Demographically-Based Evaluation of Genomic Regions under Selection in Domestic Dogs.

Controlling for background demographic effects is important for accurately identifying loci that have recently undergone positive selection. To date, the effects of demography have not yet been explicitly considered when identifying loci under selection during dog domestication. To investigate positive selection on the dog lineage early in the domestication, we examined patterns of polymorphism in six canid genomes that were previously used to infer a demographic model of dog domestication. Using an inferred demographic model, we computed false discovery rates (FDR) and identified 349 outlier regions consistent with positive selection at a low FDR. The signals in the top 100 regions were frequently centered on candidate genes related to brain function and behavior, including LHFPL3, CADM2, GRIK3, SH3GL2, MBP, PDE7B, NTAN1, and GLRA1. These regions contained significant enrichments in behavioral ontology categories. The 3rd top hit, CCRN4L, plays a major role in lipid metabolism, that is supported by additional metabolism related candidates revealed in our scan, including SCP2D1 and PDXC1. Comparing our method to an empirical outlier approach that does not directly account for demography, we found only modest overlaps between the two methods, with 60% of empirical outliers having no overlap with our demography-based outlier detection approach. Demography-aware approaches have lower-rates of false discovery. Our top candidates for selection, in addition to expanding the set of neurobehavioral candidate genes, include genes related to lipid metabolism, suggesting a dietary target of selection that was important during the period when proto-dogs hunted and fed alongside hunter-gatherers.

Comorbidities in the diseasome are more apparent than real: What Bayesian filtering reveals about the comorbidities of depression.

Comorbidity patterns have become a major source of information to explore shared mechanisms of pathogenesis between disorders. In hypothesis-free exploration of comorbid conditions, disease-disease networks are usually identified by pairwise methods. However, interpretation of the results is hindered by several confounders. In particular a very large number of pairwise associations can arise indirectly through other comorbidity associations and they increase exponentially with the increasing breadth of the investigated diseases. To investigate and filter this effect, we computed and compared pairwise approaches with a systems-based method, which constructs a sparse Bayesian direct multimorbidity map (BDMM) by systematically eliminating disease-mediated comorbidity relations. Additionally, focusing on depression-related parts of the BDMM, we evaluated correspondence with results from logistic regression, text-mining and molecular-level measures for comorbidities such as genetic overlap and the interactome-based association score. We used a subset of the UK Biobank Resource, a cross-sectional dataset including 247 diseases and 117,392 participants who filled out a detailed questionnaire about mental health. The sparse comorbidity map confirmed that depressed patients frequently suffer from both psychiatric and somatic comorbid disorders. Notably, anxiety and obesity show strong and direct relationships with depression. The BDMM identified further directly co-morbid somatic disorders, e.g. irritable bowel syndrome, fibromyalgia, or migraine. Using the subnetwork of depression and metabolic disorders for functional analysis, the interactome-based system-level score showed the best agreement with the sparse disease network. This indicates that these epidemiologically strong disease-disease relations have improved correspondence with expected molecular-level mechanisms. The substantially fewer number of comorbidity relations in the BDMM compared to pairwise methods implies that biologically meaningful comorbid relations may be less frequent than earlier pairwise methods suggested. The computed interactive comprehensive multimorbidity views over the diseasome are available on the web at Co=MorNet: bioinformatics.mit.bme.hu/UKBNetworks.

[Fitness to drive after stroke]. / Kraftfahreignung nach Schlaganfall.

In Germany, patient information and expert testimony on driving ability requires knowledge of the corresponding legislation and the Guideline for expertises on driver aptitude. The testimony should clearly identify handicaps with regard to driving, give estimates on the future risks of a sudden loss of control, and also consider personal attitudes such as inadequate behavior, lack of insight etc. Physical handicaps often can be compensated for by restrains or restrictions such as vehicle modifications, daylight driving only etc.Both, information and testimony must give estimates on the risks of a sudden loss of control while driving by stroke recurrence or epileptic seizures. In accordance with the Risk-of-Harm-Formula of the Canadian Cardiovascular Society methods are being discussed, by which an estimate of harmful traffic accidents due to stroke recurrence can be calculated.

Genome sequencing highlights the dynamic early history of dogs.

