Exacerbations and associated healthcare cost in patients with COPD in general practice

Background. Acute exacerbations are a characteristic clinical expression of chronic obstructive pulmonary disease (COPD). The objective of this study was to investigate the occurrence rate, management, and healthcare costs of exacerbations in patients with COPD in Dutch general practice. Methods. Baseline data set from the COPD on Primary Care Treatment (COOPT) trial was used. Details on the occurrence and management of exacerbations were collected by systematic medical record review for the 2-year period preceding trial inclusion. Results. The mean age of the 286 study subjects involved was 59.2 (SD 9.6) years, postbronchodilator FEV1 67.1% (SD 16.2) of predicted. Following ERS criteria, subjects suffered from: no (26%); mild (19%); moderate (40%); or severe (15%) airflow obstruction. The overall mean and median annual exacerbation rates were 0.88 (SD 0.79) and 0.5 (IQR 1.0), respectively. Exacerbation rate was not related to severity of airflow obstruction (p=0.628). Mean annual exacerbation costs per subject were € 40, € 53, € 61 and € 92 for the respective severity subgroups (p=0.012). The increase of costs in the more severe subgroups was mainly attributable to more physician consultations, diagnostic procedures, and prescription of reliever medication (e.g., bronchodilators, cough preparations). Conclusions. Occurrence of exacerbations did not depend on the severity of airflow obstruction, whereas the healthcare cost associated with exacerbations increased along with the severity of the disease

Genomic biomarkers and genetic risk factors in amyotrophic lateral sclerosis

In this thesis, we focus our biomarker discovery on gene expression in blood of an ALS mouse model and ALS patients to find ALS specific gene activity. 1. To explore the potential of blood or muscle transcriptome changes as a diagnostic biomarker. We hypothesized that blood gene expression reflects gene expression in the brain and in motor neurons. We used an SOD1 mouse model overexpressing human mutant SOD1-G93A to compare differentially expressed genes in spinal cord with differential expression in blood and muscle (Chapter 3). Next we analyzed gene expression in blood of sporadic ALS patients and healthy controls and constructed groups of co-differentially, co-expressed genes (Chapter 5). From the finding of altered gene activity in ALS patients, we profiled a larger dataset and constructed a panel that can discriminate with high accuracy between ALS patients and healthy controls (Chapter 6). 2. To find genetic variation associated with ALS and controlling gene expression in blood of ALS patients We performed a two-stage, genome-wide association study (GWAS) to find genetic risk factors associated with ALS (Chapter 7). Combining the gene expression data with genetic variation of sporadic ALS patients made it possible to select genetic variation causing differences in quantitative levels of expression (Chapter 8). This genetical genomics exercise can fine-map previously found linked loci and has the potential of finding new genetic risk factors. 3. To find the underlying pathological pathways in ALS mouse models. The exact pathological mechanism causing motor neuron degeneration is still elusive. We performed a meta-analysis of all published studies using gene expression in ALS mouse models (Chapter 2). Overlap in differential expression might provide important information on common pathological pathways. Next we determined differential gene expression in spinal cord of an SOD1 mouse model as part of our biomarker study (Chapter 3). 4. To find pathways targeted by riluzole. Since riluzole is the only effective drug in ALS, elucidating the mechanism of efficacy of this drug will immediately be relevant to the etiology of this disease. Gene expression profiles of SOD1-G93A mice treated with riluzole were compared to control animals receiving only tap water (Chapter 4). Expression profiles were determined in lumbar spinal cord at pre-symptomatic and early symptomatic ages

Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention

Ketogenic diets and orally administered exogenous ketone supplements are strategies to increase serum ketone bodies serving as an alternative energy fuel for high energy demanding tissues, such as the brain, muscles, and the heart. The ketogenic diet is a low-carbohydrate and fat-rich diet, whereas ketone supplements are usually supplied as esters or salts. Nutritional ketosis, defined as serum ketone concentrations of ≥ 0.5 mmol/L, has a fasting-like effect and results in all sorts of metabolic shifts and thereby enhancing the health status. In this review, we thus discuss the different interventions to reach nutritional ketosis, and summarize the effects on heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders. Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Mechanistic insights explaining the overall health effects of the ketogenic state, will lead to precision nutrition for the latter diseases

[An new application of gait analysis: guidance in finding the underlying health condition].

