A 60-year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland County, Western Norway.

OBJECTIVE: Investigate the incidence of multiple sclerosis during 1953-2013 and estimate the prevalence rate of MS on 1 January 2003 and 2013 in Hordaland County, Western Norway. METHODS: All patients with onset of disease in Hordaland 1953-2013 were identified in files from previous studies until 2003 and from patient records at the departments of Neurology, Haukeland University Hospital and Haugesund Hospital during 2003-2013. 1558 patients were assessed and 1402 of these were included, of whom 1035 were alive and living in Hordaland at prevalence day 1 January 2013. Annual incidence rates were calculated for 1953-2013. RESULTS: On 1 January 2003, the crude prevalence rate was 191/100 000 population and on 1 January 2013, the crude prevalence rate was 211.4 (95% CI 198.3 to 224.2) per 100 000; 270.9 (95% CI 250.6 to 292.3) for women and 151.8 (95% CI 136.8 to 167.9) for men. Prevalence peaked at ages 55-59 years for women and 60-64 years for men. The annual incidence rate increased from 1.9 (95% CI 1.2 to 2.6) per 100 000 during 1953-1957 to 7.2 (95% CI 6.0 to 8.5) during 1978-1982 and to 8.5 (95% CI 7.3 to 9.7) during 2003-2007, thus indicating a stabilising incidence over the past 35 years. The female/male ratio ranged from 1.2:1 to 1.8:1 (p=0.381) during the period. CONCLUSIONS: Stabilising rather than increasing incidence combined with the stable female/male ratio are indicative of non-fluctuating environmental factors in a geographical area otherwise characterised by lack of vitamin D effective sun exposure. The rising prevalence of MS could result from improved survival and follow-up methodology.

Clinical assessment and management of sleep disorders in multiple sclerosis: a literature review.

The major sleep disorders are common in multiple sclerosis (MS) and are associated with significant morbidity. Despite this, the rate of recognition and management of these conditions are low. All types of sleep disorders are seen in patients with MS: insomnia, circadian rhythm sleep disorders, sleep-related movement disorders, sleep-related breathing disorders, hypersomnia (narcolepsy), and parasomnia (REM sleep behavior disorder; RBD). This literature review covers the prevalence, clinical features, and treatment of sleep disorders in MS. Based on clinical experience, the spectrum of symptoms associated with MS, and the current knowledge of MS pathophysiology, we have also enclosed proposed strategies for clinical assessment and investigation of sleep disorders in MS patients.

Relative prevalence of upper respiratory tract obstructive disorders in two breeds of harness racehorses (185 cases: 1998-2006).

REASONS FOR PERFORMING STUDY: Two genetically and phenotypically distinct horse breeds are used for harness racing in Scandinavia: the Standardbred (SB) and Coldblooded Trotter. These racehorses have identical environmental, management and racing conditions. Therefore, this study was undertaken to identify and compare the relative prevalence of upper respiratory tract (URT) obstructive disorders in these 2 breeds. OBJECTIVES: To determine whether these 2 phenotypically different breeds of harness racehorses have different predispositions for URT disorders. METHODS: Retrospective study of 88 Norwegian Coldblooded Trotters (NCT) and 97 SBs referred to this hospital for URT evaluation between 1998 and 2006. Case records of all horses diagnosed with an URT disorder during resting endoscopy, and all horses undergoing high-speed treadmill videoendoscopy (HSTV) with one or more periods of induced poll flexion were evaluated. The relative prevalence of URT disorders between the 2 breeds was analysed using a Fisher's exact test. RESULTS: There was a significant (P<0.05) breed predisposition regarding 6 URT disorders. Bilateral dynamic laryngeal collapse associated with poll flexion and flaccid epiglottis was significantly more frequent in the NCT. Alar fold collapse and nasopharyngeal collapse were significantly more frequent in SBs. Epiglottic entrapment and nasal flutter were only diagnosed in the SBs. Dynamic disorders were more common than resting disorders in both breeds. CONCLUSION: URT obstructive disorders (dynamic laryngeal collapse associated with poll flexion, flaccid epiglottis, pharyngeal collapse, alar fold collapse, nasal flutter and epiglottic entrapment) are breed related, indicating an anatomic or functional cause. Periods of induced poll flexion during HSTV was essential to declare harness racehorses free of URT disorders. POTENTIAL RELEVANCE: Further anatomic or physiological studies comparing these breeds could potentially provide insight into the pathogenesis of certain URT obstructive disorders. Induced poll flexion should be included in routine HSTV examinations of all harness racehorses.

