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.

[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.

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 %.

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.

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.

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.

The effects of verapamil and propranolol on exercise tolerance in hypertensive patients.

In a single-blind, placebo-controlled crossover study the effects of verapamil (450 +/- 30 mg/day) and propranolol (160 +/- 20 mg/day) on endurance time during submaximal exercise were compared in eight patients with essential hypertension. The drugs were given in randomized order. Each active drug period was preceded by a placebo phase. Endurance tests were performed during both placebo periods and treatment with verapamil and propranolol by bicycle ergometry. Both drugs were equally effective in decreasing resting blood pressure. Verapamil and propranolol reduced exercise heart rate, the effect of propranolol being more pronounced. With placebo, endurance time during exercise was 57 +/- 11 minutes; with propranolol it was 32 +/- 7 minutes (P less than 0.05). Verapamil had no influence on endurance time. The study demonstrates that in contrast to propranolol, verapamil has no influence on exercise tolerance during submaximal work in patients with hypertension.

Rapid method for estimating the risk of acutely controversial side effects of prescription drugs.

When controversy suddenly erupts about the risk of using a prescription drug, there is an urgent need for fast methods of risk estimation. Some unexpected side-effects of prescription drugs are indications for the prescribing of another kind of drug. If the risk of such a side-effect is high, it should be reflected in clustered prescribing of the side-effect-alleviating drug in sequence with the side-effect-causing drug. The risk of drug-attributable side-effects can be estimated by comparing average incidences of initial prescriptions for the side-effect-alleviating drug before, during, and long after the dispensing of the presumed side-effect-causing drug. We monitored computerized, complete drug dispensing records of anonymous outpatients for use of flunarizine, an anti-vertigo/anti-migraine drug that case reports had suggested causes mental depression and/or Parkinsonism. Among 1284 patients who eventually got flunarizine during a 31 month period, 1 in 7 was started on an anti-depressant before or long after flunarizine; only 1 in 82 might be said to have been started on an anti-depressant because of flunarizine. There was no evidence that anti-Parkinson drugs were started because of flunarizine, though the numbers are small. The analysis takes only a few days, and can help set bounds on risks of the subset of adverse drug reactions that are themselves indications for use of other drugs.

Channelling of controlled release formulation of ketoprofen (Oscorel) in patients with history of gastrointestinal problems.

STUDY OBJECTIVE: The aim was to determine if a new controlled release formulation (Oscorel) of the non-steroidal anti-inflammatory drug (NSAID) ketoprofen has been preferentially prescribed in patients with prior history of gastro-intestinal disturbances. DESIGN: The study was a pharmacy records based comparison of the rates of prior prescribing of drugs indicated for peptic ulcer treatment in first recipients of Oscorel in 1989 versus recipients of other NSAID products. SETTING: A representative panel of Dutch community pharmacies serving approximately 425,000 people was used. MAIN RESULTS: Oscorel was launched in January 1989. Data on prescriptions dispensed in 1987-1988 to a total of 837 first users of Oscorel were analysed and compared with the dispensing history of a reference population including 30,787 patients who did not receive a prescription for Oscorel during 1989. Compared to the reference population, first users of Oscorel included a greater proportion of females, of patients 75 years and older, of heavy users of NSAIDs, and of patients switching among different NSAIDs. A total of 24.1% of first users of Oscorel had received peptic ulcer therapy in 1987-1988, versus 15.7% of the reference population. The rate ratio was 1.54, with 95% confidence interval of 1.36-1.74. Adjustment for stratifying variables caused only minor changes in the rate ratio, which remained stable on 1.5. CONCLUSIONS: Oscorel appears to have been channelled into use in patients with recognised risk factors for gastrointestinal toxicity. This preferential prescribing probably resulted from expectations and claims that this product has a lower risk of such toxicity.

Are four duplicate remeasurements sufficient for diagnosing mild hypertension?

The aim of this study was to investigate if four duplicate blood pressure (BP) remeasurements are sufficient for diagnosing hypertension in potentially hypertensive subjects. The subjects were 99 outpatients who were included on the basis of elevated diastolic (95 < or = DBP < or = 115 mm Hg) or systolic (160 < or = SBP < or = 200 mm Hg) BP. After inclusion all patients underwent nine subsequent duplicate BP measurements over a period of 7 months. None of the patients received hypotensive drug treatment during the study. Between the first (initial) and second measurements there were significant reductions in systolic (161.0-152.5 mm Hg) and diastolic (101.5-97.1 mm Hg) BPs (P < 0.01). Differences between the subsequent measurements were not statistically significant. A linear regression analysis proved that the "conceptual average BP' (the average of the last five visits) which was chosen as the reference value was stable. The decline of standard deviations of differences between two, three and four duplicate remeasurements on one hand, and the reference value on the other was found to be strikingly small. After four duplicate remeasurements, there was misclassification in 56% (systolic) and 38% (diastolic). We conclude that the numbers of two, three or four BP measurements recommended by international guidelines for diagnosing hypertension are too low. Even after four duplicate remeasurements a considerable amount of misclassification remains.

Once-daily budesonide in mild asthma.

