Neurofilament light chain: A novel blood biomarker in patients with ataxia telangiectasia.

AIM: Neurofilament light chain (NfL) is recognized as a blood biomarker in several neurodegenerative disorders, but its possible relevance in Ataxia Telangiectasia (A-T) has not been examined. The aim of this study was to investigate the biomarker potential of blood NfL concentrations in patients with A-T. METHOD: Blood (serum/plasma) NfL concentrations were measured in a Dutch and an American cohort of patients with A-T and compared to control values. Additionally, correlations between NfL concentrations and disease phenotype (classic versus variant A-T) were studied. RESULTS: In total 40 (23 Dutch and 17 American) patients with A-T (32 patients with classic A-T and 7 patients with variant A-T) and 17 age- and gender-matched (to the American cohort) healthy controls were included in this study. Blood (serum/plasma) NfL concentrations in patients with classic A-T and age ≤ 12 years were elevated compared to age matched controls. Patients with classic A-T > 12 years also had higher blood (serum/plasma) NfL concentrations (here: compared to age-dependent reference values found in the literature). Patients with classic A-T had higher blood (serum/plasma) NfL concentrations than patients with the variant phenotype. CONCLUSION: Blood (serum/plasma) NfL concentrations are elevated in patients with classic A-T and appear to correlate with the disease phenotype (classic versus variant). Therefore, blood (serum/plasma) NfL may be a promising biomarker in A-T.

Management of rare movement disorders in Europe: outcome of surveys of the European Reference Network for Rare Neurological Diseases.

BACKGROUND AND PURPOSE: The diagnosis of rare movement disorders is difficult and specific management programmes are not well defined. Thus, in order to capture and assess care needs, the European Reference Network for Rare Neurological Diseases has performed an explorative care need survey across all European Union (EU) countries. METHODS: This is a multicentre, cross-sectional study. A survey about the management of different rare movement disorders (group 1, dystonia, paroxysmal dyskinesia and neurodegeneration with brain iron accumulation; group 2, ataxias and hereditary spastic paraparesis; group 3, atypical parkinsonism; group 4, choreas) was sent to an expert in each group of disorders from each EU country. RESULTS: Some EU countries claimed for an increase of teaching courses. Genetic testing was not readily available in a significant number of countries. Regarding management, patients' accessibility to tertiary hospitals, to experts and to multidisciplinary teams was unequal between countries and groups of diseases. The availability of therapeutic options, such as botulinum toxin or more invasive treatments like deep brain stimulation, was limited in some countries. CONCLUSIONS: The management of these conditions in EU countries is unequal. The survey provides evidence that a European care-focused network that is able to address the unmet rare neurological disease care needs and inequalities is highly warranted.

Telangiectasias in Ataxia Telangiectasia: Clinical significance, role of ATM deficiency and potential pathophysiological mechanisms.

Ataxia Telangiectasia (AT) is named after the two key clinical features that characterize its classical phenotype, namely a progressive cerebellar gait disorder (ataxia) and vascular anomalies (telangiectasias) visible in the conjunctivae and skin. AT is an autosomal recessively inherited disorder, caused by mutations in the ATM gene that encodes the ATM protein. While the ataxia is subject of many publications, the telangiectasias are under emphasised. We here describe the observation that the absence or presence of ATM protein and the level of residual ATM kinase activity are related to the occurrence of telangiectasias and describe the clinical consequences of these vascular malformations. Finally, we hypothesize that ATM dysfunction dysregulates angiogenesis.

Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline.

Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence-based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2-2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9-2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1-4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacking. Based on these results, we propose that all female carriers of 40-50 years of age and female ATM c.7271T>G mutation carriers from 25 years of age onwards be offered intensified surveillance programs for breast cancer. Furthermore, all carriers should be made aware of lifestyle factors that contribute to the development of cardiovascular diseases and diabetes.

[Detailed analysis of the societal costs of diabetes mellitus]. / Gedetailleerde raming van de maatschappelijke kosten van diabetes mellitus.