Instrumented gait analysis was developed to assist in clinical decision-making to optimise treatment to improve walking in patients with complex gait problems. In this clinical lesson, two cases are presented in which instrumented gait analysis was used for a different goal. It was used to assist in finding the correct neurological or orthopaedic diagnosis in patients in whom symptoms occurred during walking. In both patients, an accurate diagnosis could not be found based on the symptoms they reported, despite a thorough analysis by the neurologist. Instead, the symptoms were caused by the compensations patients used to optimise walking and not directly by the health condition itself. Through instrumented gait analysis, the direct impact of a health condition on the gait pattern can be distinguished from compensations. It can be an asset in finding the correct diagnosis, especially in patients with complex gait problems or multiple health conditions

Mitochondrial migraine; a prevalence, impact and treatment efficacy cohort study

Contains fulltext : 220690.pdf (publisher's version ) (Open Access)Mitochondrial respiratory chain dysfunction may be predisposing for the development of migraine, reflected in high migraine prevalence in patients with mitochondrial disease. Prevalence and impact of migraine in patients with proven mitochondrial disease and the current treatment efficacy were studied using online questionnaires. Patients were selected at the Internal Medicine Department. Headache was reported by 34 (55%) out of 62 patients. Migraine-criteria were met by 85% of them. Efficacy of migraine treatment was achieved in 4 patients. Given the high prevalence of migraine and current treatment insufficiency, migraine is a major threat of quality of life patients with mitochondrial disease

Mitochondrial Migraine: Disentangling the angiopathy paradigm in m.3243A>G patients

Contains fulltext : 206787.pdf (publisher's version ) (Open Access)Migraine, characterized by recurrent attacks of predominantly unilateral throbbing headache, affects approximately 15% of the adult population and is an important cause of disability worldwide. Knowledge required for the development of new classes of antimigraine drugs might come from studying rare metabolic diseases associated with migraine. An illustrative example of a monogenetic disorder associated with migraine is the spectrum of disorders caused by the m.3243A>G mutation in the mitochondrial transfer RNA Leucine. Reported migraine prevalence figures in patients with this particular mutation vary considerably, but compared to the general population, m.3243A>G patients have a higher migraine prevalence. This burdensome symptom might sometimes even be the only clinical feature in maternal relatives carrying the m.3243A>G mutation. Although the exact sequence of events and the relative importance of factors underlying migraine in m.3243A>G MELAS spectrum disorders are still enigmatic, substantial evidence in man exist that dysfunctional mitochondria in both the vascular, the smooth muscle cells and the neuronal system and the interaction between these are at the starting point of the migraine developing pathophysiological cascade. Exclusively based on results of studies performed in patients harboring the m.3243A>G mutation, either in vivo or ex vivo, we here summarize our current understanding of mitochondrial angiopathy associated migraine in m.3243A>G patients which knowledge might lead to potential new avenues for migraine drug development

Mitochondrial Migraine: Disentangling the angiopathy paradigm in m.3243A>G patients

Migraine, characterized by recurrent attacks of predominantly unilateral throbbing headache, affects approximately 15% of the adult population and is an important cause of disability worldwide. Knowledge required for the development of new classes of antimigraine drugs might come from studying rare metabolic diseases associated with migraine. An illustrative example of a monogenetic disorder associated with migraine is the spectrum of disorders caused by the m.3243A>G mutation in the mitochondrial transfer RNA Leucine. Reported migraine prevalence figures in patients with this particular mutation vary considerably, but compared to the general population, m.3243A>G patients have a higher migraine prevalence. This burdensome symptom might sometimes even be the only clinical feature in maternal relatives carrying the m.3243A>G mutation. Although the exact sequence of events and the relative importance of factors underlying migraine in m.3243A>G MELAS spectrum disorders are still enigmatic, substantial evidence in man exist that dysfunctional mitochondria in both the vascular, the smooth muscle cells and the neuronal system and the interaction between these are at the starting point of the migraine developing pathophysiological cascade. Exclusively based on results of studies performed in patients harboring the m.3243A>G mutation, either in vivo or ex vivo, we here summarize our current understanding of mitochondrial angiopathy associated migraine in m.3243A>G patients which knowledge might lead to potential new avenues for migraine drug development

Nonspecific pattern of muscular cN-1A expression in inclusion body myositis

Contains fulltext : 214820.pdf (publisher's version ) (Open Access

Autoantibodies to Cytosolic 5 '-Nucleotidase 1A in Primary Sjogren's Syndrome and Systemic Lupus Erythematosus

Contains fulltext : 192050.pdf (publisher's version ) (Open Access