscle biopsy, plasma creatine kinase levels and genetic testing. Genes related to CNM were sequenced in patients who had centronuclear findings on muscle histology. In patients with MTM1 mutations, medical records from local hospitals were reviewed to obtain information on birth history and course of disease. RESULTS: Sixteen of 94 patients had CNM on muscle biopsy; three male patients, aged 14-25 years, carried a pathogenic MTM1 mutation, six patients carried a pathogenic DNM2 mutation and two carried pathogenic RYR1 mutations. The mutations have all been described before to cause CNM. The MTM phenotypes ranged from severe (classical) to mild; one patient had always been non-ambulant, one had lost ambulation, and one was still ambulant at 25 years. CONCLUSIONS: Our findings show that CNM caused by DNM2 mutations is the most common form of CNM in Danish patients older than 5 years, but XLMTM is not negligible even past age 5 years, and the phenotype may be much milder than generally described - also in patients with the classically described infantile form of the disease.

Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy.

OBJECTIVES: To assess skeletal muscle weakness and progression as well as the cardiopulmonary involvement in oculopharyngeal muscular dystrophy (OPMD). MATERIALS AND METHODS: Cross-sectional study including symptomatic patients with genetically confirmed OPMD. Patients were assessed by medical history, ptosis, ophthalmoplegia, facial and limb strength, and swallowing capability. Cardiopulmonary function was evaluated using forced expiratory capacity in 1 s (FEV1), electrocardiogram (ECG), Holter monitoring, and echocardiography. RESULTS: We included 13 symptomatic patients (six males, mean age; 64 years (41-80) from 8 families. Ptosis was the first symptom in 8/13 patients followed by limb weakness in the remaining 5 patients Dysphagia was never the presenting symptom. At the time of examination, all affected patients had ptosis or had previously been operated for ptosis, while ophthalmoplegia was found in 9 patients. Dysphagia, tested by cold-water swallowing test, was abnormal in 9 patients (17-116 s, ref <8 s). Six patients could not climb stairs of whom two were wheelchair bound and one used a rollator. Six patients had reduced FEV1 (range 23%-59%). No cardiac involvement was identified. CONCLUSIONS: Limiting limb weakness is common in OPMD and can even be the presenting symptom of the disease. In contrast, dysphagia was not the initial symptom in any of our patients, although it was obligatory for diagnosing OPMD before genetic testing became available. Mild respiratory dysfunction, but no cardiac involvement, was detected.

Excess risk of hip fractures attributable to the use of antidepressants in five European countries and the USA.

SUMMARY: The association between antidepressant use and hip fracture remains unclear. We conducted a systematic review to estimate Population Attributable Risks (PAR) for France, Germany, Italy, Spain, UK, and the USA. We report a heterogeneous prevalence of antidepressant use and related PARs, both lowest for Italy and highest for the USA. INTRODUCTION: Antidepressant use has been associated with an increased hip fracture risk in observational studies. However, the potential contribution of antidepressant consumption on the population rate of hip fractures has not been described. Our aim was to estimate the impact of the use of different classes of antidepressants on the rate of hip fracture at a population-level in France, Germany, Italy, Spain, the UK, and the USA. METHODS: We conducted a systematic literature review to estimate the pooled relative risk (RR) of hip fracture according to use of antidepressants. Prevalence rates of antidepressant use (Pe) in 2009 were calculated for each country using the The Intercontinental Medical Statistics database and three public databases from Denmark, the Netherlands, and Norway. Both the RR and Pe were used to calculate PAR of hip fractures associated with antidepressant use. RESULTS: The literature review showed an increased risk of hip fractures in antidepressant users (RR, 1.7; 95 % confidence interval (CI), 1.5-2.0). Rates of antidepressant use showed considerable differences between countries, ranging from 4.4 % (Italy) to 11.2 % (USA) in the year 2009. The estimated PAR of antidepressants on hip fracture rates were 3.0 % (95 % CI, 2.0-4.1; Italy), 3.1 % (95 % CI, 2.1-4.3; Germany), 3.8 % (95 % CI, 2.6-5.3; France), 4.8 % (95 % CI, 3.3-6.5; Spain), 4.9 % (95 % CI, 3.4-6.8; UK), and 7.2 % (95 % CI, 5.0-9.9; USA). PARs differed for different types of antidepressants, with highest attributable risks for selective serotonin reuptake inhibitors. CONCLUSIONS: These findings suggest that the potential contribution of antidepressant use to the population rate of hip fractures in the five large EU countries and the USA varies between 3 and 7 %.