Serum amyloid A transcription in Atlantic salmon (Salmo salar L.) hepatocytes is enhanced by stimulation with macrophage factors, recombinant human IL-1 beta, IL-6 and TNF alpha or bacterial lipopolysaccharide.

Serum amyloid A (A-SAA) has previously been reported to be an acute-phase protein in salmonids. Hepatocytes represent a major source of A-SAA in salmonids, but nothing is known about hepatocyte SAA synthesis in fish. In the present work, the expression of A-SAA transcripts in primary cultures of Atlantic salmon hepatocytes in response to macrophage derived cytokines, human recombinant cytokines and bacterial lipopolysaccharide (LPS) was studied by Northern blot analysis. The macrophage supernatants were prepared by stimulating Atlantic salmon head kidney macrophages with LPS, yeast glucan or a leukocyte derived macrophage activating factor (MAF). The supernatants from glucan- or MAF-stimulated macrophages had no effect on A-SAA expression of the hepatocytes, while supernatants from LPS-stimulated macrophages gave about a 2-fold increase in expression. The combination of either glucan and MAF, or LPS and MAF were more effective and these supernatants gave a 3.4- and 5.2-fold increase in A-SAA expression, respectively. The hepatocytes were also treated with the human recombinant cytokines TNFalpha, IL-1beta and IL-6, alone or in combination. The A-SAA response to each of them alone was modest, but TNFalpha and IL-6 or IL-1beta and IL-6 in combination gave a higher response than each cytokine alone. These data suggest that the expression of A-SAA by hepatocytes from Atlantic salmon is induced by cytokine-like molecules. Interestingly, hepatocytes treated directly with LPS gave a more than 10-fold increase in SAA mRNA expression, but it is not known if this is a direct effect of LPS on the hepatocytes or if it is mediated by other contaminating cell types.

Onset of bronchodilation and finger tremor induced by salmeterol and salbutamol in asthmatic patients.

Salmeterol is a beta-agonist with bronchodilator properties that last for at least 12 h after inhalation. However, the onset of action of salmeterol immediately after inhalation has not been sufficiently investigated. In the present study, the onset of action and tremor-inducing effect of two doses of inhaled salmeterol (50 and 100 microg) were compared with inhaled salbutamol (200 and 400 microg) and placebo. Lung function was measured using forced expiratory volume in 1 s (FEV1), and tremor was measured using a linear accelerometer. With salbutamol there was rapid bronchodilation, both doses producing more than 15% improvement in mean FEV1 within 2 mins of inhalation. With salmeterol, on the other hand, significant bronchodilation was delayed until 7 mins versus placebo, and the full bronchodilation effect was not achieved until 60 mins after inhalation. There was a much more rapid onset of tremor with salbutamol (400 microg) than salmeterol. There was a much slower onset of bronchodilation with salmeterol than salbutamol. Therefore, salmeterol cannot be recommended to relieve acute symptoms.

Efficacy of cumulative doses of salbutamol administered via Turbuhaler or Diskhaler in patients with reversible airway obstruction.

The study aimed to estimate the relative dose potency of salbutamol inhaled via Turbuhaler and Diskhaler. The 24 adult patients participating had chronic reversible airway obstruction. The study was of a double-blind, double-dummy, crossover, randomized design. Five doses of salbutamol Turbuhaler, 50, 50, 100, 200, and 400 microg, were given on one study day at intervals of 30 min. On another study day, five doses of salbutamol Diskhaler, 200, 200, 400, 800, and 1600 microg, were given with the same interval. The treatment days were separated by a washout period of at least 24 h. The inhalation technique was standardized and supervised. Efficacy variables were recorded before and after each study dose. The primary efficacy variable was forced expiratory volume in 1 s (FEV1). When parallel and linear cumulative dose-response curves were statistically compared on a logarithmic scale, the dose potency of salbutamol Turbuhaler vs salbutamol Diskhaler was 1.99 (95% confidence interval 1.52-2.54). This study indicates that only half the dose of salbutamol is required via Turbuhaler as via Diskhaler for the same bronchodilating effect.

Candesartan cilexetil: safety and tolerability in healthy volunteers and patients with hypertension.