To identify genetic changes underlying dog domestication and reconstruct their early evolutionary history, we generated high-quality genome sequences from three gray wolves, one from each of the three putative centers of dog domestication, two basal dog lineages (Basenji and Dingo) and a golden jackal as an outgroup. Analysis of these sequences supports a demographic model in which dogs and wolves diverged through a dynamic process involving population bottlenecks in both lineages and post-divergence gene flow. In dogs, the domestication bottleneck involved at least a 16-fold reduction in population size, a much more severe bottleneck than estimated previously. A sharp bottleneck in wolves occurred soon after their divergence from dogs, implying that the pool of diversity from which dogs arose was substantially larger than represented by modern wolf populations. We narrow the plausible range for the date of initial dog domestication to an interval spanning 11-16 thousand years ago, predating the rise of agriculture. In light of this finding, we expand upon previous work regarding the increase in copy number of the amylase gene (AMY2B) in dogs, which is believed to have aided digestion of starch in agricultural refuse. We find standing variation for amylase copy number variation in wolves and little or no copy number increase in the Dingo and Husky lineages. In conjunction with the estimated timing of dog origins, these results provide additional support to archaeological finds, suggesting the earliest dogs arose alongside hunter-gathers rather than agriculturists. Regarding the geographic origin of dogs, we find that, surprisingly, none of the extant wolf lineages from putative domestication centers is more closely related to dogs, and, instead, the sampled wolves form a sister monophyletic clade. This result, in combination with dog-wolf admixture during the process of domestication, suggests that a re-evaluation of past hypotheses regarding dog origins is necessary.

VariantMetaCaller: automated fusion of variant calling pipelines for quantitative, precision-based filtering.

BACKGROUND: The low concordance between different variant calling methods still poses a challenge for the wide-spread application of next-generation sequencing in research and clinical practice. A wide range of variant annotations can be used for filtering call sets in order to improve the precision of the variant calls, but the choice of the appropriate filtering thresholds is not straightforward. Variant quality score recalibration provides an alternative solution to hard filtering, but it requires large-scale, genomic data. RESULTS: We evaluated germline variant calling pipelines based on BWA and Bowtie 2 aligners in combination with GATK UnifiedGenotyper, GATK HaplotypeCaller, FreeBayes and SAMtools variant callers, using simulated and real benchmark sequencing data (NA12878 with Illumina Platinum Genomes). We argue that these pipelines are not merely discordant, but they extract complementary useful information. We introduce VariantMetaCaller to test the hypothesis that the automated fusion of measurement related information allows better performance than the recommended hard-filtering settings or recalibration and the fusion of the individual call sets without using annotations. VariantMetaCaller uses Support Vector Machines to combine multiple information sources generated by variant calling pipelines and estimates probabilities of variants. This novel method had significantly higher sensitivity and precision than the individual variant callers in all target region sizes, ranging from a few hundred kilobases to whole exomes. We also demonstrated that VariantMetaCaller supports a quantitative, precision based filtering of variants under wider conditions. Specifically, the computed probabilities of the variants can be used to order the variants, and for a given threshold, probabilities can be used to estimate precision. Precision then can be directly translated to the number of true called variants, or equivalently, to the number of false calls, which allows finding problem-specific balance between sensitivity and precision. CONCLUSIONS: VariantMetaCaller can be applied to small target regions and whole exomes as well, and it can be used in cases of organisms for which highly accurate variant call sets are not yet available, therefore it can be a viable alternative to hard filtering in cases where variant quality score recalibration cannot be used. VariantMetaCaller is freely available at http://bioinformatics.mit.bme.hu/VariantMetaCaller .

Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients (INSPiRE-TMS): a protocol for a randomised controlled trial.

BACKGROUND: Patients with recent stroke or TIA are at high risk for new vascular events. Several evidence based strategies in secondary prevention of stroke are available but frequently underused. Support programs with multifactorial risk factor modifications after stroke or TIA have not been investigated in large-scale prospective controlled trials so far. INSPiRE-TMS is a prospective, multi-center, randomized open intervention trial for intensified secondary prevention after minor stroke and TIA. METHODS/DESIGN: Patients with acute TIA or minor stroke admitted to the participating stroke centers are screened and recruited during in-hospital stay. Patients are randomised in a 1:1 ratio to intervention (support program) and control (usual care) arms. Inclusion of 2.082 patients is planned. The support program includes cardiovascular risk factor measurement and feedback, monitoring of medication adherence, coaching in lifestyle modifications, and active involvement of relatives. Standardized motivational interviewing is used to assess and enhance patients' motivation. Primary objective is a reduction of new major vascular events defined as nonfatal stroke and myocardial infarction or vascular death. Recruitment time is planned for 3.5 years, follow up time is at least 2 years for every patient resulting in a total study time of 5 years (first patient in to last patient out). DISCUSSION: Given the high risk for vascular re-events in acute stroke and the available effective strategies in secondary prevention, the INSPIRE-TMS support program has the potential to lead to a relevant reduction of recurrent events and a prolongation of the event-free survival time. The trial will provide the basis for the decision whether an intensified secondary prevention program after stroke should be implemented into regular care. A cost-effectiveness evaluation will be performed. TRIAL REGISTRATION: clinicaltrials.gov: 01586702.