Inhaled steroid therapy is the most important treatment in the management of chronic asthma and currently twice-daily administration is recommended in mild to moderate asthma. Compliance is often a problem in asymptomatic patients and may lead to reduced disease control. Our aim was to investigate whether budesonide 0.2 mg once daily administered via the Turbuhaler is as effective as 0.1 mg twice daily. A randomized, double-blind, parallel group study was carried out in which 76 adult patients with mild to moderate asthma (FEV1 86% of predicted) were allocated to budesonide once or twice daily. After a run-in period of 2 weeks on present inhaled steroid treatment (0.2-0.5 mg day-1) there was an 8 week treatment period, followed by a washout period in which patients received no steroid for 4 weeks unless a drop in morning peak flow of at least 20% occurred or the use of beta 2-agonists increased by 50%. Both treatment groups improved minimally in peak flow (1.7 and 4.31 min-1 in the once-daily and twice-daily groups respectively) but the differences between the two groups were not significant. Testing the reverse hypothesis revealed clinical equivalence. The 90% confidence interval of the difference in the change of peak flow from run-in was between +30 and -30 l min-1, the limits deemed to be clinically relevant. There were no differences in symptom scores, beta 2-agonist use or spirometry measurements between the two groups. In the washout period there was a significant deterioration in peak flow and symptoms. This study shows that 0.2 mg budesonide given once a day is as affective as 0.1 mg given twice daily in patients with mild to moderate asthma.

Milacemide treatment in mice enhances acquisition of a Morris-type water maze task.

The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor appears to be involved with processes of learning and memory. A neutral amino acid binding site is known to exist on the NMDA complex. Glycine binds with high affinity to this site and has been found to potentiate NMDA activity. 2-N-Pentylaminoacetamide HCl (milacemide) is a glycine agonist that has been found to enhance performance of rodents in passive and active avoidance tasks and has improved the performance of humans in several word retrieval tasks. We evaluated the effects of milacemide on the performance of male C57BL/6J mice in a complex spatial task, the Morris water maze. Because NMDA receptor activation appears involved in induction of long-term potentiation, it was hypothesized that milacemide administration would be involved in task acquisition. Therefore, mice were treated with either milacemide (10 mg/kg) or vehicle 1 h prior to training on each of 4 consecutive days. Results indicated that mice treated with milacemide learned the task significantly faster than controls over 4 days of training, as measured by mean distance (cm) to reach the goal platform. Therefore, agonism of the glycine site on the NMDA receptor appears to facilitate performance of learning in a spatial memory task.

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.

[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.

[Prevalence of chronic fatigue syndrome in 4 family practices in Leiden]. / Prevalentie van chronische-vermoeidheidsyndroom in 4 huisartspraktijken in de regio Leiden.

OBJECTIVE: To determine the prevalence of chronic fatigue syndrome (CFS) in general practice. DESIGN: Descriptive. SETTING: General practice and primary health care centres in Leyden region, the Netherlands. METHOD: RNUH-LEO is a computerized database which contains the anonymous patient information of one general practice (with two practitioners) and four primary health care centres. The fourteen participating general practitioners were asked what International Classification of Primary Care (ICPC) code they used to indicate a patient with chronic fatigue or with CFS. With these codes and with the code for depression patients were selected from the database. It then was determined whether these patients met the criteria of CFS by Holmes et al. RESULTS: The general practitioners used 10 codes. Including the code for depression a total of 601 patients were preselected from a total of 23,000 patients in the database. Based on the information from the patients' records in the database, 42 of the preselected patients were selected who might fulfill the Holmes' criteria of CFS. According to the patients' own general practitioner, 25 of the 42 patients would fulfil the Holmes' criteria. The men:women ratio was 1:5. The prevalence of CFS in the population surveyed was estimated to be at least 1.1 per 1,000 patients.

[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.

["I came as a stranger, will leave as a stranger." From alienation to hostility to foreigners in the young generation]. / "Fremd bin ich eingezogen, fremd zieh ich wieder aus."--Von der Entfremdung zur Fremdenfeindlichkeit in der jungen Generation.

After a historical review of the discussion of the concept of strangeness and alienation since the beginning of the 19th century, the question of the background of the current discussion of "the alien" arises. The assumption is that the experience of strangeness and self-alienation took a qualitative and quantitative leap at the point in technological development when the dialectic between human and machine was resolved in favor of the machine's domination, and when the "mega-machine" made the end of the human species conceivable and probable. Findings from empirical research on children and youth support this assumption. The causes are traced why the younger generation in particular is affected by the structural violence of strangeness that permeates all areas of life. Its inflating influence on the development of the ego and self is depicted. In accordance with the assumption, hostility toward and hatred of foreigners are to be grasped as symptoms of a loss of identity, caused by experiences of alienation deeper and more comprehensive than current societal triggers reveal.

[The efficacy of drug therapy in structural lesions of the hair and in diffuse effluvium--comparative double blind study]. / Die Wirksamkeit einer medikamentösen Therapie bei Haarstrukturschäden und diffusen Effluvien--vergleichende Doppelblindstudie.

Growth and quality of hair was studied after treatment with Pantogar, another prescription (Verum-2) and placebo for four months in 60 patients with diffuse effluvium capillorum and agnogenic structural alternations of hair. Efficacy was assessed by measurements of swelling, dye-binding and thickness for hair-quality and evaluation of hair-density and trichograms for hair-growth. Statistical analysis of swelling properties and trichogram data indicated that Pantogar was effective, the second preparation improved quality of hair and retarded hair loss. Placebo was ineffective judged by the used parameters. Tolerance of the treatment was good and adverse effects could not be substantiated.