The tolerability and safety of candesartan cilexetil has been evaluated in over 5000 subjects enrolled into double-blind or open-label clinical studies. In double-blind clinical trials in patients with primary hypertension, candesartan cilexetil 2-16 mg once-daily was associated with a low incidence of adverse events and drug-related withdrawals, similar to placebo. The drug showed no evidence of dose-dependent adverse events and it was equally well tolerated by men and women and by elderly (> or =65 years) and younger (<65 years) patients alike. Candesartan cilexetil had no effect on blood glucose control or serum lipid profile in patients with type II diabetes. It was very well tolerated also when given in combination with hydrochlorothiazide or amlodipine and during long-term open-label therapy (up to 1 year). Candesartan cilexetil therefore possesses an excellent tolerability profile that extends to a wide variety of patients including the elderly and it does not aggravate co-existing risk factors such as hyperlipidaemia or glucose intolerance. It therefore appears to offer a better tolerated alternative to other commonly used antihypertensive agents.

Physicochemical characterisation of mangafodipir trisodium.

PURPOSE: To determine the structure and various physicochemical properties of mangafodipir (MnDPDP) trisodium, the active ingredient of Teslascan, a new-organ-specific contrast medium for MR imaging. MATERIAL AND METHODS: The structure of MnDPDP trisodium crystals was determined by X-ray crystallography. The possible existence of polymorphism in MnDPDP trisodium was evaluated by powder X-ray diffraction, optical microscopy, thermal analysis and IR spectroscopy. In addition, various spectroscopic techniques and physicochemical measurements were used for characterisation of MnDPDP trisodium. RESULTS: The crystallographic data obtained for MnDPDP trisodium show that the general core structure of the MnDPDP anion is similar to that seen in related substances. The metal coordination geometry is a distorted octahedron defined by 2 phenolate oxygens, 2 carboxylate oxygens and 2 amine nitrogens. The unit cell contains 2 MnDPDP anions, 6 sodium ions and 50 water molecules. The various spectroscopic data are consistent with the structure determined by X-ray crystallography. The product (Teslascan) has low viscosity, is isotonic with blood and has a physiological pH. CONCLUSION: MnDPDP trisodium is a crystalline, hygroscopic solid which is readily soluble in water. No evidence of polymorphism was seen in the samples studied.

The lack of respiratory effects of the ocular hypotensive drug latanoprost in patients with moderate-steroid treated asthma.

The use of beta blockers for glaucoma treatment may cause serious bronchoconstriction in patients with chronic obstructive pulmonary disease. The synthetic prostaglandin (PG) F2 alpha-analogue latanoprost (13,14,dihydro-17-phenyl-18,19,20-trinor-PGF-2-alpha-iso propylester) represents a new class of drugs for glaucoma treatment. In this study the pulmonary tolerability to latanoprost in 12 healthy volunteers and 11 (one withdrawal due to a sty before latanoprost treatment) subjects with moderate but stable steroid-treated intrinsic asthma was examined. Asthmatic subjects received 30 microliters of vehicle (placebo) at the scheduled administration times on baseline day. On a second day, a minimum of one week later, increasing concentrations (0.35, 115 and 350 micrograms/ml) of latanoprost were added to the vehicle and given topically to both eyes. Healthy volunteers were given latanoprost only. ECG, blood pressure, heart rate, forced expiratory volume (FEV1), peak expiratory outflow (PEF) and forced vital capacity (FVC) were recorded immediately prior to and 15, 30, 45 and 60 minutes after latanoprost. Asthmatic patients inhaled salbutamol (0.2 mg) at 60 minutes after the highest latanoprost dose. There were no significant differences in pulmonary function, blood pressure or heart rate after latanoprost in the healthy volunteers. Moreover, all parameters were unaffected in asthmatic patients on the day latanoprost was given compared to the baseline day. Latanoprost did not dampen the bronchodilator response to beta-2-adrenergic stimulation. It is concluded that latanoprost did not affect lung function in healthy subjects or in asthmatics after a total accumulated dose 10 times that clinically recommended for glaucoma treatment. Therefore, latanoprost appears to be safe for glaucoma treatment in patients with steroid-treated stable moderate intrinsic asthma.

Airway effects of direct left-sided cervical vagal stimulation in patients with complex partial seizures.