Differential Switch Costs in Typically Achieving Children and Children With Mathematical Difficulties.

Children with mathematical difficulties need to spend more time than typically achieving children on solving even simple equations. Since these tasks already require a larger share of their cognitive resources, additional demands imposed by the need to switch between tasks may lead to a greater decline of performance in children with mathematical difficulties. We explored differential task switch costs with respect to switching between addition versus subtraction with a tablet-based arithmetic verification task and additional standardized tests in elementary school children in Grades 1 to 4. Two independent studies were conducted. In Study 1, we assessed the validity of a newly constructed tablet-based arithmetic verification task in a controlled classroom-setting (n = 165). Then, effects of switching between different types of arithmetic operations on accuracy and response latency were analyzed through generalized linear mixed models in an online-based testing (Study 2; n = 3,409). Children with mathematical difficulties needed more time and worked less accurately overall. They also exhibited a stronger performance decline when working in a task-switching condition, when working on subtraction (vs. addition) items and in operations with two-digit (vs. one-digit) operations. These results underline the value of process data in the context of assessing mathematical difficulties.

Dementia care in the general practice setting: a cluster randomized trial on the effectiveness and cost impact of three management strategies.

OBJECTIVE: To compare a complex nondrug intervention including actively approaching counseling and caregiver support groups with differing intensity against usual care with respect to time to institutionalization in patients with dementia. METHODS: Within this three-armed cluster-randomized controlled trial, 390 community-dwelling patients aged 65 years or older with physician-diagnosed mild to moderate dementia and their caregivers were enrolled via 129 general practitioners in Middle Franconia, Germany. The intervention included general practitioners' training in dementia care and their recommendation of support groups and actively approaching caregiver counseling. Primary study end point was time to institutionalization over 2 years. In addition, long-term intervention effects were assessed over a time horizon of 4 years. Secondary end points included cognitive functioning, (instrumental) activities of daily living, burden of caregiving, and health-related quality of life after 2 years. Frailty models with strict intention-to-treat approach and mixed linear models were applied to account for cluster randomization. Health care costs were assessed from the societal perspective. RESULTS: After 2 (4) years, 12% (24%) of the patients were institutionalized and another 21% (35%) died before institutionalization. No significant differences between study groups were observed with respect to time to institutionalization after 2 and 4 years (P 0.25 and 0.71, respectively). Secondary end points deteriorated, but differences were not significant between study groups. Almost 80% of the health care costs were due to informal care. Total annual costs amounted to more than €47,000 per patient and did not differ between study arms. CONCLUSION: The intervention showed no effects on time to institutionalization and secondary outcomes.

Excess costs of dementia disorders and the role of age and gender - an analysis of German health and long-term care insurance claims data.

BACKGROUND: Demographic ageing is associated with an increasing number of dementia patients, who reportedly incur higher costs of care than individuals without dementia. Regarding Germany, evidence on these excess costs is scarce. Adopting a payer perspective, our study aimed to quantify the additional yearly expenditures per dementia patient for various health and long-term care services. Additionally, we sought to identify gender-specific cost patterns and to describe age-dependent cost profiles. METHODS: The analyses used 2006 claims data from the AOK Bavaria Statutory Health Insurance fund of 9,147 dementia patients and 29,741 age- and gender-matched control subjects. Cost predictions based on two-part regression models adjusted for age and gender and excess costs of dementia care refer to the difference in model-estimated means between both groups. Corresponding analyses were performed stratified for gender. Finally, a potentially non-linear association between age and costs was investigated within a generalized additive model. RESULTS: Yearly spending within the social security system was circa €12,300 per dementia patient and circa €4,000 per non-demented control subject. About two-thirds of the additional expenditure for dementia patients occurred in the long-term care sector. Within our study sample, male and female dementia patients incurred comparable total costs. However, women accounted for significantly lower health and significantly higher long-term care expenditures. Long-term care spending increased in older age, whereupon health care spending decreased. Thus, at more advanced ages, women incurred greater costs than men of the same age. CONCLUSIONS: Dementia poses a substantial additional burden to the German social security system, with the long-term care sector being more seriously challenged than the health care sector. Our results suggest that female dementia patients need to be seen as a key target group for health services research in an ageing society. It seems clear that strategies enabling community-based care for this vulnerable population might contribute to lowering the financial burden caused by dementia. This would allow for the sustaining of comprehensive dementia care within the social security system.