Potential impact of benzodiazepine use on the rate of hip fractures in five large European countries and the United States.

Benzodiazepine use increases the risk of falls and has been associated with an increased risk of hip fractures. Our aim was to estimate the possible population impact of the use of benzodiazepines on the rate of hip fracture in France, Germany, Italy, Spain, the United Kingdom, and the United States. We conducted a literature review to estimate the pooled relative risk (RR) for hip fractures and use of benzodiazepines. Prevalence rates of benzodiazepine use in 2009 were calculated for each country using the IMS MIDAS database and three public databases in Denmark, the Netherlands, and Norway. Both the RR and prevalence rates were used for calculation of population attributable risks (PARs) of hip fractures associated with benzodiazepine use. The literature review showed an increased risk of hip fractures in benzodiazepine users (RR = 1.4, 95 % CI 1.2-1.6). Rate of benzodiazepine use showed considerable differences between countries, ranging from 4.7 % to 22.3 % of population ever in a 1-year period. These are reflected in results for the PARs; estimated attributions of benzodiazepines to the rate of hip fractures were 1.8 %, 95 % CI 1.1-2.6 (Germany); 2.0 %, 95 % CI 1.2-2.8 (United Kingdom); 5.2 %, 95 % CI 3.2-7.3 (Italy); 7.4 %, 95 % CI 4.5-10.0 (France); 8.0 %, 95 % CI 4.9-11.0 (United States); and 8.2 %, 95 % CI 5.1-12.0 (Spain). PAR estimates suggest that the potential attribution of benzodiazepine use on the population rate of hip fractures in the five specified European countries and the United States varies between 1.8 % and 8.2 %. During the next phase of the IMI-PROTECT study, a comparison with individual patient data will show whether this approach is valid.

Clinical risk factors as predictors of postmenopausal osteoporosis in general practice.

BACKGROUND: Case-finding strategies to identify women with high risk for osteoporotic fractures have recently been proposed, but little information about such an approach in general practice is known. AIM: To study the validity of the proposed case-finding strategy for osteoporosis. DESIGN OF STUDY: Survey using case-finding strategy. SETTING: Seven hundred and twelve women aged between 55 and 84 years, randomly selected from a general practice in The Netherlands. METHOD: Of the 712 randomly selected women, 449 women participated. Information was obtained from a questionnaire, direct questioning, and computerised patients files. Bone mineral density of the femoral neck was measured by dual energy X-ray absorptiometry and vertebral morphometry was performed on lateral X-rays of the spine. Osteoporosis was defined by a bone mineral density T-score of less than 2.5 and/or the presence of severe vertebral deformities. Sensitivity, specificity, and predictive values were calculated for the whole set of risk factors; those significantly associated with osteoporosis and in logistic models. RESULTS: Clinical risk factors were present in 55% of the women and identified 68% of the women with osteoporosis. Three risk factors--a low body mass index, fragility fractures, and severe kyphosis and/or loss of height--were associated significantly with osteoporosis; they were present in 33% of the women and identified 60% of those with osteoporosis. A logistic model based on age and fragility fractures selected 32% of the women and identified 76%. CONCLUSION: No single risk factor could assist in identifying women with osteoporosis. A simplified case-finding strategy using only three risk factors, that is suitable for primary care, reduces the number of women to be evaluated by two-thirds; however, this is at the cost of missing the diagnosis in 40% of the women with osteoporosis. Addition of spine radiographs to the case-finding approach helped to obtain a better risk profile of the women and had also practical consequences for the management of some. We propose that radiographs should be included in any case-finding strategy.