Airway nerves have been implied in obstructive lung diseases for many years. In experimental animals, vagal stimulation produces several features of asthma, including airflow obstruction and airway plasma exudation. Vagal stimulation is a novel and effective therapy in patients with refractory epilepsy. We evaluated the airway response to left-sided cervical electrical stimulation using 1 Hz (low stimulation: 30 s, once every 90 min) and 30 Hz (high stimulation: 30 s, every 5 min) in a randomized double-blinded fashion for 3 months in epileptic patients participating in a phase two efficacy study. In eight patients with high stimulation and six with low stimulation, no effect on FEV1 (forced expiratory volume in 1 s) was seen over 3 months chronic stimulation. In a follow-up, up to 9 months, no further deterioration of lung function was observed. Of five patients without concomitant lung disease who consented to more extended experiments, one patient produced a reduction of FEV1 with variable frequency and current stimulation (10-87 Hz and 0.5-2.5 mA respectively). In one patient with obstructive lung disease, however, increased frequency and current stimulation led to a stimulation-dependent decrease in FEV1. After the addition of inhaled ipratropium bromide (160 micrograms, dry powder) to this patient, there was a clear improvement of baseline FEV1, but only a slight improvement of the stimulation-induced deterioration of FEV1. We conclude that long-term vagal stimulation in patients without concomitant lung disease does not induce any significant changes in FEV1. However, in patients with obstructive lung disease, intense vagal stimulation can cause a deterioration of lung function.(ABSTRACT TRUNCATED AT 250 WORDS)

Dyspnoea, asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE: To evaluate the occurrence of asthma and dyspnoea precipitated or worsened by angiotensin converting enzyme inhibitors. DESIGN: Summary of reports of adverse respiratory reaction in relation to treatment with angiotensin converting enzyme inhibitors that were submitted to Swedish Adverse Drug Reactions Advisory Committee and to World Health Organisation's international drug information system until 1992. Sales of angiotensin converting enzyme inhibitors in Sweden were also summarised. SUBJECTS: Patients receiving angiotensin converting enzyme inhibitors who reported adverse respiratory reactions. MAIN OUTCOME MEASURES: Clinical characteristics of adverse reactions of asthma, bronchospasm, and dyspnoea. RESULTS: In Sweden 424 adverse respiratory reactions were reported, of which most (374) were coughing. However, 36 patients had adverse drug reactions diagnosed as asthma, bronchospasm, or dyspnoea. In 33 of these cases the indication for treatment with angiotensin converting enzyme inhibitors was hypertension, in only three heart failure. The respiratory symptoms occurred in about half of the patients within the first two weeks of treatment, and about one third needed hospitalisation or drug treatment. Dyspnoea symptoms occurred in conjunction with other symptoms from the airways or skin in 23 out of the 36 cases. In the WHO database there were 318 reports of asthma or bronchospasm, 516 reports of dyspnoea, and 7260 reports of cough in relation to 11 different angiotensin converting enzyme inhibitors. CONCLUSION: Symptoms of airway obstruction in relation to treatment with angiotensin converting enzyme inhibitors seem to be a rare but potentially serious reaction generally occurring within the first few weeks of treatment.

Twelve months, treatment with inhaled salmeterol in asthmatic patients. Effects on beta 2-receptor function and inflammatory cells.