Costs of care for dementia patients in community setting: an analysis for mild and moderate disease stage.

OBJECTIVE: Rising life expectancy is associated with higher prevalence rates of dementia disorders. When disease progresses the patients' call on formal health care services and on social support grows which imposes increasing costs of care. The aim of this study was to investigate the costs for patients with mild and moderate dementia in community setting in Germany. METHODS: We assessed total costs of care and individual cost components for 383 community-living dementia patients alongside a cluster-randomized trial from societal and health insurance perspective. Utilization of formal health care services was based on insurance claims data and time dedicated to informal care was assessed within caregiver interviews. We estimated costs using a two-part regression model adjusting for age, gender and cluster-effects. RESULTS: Costs of care equal €47,747 (Euros) from societal perspective which is almost the 4.7-fold of health insurance expenditures. Valued informal care covers 80.2% of societal costs and increases disproportionally when disease progresses. In moderate dementia the corresponding amount exceeds the one in mild dementia by 69.9%, whereas costs for formal health care services differ by 14.3%. CONCLUSION: Due to valued informal care, costs of care for community-living patients with moderate dementia are significantly higher than for patients with mild dementia. Informal care is a non-cash item saving expenditures for professional care. To relieve social security system and family caregivers as well as to allow dementia patients to stay at home as long as possible, concepts fostering community-based dementia care and support to family caregivers need to be further developed.

[Genetic variability of the oxytocine receptor: an in silico study]. / Az oxitocinreceptor genetikai variabilitásának in silico elemzése.

UNLABELLED: There is an ongoing extensive study on the polymorphisms of the oxytocine receptor (OXTR) gene and their relation to certain psychological traits and psychiatric disorders, however the results are contradictory. One of the sources of inconsistency could originate from the fact that the OXTR gene contains more than 270 SNPs (single nucleotide polymorphisms) without clarified molecular effect. GOALS: The aim of this study was an in silico analysis of sequence variations between the human and dog OXTR gene. RESULTS: Comparative analysis of the human and the dog OXTR amino acid sequence revealed that the most robust difference between the two proteins is a five amino acid containing fragment which is present in the human but absent in the dog receptor. In silico addition of this sequence to the dog receptor resulted in a dramatic change in the conformation of the intracellular region. CONCLUSION: In silico comparative analysis of OXTR gene variants among species and individuals might serve as an important cue for predicting the functional effects of genetic variants.

Counsellors contact dementia caregivers--predictors of utilisation in a longitudinal study.

BACKGROUND: Counselling of family members is an established procedure in the support of dementia patients' relatives. In absence of widespread specialised dementia care services in most countries, however, counselling services are often not taken up or only very late in the course of the disease. OBJECT: In order to promote acceptance of this service, a new counselling concept was implemented where general practitioners recommended family counsellors, who then actively contacted the family caregivers to offer counselling ("Counsellors Contact Caregivers", CCC). The research questions were: To what extent can the rate of family counselling be increased by CCC? What are the predictors for usage of this form of family counselling? METHODS: The study started in June 2006 in Middle Franconia for patients with mild to moderate dementia. At baseline, 110 family caregivers were offered counselling based on the CCC guideline. Data was analysed from 97 patient-caregiver dyads who received counselling for one year. The mean age of the patients with dementia (67 women and 30 men) was 80.7 years (SD = 6.2). The mean age of their primary family caregivers (68 women, 23 men) was 60.8 years (SD = 13.8). RESULTS: 35 family members (36%) made use of more extensive counselling (more than one personal contact). By contrast, 29 family members (30%) had no personal contact or only one personal contact (33 cases, 34%). The factors "spouse" (p = .001) and "degree of care" (p = .005) were identified as significant predictors for acceptance of extensive counselling. CONCLUSIONS: Actively contacting patients and their caregivers is a successful means of establishing early and frequent contact with family members of patients with mild to moderate dementia. Use of extensive counselling is made especially by spouses of patients requiring intensified care. TRIAL REGISTRATION: ISRCTN68329593.