Fluorine determination in human and animal bones by particle-induced gamma-ray emission.

Fluorine was determined in the iliac crest bones of patients and in ribs collected from post-mortem investigations by particle-induced gamma-ray emission based on the 19F(p,p'gamma)19F reaction, using 2.0/2.5 MeV protons. The results indicate that for 68% of the human samples the F concentration is in the range 500-1999 microg g(-1). For comparison purposes fluorine was also determined in some animal bones; in some animal tissues lateral profiles of fluorine were measured.

An assessment of structured care assistance in the management of patients with type 2 diabetes in general practice.

OBJECTIVE: To study differences in diabetes-related parameters in type 2 diabetic patients treated with the support of a Diabetes Service compared to conventional general practice care. DESIGN: Parallel clinical trial with randomisation at practice level. SETTING: Fifteen general practices. PATIENTS: Type 2 diabetic patients, aged < 76 years, treated by a GP. MAIN OUTCOME MEASURES: Level of glycated haemoglobin (HbA1c). RESULTS: 246 patients entered the study. Final mean HbA1c of all evaluable patients allocated to the intervention (n = 84) was 7.1+/-1.2%, vs 7.5+/-1.8% in the controls (n = 140) (p = 0.06). Patients who were initially poorly controlled (Fasting Blood Glucose > 10 mmol/l) had a significantly lower final HbA1c if they were in an intervention practice (p=0.001). Fewer patients in intervention practices were referred to hospital specialists (1 vs 14). CONCLUSIONS: Support by the Dutch Diabetes Service did not significantly influence glycated haemoglobin. The subgroup of initially poorly controlled patients developed a significantly lower HbA1c in intervention practices (supported by a Diabetes Service) than in control practices.

Circadian phase-shifted rats show normal acquisition but impaired long-term retention of place information in the water task.

It is thought that circadian rhythms may influence learning and memory processes. However, research supporting this view does not dissociate a mnemonic impairment from other performance deficits. Furthermore, published reports do not specify the type of memory system influenced by the circadian system. The present study assessed the effects of phase shifting on acquisition and expression of place navigation in the water maze, a task sensitive to hippocampal dysfunction. The results showed that phase-shifting circadian rhythms in rats impaired the expression of place information on a retention test but not initial acquisition or encoding of place information. These results suggest that disruption of circadian rhythms may impair consolidation of previously encoded hippocampal place information.

Oxygen determination in calcium fluoride by deuteron activation analysis.

Oxygen at trace level in calcium fluoride was determined by instrumental deuteron activation analysis based on the 16O(d,n)17F reaction. The irradiations were performed with 2.5 MeV deuterons for 60 s at currents ranging from 300 to 500 nA. The results obtained for powders and single crystals were compared.

The relationship between phalangeal bone density and vertebral deformities.

Radiographic absorptiometry (RA) of the phalanges is a convenient and reliable technique for measuring bone mineral density (BMD). It needs only a radiograph of the hand, which can be sent for evaluation to a central facility, whereas other techniques require specialized equipment. We assessed the relationship between RA measurements and the presence of vertebral deformities in a population-based cohort of postmenopausal women, and to compare the results with simultaneously obtained BMD of the hip by dual-energy X-ray absorptiometry (DXA). A total of 389 women aged 55-84 (mean age 67.2 years, SD 8.7) were randomly selected from a large general practice. RA, DXA of the hip, and vertebral deformities in the lateral spine X-rays by vertebral morphometry were assessed. Thirty-eight women (9.8%) had severe (grade II) vertebral deformities, and their BMD at the phalanges and femoral neck was significantly lower than that of women without severe vertebral deformities. Odds ratios for the presence of severe vertebral deformities of 1.5 (95% CI: 1.1-2.1) for RA and 1.3 (95% CI: 0.9-1. 9) for DXA, together with similar receiver operating characteristics curves, were found using age-adjusted logistic regression. Phalangeal BMD is related to vertebral deformities at least as closely as BMD of the femoral neck BMD. RA may therefore help to evaluate fracture risk, especially if no DXA equipment is available.