OBJECTIVE: Estimation of the societal costs of diabetes and related complications in support of the revision of the diabetes guidelines. DESIGN: Retrospective and descriptive cross-sectional study. METHODS: Relative risks (RRs) of diabetes complications, by age, were determined by comparing patients with and without diabetes. Using existing 1994 General Practitioner registry data on prevalence, on costs of illnesses and on absenteeism, the contribution of diabetes to the costs of other illnesses was estimated on the basis of aetiological fractions calculated with the RRs found. Cost due to absenteeism by diabetes complications were calculated using the friction method. RESULTS: In 1994, the societal cost of diabetes were 1.67 milliard Dutch guilders (1.55-1.87; range determined by applying the 95% confidence intervals of the RRs; in Euro: 758 million (703-848). The costs due to absenteeism from work were almost 0.2 milliard. The medical costs of diabetes were 2.5% of the health care budget. The contribution of diabetes to the medical costs of cardiovascular diseases was 14%.

Diabetes nephropathy in the Netherlands: a cost effectiveness analysis of national clinical guidelines.

BACKGROUND: In the Netherlands a program on quality assurance in medical care has started in 1996. Clinical professionals, patient organizations and health services researchers formulate evidence based guidelines with a concomitant cost-effectiveness analysis. OBJECTIVES: To examine the cost-effectiveness of guideline recommendations for prevention of nephropathy in diabetes mellitus type 1 and 2. RESEARCH DESIGN: A semi-Markov compartment model was developed. Data from international publications on epidemiological surveys and randomized trials, together with national data on health care use and costs, were used to feed the model. A cohort of diabetes patients without renal disease enters the model. MEASURES: Complication (end-stage renal disease) free years, QALY's, and life-time medical costs per patient treated according to guideline recommendations or current anti-diabetic strategy. RESULTS: Guideline treatment for type 1 diabetes yields 4.2 complication free life years, at a cost-effectiveness ratio of 13 500 (Dutch guilders) NLG per QALY. Type 2 diabetes patients gain 0.2 complication free life years at a cost-effectiveness ratio of 31 000 NLG per QALY. CONCLUSION: Guideline development for diabetes nephropathy, with concomitant cost-effectiveness calculations, has resulted in a transparent guideline with explicit information on long-term cost and effects. The project has brought health care providers and health services researchers together.

Thermodynamics of micellar systems: comparison of mass action and phase equilibrium models for the calculation of standard Gibbs energies of micelle formation.

Micellar colloids are distinguished from other colloids by their association-dissociation equilibrium in solution between monomers, counter-ions and micelles. According to classical thermodynamics, the standard Gibbs energy of formation of micelles at fixed temperature and pressure can be related to the critical micelle concentration. This relation is different for two models which are widely used to describe micelle formation, namely the Phase Separation and the Mass Action Models. These approaches and the assumptions upon which they are based are analysed in this paper. We show that the two models can be generalised to include surfactant salts having different stoichiometries.

Simulating the self-assembly of gemini (dimeric) surfactants.

The morphologies and dynamics of aggregates formed by surfactant molecules are known to influence strongly performance properties spanning biology, household cleaning, and soil cleanup. Molecular dynamics simulations were used to investigate the morphology and dynamics of a class of surfactants, the gemini or dimeric surfactants, that are of potential importance in several industrial applications. Simulation results show that these surfactants form structures and have dynamic properties that are drastically different from those of single-chain surfactants. At the same weight fraction, single-chain surfactants form spherical micelles whereas gemini surfactants, whose two head groups are coupled by a short hydrophobic spacer, form thread-like micelles. Simulations at different surfactant concentrations indicate the formation of various structures, suggesting an alternative explanation for the unexpected viscosity behavior of gemini surfactants.

Reappearance of Plasmodium malariae in Suriname?

Plasmodium malariae has not been reported from Suriname since 1979. In 1989 an increasing number of P. vivax infections among Bush-negroes returning from the eastern part of the interior was reported in Paramaribo. A microscopical re-examination of all malaria cases in the eastern part of the country failed to confirm any P. vivax infections, but instead P. malariae infections were diagnosed. A study followed to determine the Duffy blood group antigens of 4 Bush-negroes allegedly with a P. vivax infection in their medical history and of 28 and 32 unselected Bush-negroes and Amerindians respectively. Three of the 4 former Bush-negroes had the FyB antigen, while only 7% of the unselected Bush-negroes had this antigen. This low frequency of the genotype is incompatible with reports of high P. vivax prevalences in Bush-negro populations. The Amerindians tested showed a low proportion of Fy0 genotype, which is compatible with the frequent diagnosis of P. vivax among this ethnic group. Reports of P. vivax infections among Bush-negroes are due to misdiagnosis of P. malariae, emphasizing the need to include all 4 species of human Plasmodium when (re)training microscopists. The question whether P. malariae reappeared in Suriname due to increased contact with the simian reservoir, or was simply missed, is discussed.