Effects of general practitioner training and family support services on the care of home-dwelling dementia patients--results of a controlled cluster-randomized study.

BACKGROUND: More than 90% of dementia patients are cared for by their general practitioners, who are decisively involved in the diagnosis, therapy and recommendation of support services. OBJECTIVE: To test whether special training of general practitioners alters the care of dementia patients through their systematic recommendation of caregiver counseling and support groups. METHOD: 129 general practitioners enrolled 390 dementia patients and their informal caregivers in a prospective, three-arm cluster-randomized 2-year study. Arm A constituted usual care, in Arm B and C support groups and caregiver counseling (in Arm B one year after baseline, in Arm C at baseline) were recommended by the general practitioners. The general practitioners received arm-specific training. Diagnostic and therapeutic behavior of physicians was recorded at baseline. Informal caregivers were questioned in follow-up after 2 years about the utilization of support services. RESULTS: The diagnostic behavior of the general practitioners conforms to relevant guidelines. The procedure in newly-diagnosed patients does not differ from previously diagnosed patients with the exception of the rate of referral to a specialist. About one-third of the newly-diagnosed dementia patients are given an anti-dementia drug. The utilization of support groups and counseling increased five- and fourfold, respectively. Utilization of other support services remained low (< 10%), with the exception of home nursing and institutional short-term nursing. CONCLUSION: Trained general practitioners usually act in conformity with guidelines with respect to diagnosing dementia, and partly in conformity with the guidelines with respect to recommended drug therapy. Recommendations of support services for informal caregivers by the general practitioner are successful. They result in a marked increase in the utilization rate for the recommended services compared to offers which are not recommended by the general practitioner. TRIAL REGISTRATION: ISRCTN68329593.

A support programme for secondary prevention in patients with transient ischaemic attack and minor stroke (INSPiRE-TMS): an open-label, randomised controlled trial.

BACKGROUND: Patients with recent stroke or transient ischaemic attack are at high risk for a further vascular event, possibly leading to permanent disability or death. Although evidence-based treatments for secondary prevention are available, many patients do not achieve recommended behavioural modifications and pharmaceutical prevention targets in the long-term. We aimed to investigate whether a support programme for enhanced secondary prevention can reduce the frequency of recurrent vascular events. METHODS: INSPiRE-TMS was an open-label, multicentre, international randomised controlled trial done at seven German hospitals with acute stroke units and a Danish stroke centre. Patients with non-disabling stroke or transient ischaemic attack within 2 weeks from study enrolment and at least one modifiable risk factor (ie, arterial hypertension, diabetes, atrial fibrillation, or smoking) were included. Computerised randomisation was used to allocate patients (1:1) either to the support programme in addition to conventional care or to conventional care alone. The support programme used feedback and motivational interviewing strategies with eight outpatient visits over 2 years aiming to improve adherence to secondary prevention targets. The primary outcome was the composite of major vascular events consisting of stroke, acute coronary syndrome, and vascular death, assessed in the intention-to-treat population (all patients who underwent randomisation, did not withdraw study participation, and had at least one follow-up). Outcomes were assessed at annual follow-ups using time-to-first-event analysis. All-cause death was monitored as a safety outcome. This trial is registered with ClinicalTrials.gov, NCT01586702. FINDINGS: From Aug 22, 2011, to Oct 30, 2017, we enrolled 2098 patients. Of those, 1048 (50·0%) were randomly assigned to the support programme group and 1050 (50·0%) patients were assigned to the conventional care group. 1030 (98·3%) patients in the support group and 1042 (99·2%) patients in the conventional care group were included in the intention-to-treat analysis. The mean age of analysed participants was 67·4 years and 700 (34%) were women. After a mean follow-up of 3·6 years, the primary outcome of major vascular events had occurred in 163 (15·8%) of 1030 patients of the support programme group and in 175 (16·8%) of 1042 patients of the conventional care group (hazard ratio [HR] 0·92, 95% CI 0·75-1·14). Total major vascular event numbers were 209 for the support programme group and 225 for the conventional care group (incidence rate ratio 0·93, 95% CI 0·77-1·12; p=0·46) and all-cause death occurred in 73 (7·1%) patients in the support programme group and 85 (8·2%) patients in the conventional care group (HR 0·85, 0·62-1·17). More patients in the support programme group achieved secondary prevention targets (eg, in 1-year-follow-up 52% vs 42% [p<0·0001] for blood pressure, 62% vs 54% [p=0·0010] for LDL, 33% vs 19% [p<0·0001] for physical activity, and 51% vs 34% [p=0·0010] for smoking cessation). INTERPRETATION: Provision of an intensified secondary prevention programme in patients with non-disabling stroke or transient ischaemic attack was associated with improved achievement of secondary prevention targets but did not lead to a significantly lower rate of major vascular events. Further research is needed to investigate the effects of support programmes in selected patients who do not achieve secondary prevention targets soon after discharge. FUNDING: German Federal Ministry of Education and Research, Pfizer, and German Stroke Foundation.