Radiographic absorptiometry of the phalanges as a screening instrument to detect osteoporosis of the hip.

OBJECTIVE: To determine the validity of radiographic absorptiometry (RA) of the phalanges in detecting osteoporosis of the femoral neck, measured by dual energy X-ray absorptiometry (DXA). MATERIAL AND METHODS: In a group practice, 494 Caucasian women aged 55 to 84 years were recruited. Hand radiographs and DXA measurements of the hip were performed in 449 women. 409 (91.1%) hand radiographs had sufficient quality for analysis by RA. Change of bone mass by age was obtained by using linear regression. Correlations between RA and DXA were calculated. Sensitivity and specificity of RA were calculated for several RA cut-off levels. RESULTS: The mean bone mineral density at the femoral neck was 0.866 g/cm2 and 92.57 arbitrary units at the phalanges. A moderate correlation of 0.53 (p<0.01) was found between RA and DXA. Depending on the cut-off level used, the sensitivity and specificity of RA in detecting osteoporosis at the femoral neck was 0.84-0.55 and 0.61-0.88, respectively. CONCLUSION: RA may be used as a screening technique to detect osteoporosis, but confirmation is necessary in the subgroup with a positive outcome on RA.

Usefulness of armspan and height comparison in detecting vertebral deformities in women.

The prevalence of vertebral fractures in women increases with age but only about one third of these fractures are symptomatic. On the other hand, the presence of vertebral fractures is an independent risk factor for new osteoporotic fractures. In the present study we examined the hypothesis that differences between armspan and height are related to the presence of vertebral deformities in a cohort of 494 women aged between 55 and 84 years (mean age 67.6 years, SD 8.2 years) who were randomly selected from a large general practice in The Netherlands. Height and armspan were measured and vertebral morphometry of lateral radiographs of the spine was performed. Both height and armspan decreased significantly with age. The correlation between armspan and height was 0.83. Vertebral deformities were present in 32.7% of the women (grade I in 22.4% and grade II in 10.3%). Only the prevalence of grade II deformities rose with age. The variation of the difference between armspan and height in the groups with or without grade II vertebral deformities was comparable and relatively large (range > 15 cm). The difference in mean values was small between those groups (1.6 cm) and could not differentiate between women with and without vertebral deformities. Our data show that the presence of vertebral deformities cannot be detected by the difference between armspan and height.

Relationship between blood glucose level and mortality in type 2 diabetes mellitus: a systematic review.

AIM: To review the relationship between blood glucose level and mortality in patients with Type 2 diabetes mellitus (DM) as reported in the literature. METHODS: Literature search using Medline Search: January 1966 - April 1998. KEYWORDS: Diabetes, Non Insulin Dependent, Mortality. Inclusion criteria for papers were: Type 2 DM; follow-up for at least 3 years; glucose or glycated haemoglobin (HbA1c) was used as parameter; published in the form of an article. Additionally all references in the selected articles that dealt with the relationship between blood glucose level and mortality in Type 2 DM were included in the search. RESULTS: Twenty-seven eligible articles were found. Twenty-three of them showed a positive association: measures of elevated blood glucose concentrations were associated with higher mortality; in 15 out of 23 studies the positive association was statistically significant, in two only for postprandial blood glucose. One study found a nonsignificant negative relationship in a very old population. CONCLUSION: In the literature there is a positive, but rather weak, association between the measures of blood glucose control and the risk of dying of patients with Type 2 DM. In the six larger studies (more than 100 deceased patients) that used a continuous categorization of glycaemia, the Risk ratio per unit varies from 1.03 to 1.12.

[Prevalence of osteoporosis in postmenopausal women in family practice]. / Prevalentie van osteoporose bij postmenopauzale vrouwen in een huisartspraktijk.