Salmeterol is a new beta 2-receptor agonist with a prolonged duration of action after inhalation, exceeding 12 h in most patients. We have performed a 12-month open follow-up study on 11 patients with reversible asthma. All patients were given salmeterol inhalations (50 micrograms twice daily). Additional asthma treatment included inhaled corticosteroids in all patients, and oral slow-release theophylline or beta 2-receptor agonists in a minority of patients (3 and 1, respectively). Before salmeterol treatment was initiated and after 3, 6, 9 and 12 months of salmeterol treatment, a cumulative dose-response curve to inhaled salbutamol (100, 300 and 900 micrograms) was performed, and FEV1 measured. We also evaluated the effect of each salbutamol dose on finger tremor, systemic blood pressure and heart rate. Blood tests, including white blood count and electrolytes, were taken at each visit. After salmeterol treatment was initiated, morning FEV1, measured before the morning asthma medication, was significantly improved (p < 0.05). The responsiveness to inhaled salbutamol was not decreased during salmeterol treatment, except in one patient with asthma worsening over the study year. Baseline finger tremor measured before salbutamol dose-response curves, was significantly lower at the 12-month visit than before treatment was initiated (p < 0.05). Effects of salbutamol on systemic blood pressure, heart rate or finger tremor was not significantly changed during salmeterol treatment. We found a successive and significant decrease in blood eosinophils (p < 0.05) during the 12 months of salmeterol treatment, when the patient with asthma worsening was excluded in the analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Angio-oedema in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE: To evaluate and describe the clinical course of angio-oedema reactions induced by angiotensin converting enzyme inhibitors. DESIGN AND METHODS: All reports of angio-oedema reactions associated with angiotensin converting enzyme inhibitors submitted to Swedish Adverse Reactions Advisory Committee were reviewed and the clinical courses summarised. Numbers of cases judged to be induced by angiotensin converting enzyme inhibitors were related to their annual usage, estimated from total sales of defined daily doses, as well as to the estimated number of new patients. All cases of angio-oedema associated with angiotensin converting enzyme inhibitors reported to the World Health Organisation's international drug information system were also summarised. RESULTS: 36 of the 38 reported cases in Sweden between 1981 and 1990 were judged to be related to angiotensin converting enzyme inhibitors. During 1981 through 1990, altogether 1309 cases of angio-oedema associated with angiotensin converting enzyme inhibitors were registered with the international drug information system. The incidence of reported cases of angio-oedema increased largely in parallel with the increased sales (usage) of angiotensin converting enzyme inhibitors. Of the 36 Swedish patients, 77% experienced the reaction within the first three weeks after starting treatment. 10 patients needed hospitalisation, two of whom had life threatening laryngeal obstruction. With one exception all 36 patients were free of symptoms within one week after discontinuing the drug. CONCLUSIONS: Angio-oedema induced by angiotensin converting enzyme inhibitors is a rare but potentially life threatening reaction, which in most instances occurs shortly after the start of treatment. Any patient in whom the reaction is suspected should have the treatment interrupted and, if necessary, be admitted for observation.

Inborn errors of carnosine and homocarnosine metabolism.

Serum carnosinase deficiency with carnosinuria has been reported in 23 children with neurological signs and/or mental retardation. In adults four cases in one family had serum carnosinase deficiency, carnosinuria, and in addition elevated homocarnosine in CSF and in the brain. The mother was one of these cases but had no clinical symptoms; however her three children have spastic paraparesis, retinitis pigmentosa and mental retardation. Serum carnosinase deficiency alone is not the cause of the neurological symptoms. When two of the affected children consumed carnosine, anserine or homocarnosine, they metabolized these compounds much less rapidly than did two normal control individuals.

Cystathioninuria in Down's syndrome.

Secondary cystathioninuria is associated with various pathological conditions (Gjessing, 1963; Gjessing & Mauritzen, 1965; Endres & Wuttge, 1978). In many cases, cystathioninuria has been associated with mental retardation (Harris et al., 1959; Robb et al., 1984). As far as the authors know, cystathioninuria has not previously been described in Down's syndrome. In 1981, in the author's institution for the mentally retarded, all patients with Down's syndrome were screened with regard to aminoaciduria, using thin layer chromatography. In the course of this process, a case of cystathioninuria was discovered. The results are presented in detail.

Fasting plasma amino acid concentrations in PKU children on two different levels of protein intake.

Two groups of children with phenylketonuria were treated with different amounts of protein. One group (RDA group) received protein as recommended by the U.S. Food and Nutrition Board, the other (FAO group) the amount recommended by the FAO/WHO 1973 ad hoc Expert Committee. Two of the children in the FAO group showed a decrease in length/growth velocity which raised the question of the adequacy of the protein content in the diet. Since deviations from normal plasma amino acids have been observed in protein deficient, energy-adequate diets, we examined these parameters in the PKU children. In the two children with retardation in length/growth, very high glycine values as well as very high alanine values were observed at the end of the study. These observations strengthened our suspicion that the FAO/WHO 1973 recommendations are marginal.

Cystathioninuria in a profoundly mentally retarded woman with spastic tetraplegia, deafness and abnormal liver function tests.

This article describes a profoundly mentally retarded woman with spastic tetraplegia, deafness and abnormal liver function tests with a secondary cystathioninuria. The cystathioninuria could be corrected with vitamin B6 supplementation.