Dementia care initiative in primary practice: study protocol of a cluster randomized trial on dementia management in a general practice setting.

BACKGROUND: Current guidelines for dementia care recommend the combination of drug therapy with non-pharmaceutical measures like counselling and social support. However, the scientific evidence concerning non-pharmaceutical interventions for dementia patients and their informal caregivers remains inconclusive. Targets of modern comprehensive dementia care are to enable patients to live at home as long and as independent as possible and to reduce the burden of caregivers. The objective of the study is to compare a complex intervention including caregiver support groups and counselling against usual care in terms of time to nursing home placement. In this paper the study protocol is described. METHODS/DESIGN: The IDA (Initiative Demenzversorgung in der Allgemeinmedizin) project is designed as a three armed cluster-randomized trial where dementia patients and their informal caregivers are recruited by general practitioners. Patients in the study region of Middle Franconia, Germany, are included if they have mild or moderate dementia, are at least 65 years old, and are members of the German AOK (Allgemeine Ortskrankenkasse) sickness fund. In the control group patients receive regular treatment, whereas in the two intervention groups general practitioners participate in a training course in evidence based dementia treatment, recommend support groups and offer counseling to the family caregivers either beginning at baseline or after the 1-year follow-up. The study recruitment and follow-up took place from July 2005 to January 2009. 303 general practitioners were randomized of which 129 recruited a total of 390 patients. Time to nursing home admission within the two year intervention and follow-up period is the primary endpoint. Secondary endpoints are cognitive status, activities of daily living, burden of care giving as well as healthcare costs. For an economic analysis from the societal perspective, data are collected from caregivers as well as by the use of routine data from statutory health insurance and long-term care insurance. DISCUSSION: From a public health perspective, the IDA trial is expected to lead to evidence based results on the community effectiveness of non-pharmaceutical support measures for dementia patients and their caregivers in the primary care sector. For health policy makers it is necessary to make their decisions about financing new services based on strong knowledge about the acceptance of measures in the population and their cost-effectiveness. TRIAL REGISTRATION: ISRCTN68329593.

Position paper: ability to drive in cerebrovascular diseases.

The regulations for fitness to drive after a cerebrovascular accident in the German Driving License Regulations (FeV) and the German Evaluation Guidelines for Driving Ability (BGL). are not up to date with the current medical knowledge and not consistent with regulations regarding cardiovascular diseases. This position paper presented by six medical and neuropsychological societies in Germany provides a guideline for the assessment of driving ability after diagnosis of a cerebrovascular disease and addresses three major questions: If there is a functional limitation, how can it be compensated for? What is the risk of sudden loss of control while driving in the future? Are there behavioral or personality changes or cognitive deficiencies interfering with safety while driving? Recommendations for the assessment of driving ability in different cerebrovascular diseases are presented. This article is a translation of the position paper published in Nervenarzt: Marx, P., Hamann, G.F., Busse, O. et al. Nervenarzt 90(4): 388-398.

Increased prevalence of microangiopathic brain lesions among siblings of patients with lacunar stroke. A prospective multicenter study.