OBJECTIVE: To assess the prevalence of osteopenia, osteoporosis and severe vertebral deformities in general practice. DESIGN: Cross-sectional study. METHODS: Of a randomly selected group of 712 women aged 55 to 84 years in a general practice in Noordwijk, the Netherlands, 449 (63%) participated in a study in 1996, in which Dual Energy X-ray Absorptiometry (DXA) of the femoral neck was performed: in 428 women vertebral morphometry of lateral radiographs of the spine was also done. The World Health Organization definitions of osteopenia and osteoporosis were used. RESULTS: The mean bone mineral density (BMD) was 0.866 g/cm2 (SD: 0.135). With increasing age the BMD decreased statistically significantly by 0.0073 g/cm2/year. There were 189 women with osteopenia (42%). 33 (7%) with osteoporosis and 44 (10%) with one or more severe vertebral deformities. A significantly lower mean BMD was found in those with severe vertebral deformities than in those without.

Infants colonized with enterotoxin-producing staphylococci at 3 months display a decreased frequency of interferon-gamma-producing CD45RO lymphocytes upon stimulation with staphylococcal enterotoxin A at birth but not at 6 months of age.

The aim of the study was to elucidate the relationship between the cytokine response to staphylococcal enterotoxin A (SEA) at birth and subsequent staphylococcal colonization in the first months of life. In a cohort of 45 newborns, cord blood lymphocytes were stimulated with SEA (10 ng/ml) in vitro, re-stimulated with PMA (phorbol myristate acetate) and ionomycin at day 3 and assessed for CD45RO expression and cytokine generation by flow cytometry. The infants were classified into three groups according to nasal staphylococcal colonization and enterotoxin generation at 3 months: There were 16 infants with either no colonization or non-enterotoxin-producing staphylococci, 16 infants with enterotoxins B, C, D and E, and 13 infants colonized with SEA-producing staphylococci. At birth, the group without subsequent colonization displayed a significantly higher frequency of CD45RO-positive interferon-gamma-producing cells (1.7%; range 0.0-9.3%) in comparison to the SEA-positive group (0.1%; range 0.0-0.4%) and also to the group positive for other enterotoxins (0.50%; range 0.0-2.5%). Comparable but less pronounced results were found for interleukin-5 but not for interleukins 2 and 4. At 6 months, no differences in cytokine generation were detected between the three groups. The results provide evidence that a non-specific immunologic immaturity at birth is a risk factor for early bacterial colonization. Furthermore, it is remarkable that this immaturity is similar to that seen in infants destined to be atopic with respect to disequilibrium of interferon-gamma to interleukin-4 generation. Thus the link between early staphylococcal colonization and subsequent atopy requires further investigation.

[Incidental high blood pressure in family practice: due to hypertension and/or left ventricular hypertrophy in more than half of the patients]. / Incidenteel verhoogde bloeddruk in de huisartspraktijk: bij meer dan de helft van de patiënten hypertensie en (of) linkerventrikelhypertrofie.

OBJECTIVE: To determine if patients with incidentally high blood pressure actually have hypertension and if these patients have an increased left ventricular mass. DESIGN: Cross-sectional study. SETTING: Two family practices with 8 general practitioners in Leiden and Noordwijk, the Netherlands. METHODS: From the Family Practice Network in the Leiden area 133 (67%) out of 200 patients with incidental high blood pressure, who did not receive antihypertensive medication, participated in the study. Their blood pressure was measured 6 times with a mercury manometer, an automatic, non-invasive ambulatory blood pressure monitoring during 24 hours was performed once and their left ventricular mass was measured by means of echocardiography. RESULTS: Of the 133 selected patients 46% had a mean diastolic blood pressure > 95 mmHg measured with the mercury manometer and 64% had a mean 24-hr diastolic blood pressure > 90 mmHg measured with the ambulatory blood pressure monitor. The correlation between both blood pressure measurements was moderate (correlation coefficient 0.73). Left ventricular hypertrophy was found in 53% of the patients, irrespective of their blood pressures. CONCLUSION: In this investigation 45-65% of patients with an incidentally high blood pressure had a mean diastolic pressure > 95 mmHg as measured with a mercury manometer and (or) a mean 24-hr diastolic blood pressure > 90 mmHg as measured with the ambulatory blood pressure monitor; 53% had left ventricular hypertrophy.