BACKGROUND: Family and twin studies suggest predisposing genetic factors in stroke. Lacunar infarcts represent a homogeneous phenotype, which is a prerequisite for genetic analyses. Applying an affected sib -pair analysis, we prospectively assessed the prevalence of microangiopathic brain lesions (MBL) and associated risk factors among siblings of patients with lacunar stroke. METHODS: Index patients fulfilled clinical criteria of a lacunar stroke in combination with a corresponding MBL on CT or MRI. Siblings were characterized as affected if MBL demonstrated on MRI. The prevalence of MBL was compared with population prevalence data extracted from other studies. RESULTS: From 784 patients screened, 81 index patients with lacunar stroke and 97 siblings were recruited, of which 42% were identified as affected. Compared with data from unselected historical controls and stratified by age groups, prevalence was between 2 and 5 times higher. CONCLUSIONS: Our results indicate that genetic stroke studies are feasible even in subtypes of ischemic stroke. The high prevalence of MBL among siblings of patients with lacunar infarct might suggest a familial aggregation. However, due to the small sample size these results need to be interpreted with caution and require confirmation by planned genetic analyses.

Side effects of intravenous immunoglobulins in neurological autoimmune disorders--a prospective study.

The increased use of intravenous immunoglobulins (IVIg) in the treatment of neurological autoimmune diseases has led to more awareness of adverse reactions. We studied prospectively the side effects of IVIg during 84 treatment courses with a total of 341 infusions under routine clinical conditions. Mild reactions were common. Headache was noted most often, occurring during 30% of treatment courses. There were three severe adverse events (3.6% of all treatment courses) that led to discontinuation of the treatment, namely thrombosis of the jugular vein, allergic reaction and retrosternal pressure. Significant changes in laboratory findings were seen for leucocytes, erythrocytes, haematocrit, haemoglobin, ALAT and ASAT. None of these changes were clinically relevant. The elevation of liver enzymes was dependent on the IVIg preparation used, while there was no association with the underlying disease, age, or gender of the patient. In conclusion, this prospective study confirms the high frequency of mild, self-limited side effects of IVIg. Elevation of liver enzymes may possibly be associated with certain IVIg preparations. Bearing these complications in mind, this prospective study supports the notion that IVIg can generally be regarded as safe, leading to severe adverse events during only 3 (0.9%) of 341 infusions (or 3 of 84 treatment courses, 3.6 %). However, careful monitoring for severe side effects remains mandatory, and we propose that laboratory findings like full blood count, renal and liver function should be monitored routinely.

What determines the CSF concentrations of albumin and plasma-derived IgG?

OBJECTIVES: To estimate the mean influence of the main determinants of the cerebrospinal fluid (CSF) concentration of albumin and plasma-derived immunoglobulin G (IgG). METHODS: Correlations of serum and CSF concentrations of albumin and IgG and assumptions of the mode of action of the determinants (plasma concentration, barrier permeability, and CSF flow) are used to quantify the determinants' influences in a sample of 1700 patients. RESULTS: We estimated in patients with normal CSF albumin that the serum concentrations of albumin and IgG explained 3.3% and 23% of the variation of the respective CSF concentrations, whereas the barrier permeability accounted for 41.9% and 22.2%, and CSF flow for 54.8%. In patients with pathologic CSF albumin concentration, the serum concentrations were estimated to explain 0.2% and 8.2% of the variation of the respective CSF concentrations, the barrier permeability 19.7% and 11.7%, and CSF flow 80.1%. CONCLUSIONS: CSF flow had the strongest mean influence, especially at elevated CSF albumin levels. The serum concentrations and barrier permeabilities of albumin and IgG influenced the respective CSF concentrations quite differently, which should be due to the different physicochemical properties of the two molecules. Mean influences from large patient samples, as explored here, can give only an overview. Understanding the determinants in individuals will need further specific measurements, especially of CSF flow.

Comparison of intravenous immunoglobulin preparations on microglial function in vitro: more potent immunomodulatory capacity of an IgM/IgA-enriched preparation.

Intravenous immunoglobulins (IVIg) have been used successfully as an immunomodulating treatment for patients with inflammatory diseases of the central nervous system (CNS) including multiple sclerosis (MS). It was shown previously that IVIg could modulate the functions of microglia, the main immune cell in the CNS. We have compared five commercially available IVIg preparations on their capacity to modulate tumor necrosis factor (TNF)-alpha secretion and nitric oxide production in cultured microglia. All preparations induced a dose-dependent stimulation of TNF-alpha secretion as measured by ELISA. There were some small differences between preparations consisting of IgG, while the preparation enriched for IgM and IgA induced a considerably higher TNF-alpha production at 1 mg/mL and 10 mg/mL. Similar results were seen for nitric oxide production as measured indirectly by the Griess reaction. These results indicate that IgM/IgA-enriched IVIg may be a more potent immunomodulator than pure IgG preparations on inflammatory reactions in the CNS.