GBA-associated parkinsonism and dementia: beyond α-synucleinopathies?

BACKGROUND AND PURPOSE: To date the role of GBA mutations beyond α-synucleinopathies in the parkinsonism-dementia spectrum is still unclear. The aim of the study was to screen for GBA mutations in progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), primary progressive aphasia (PPA) and the behavioural variant of frontotemporal dementia (bvFTD). METHODS: In all, 303 patients with a clinical diagnosis of PSP (n = 157), CBS (n = 39), PPA (n = 35) and bvFTD (n = 72) and 587 neurologically healthy controls were screened for the most common GBA mutations. RESULTS: GBA mutations were detected in one healthy control and four patients with a clinical diagnosis of PSP (n = 1), probable CBS (n = 2) and PPA (n = 1, with concomitant C9orf72 expansion). Overall the prevalence of GBA mutations was low in non-α-synucleinopathies but significantly higher in the CBS subgroup compared to controls. CONCLUSION: Although numbers are small, our findings indicate that the clinical phenotype of GBA-associated neurodegenerative disease is more heterogeneous than previously assumed, including phenotypes not usually associated with underlying α-synucleinopathies. This may be of relevance, once causal therapeutic strategies for GBA-associated neurodegenerative disease are developed.

Risk of recurrent cervical artery dissection during pregnancy, childbirth and puerperium.

BACKGROUND AND PURPOSE: Hormonal and mechanical factors might increase the risk for cervical artery dissection (CAD) during pregnancy and the puerperium. There is uncertainty how to counsel women with a previous CAD regarding the risk of CAD recurrence during pregnancy and the puerperium. METHODS: In an observational study of four stroke centers, all women aged 16-45 years with primary CAD in the previous decade were asked to participate in a standardized assessment on long-term follow-up with a special focus on pregnancies and recurrent CAD. RESULTS: Ninety-two women were identified and 53 of them were included in the analysis (60%). Eleven women declined to participate, 28 were untraceable. The 39 non-participants did not differ from participants regarding key baseline characteristics. Average follow-up time was 72 months. Nine women (17%) had recurrent CAD after a median of 14 days (range 2 days to 117 months). Eleven women (20%) had a total of 13 completed pregnancies at a median of 44 months (range 12-84 months) after index CAD. Two of the pregnant women (18%) had suffered recurrent CAD ≥18 months prior to the pregnancy. All 13 pregnancies and puerperia went without recurrent CADs or cerebrovascular events. This includes giving birth by vaginal delivery (n = 6) and caesarean section (n = 7). None of the five women with typical connective tissue disease became pregnant. CONCLUSIONS: Our observation suggests that the risk of recurrent CAD may not be greatly increased with pregnancies starting at least 12 months after CAD in women without typical connective tissue disease.

Smoking Modifies the Genetic Risk for Early-Onset Periodontitis.

Periodontitis has low-prevalence, highly severe disease manifestations with an early onset and rapid progression. The diagnosis is based on severe destruction of the alveolar bone in adolescents and young adults. Genetic susceptibility variants and smoking are well-established risk factors, but their interactions in modifying disease susceptibility have not been studied. We aimed to identify genetic risk variants of early-onset periodontitis that unmask their effects on tobacco smoke exposure. To this end, we analyzed 79,780,573 common variants in 741 northwest Europeans diagnosed to have >30% bone loss at >2 teeth before 35 y of age, using imputed genotypes of the OmniExpress BeadChip. Never versus ever smokers were compared in a logistic regression analysis via a case-only approach. To explore the effect of tobacco smoke on the expression of the G×S-associated genes, cultures of primary gingival fibroblasts (n = 9) were exposed to cigarette smoke extract, and transcripts were quantified by reverse transcription polymerase chain reaction. We identified 16 loci for which our analysis suggested an association with G×S increased disease risk (P < 5 × 10-5). Nine loci had previously been reported to be associated with spirometric measures of pulmonary function by an earlier G×S genome-wide association study. Genome-wide significant cis expression quantitative trait loci were reported for G×S-associated single-nucleotide polymorphisms at ST8SIA1 and SOST, indicating a causal role of these genes in tobacco-related etiopathology. Notably, SOST is a negative regulator of bone growth, and ST8SIA1 has a role in tissue remodeling. Cigarette smoke extract significantly altered the expression of 2 associated genes: SSH1 (P = 5 × 10-07), which is required for NF-κB activation and innate immune responses to bacterial invasion, and ST8SIA1 (P = 0.0048). We conclude that the genetic predisposition to early-onset periodontitis is in part triggered by smoking and that tobacco smoke directly affects the expression of genes involved in bone homeostasis, tissue repair, and immune response.

Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility.

Periodontitis is one of the most common inflammatory human diseases with a strong genetic component. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWASs) of chronic periodontitis (CP) have largely been unsuccessful in identifying common susceptibility factors. A combination of quantitative trait loci (QTL) mapping in mice with association studies in humans has the potential to discover novel risk loci. To this end, we assessed alveolar bone loss in response to experimental periodontal infection in 25 lines (286 mice) from the Collaborative Cross (CC) mouse population using micro-computed tomography (µCT) analysis. The orthologous human chromosomal regions of the significant QTL were analyzed for association using imputed genotype data (OmniExpress BeadChip arrays) derived from case-control samples of aggressive periodontitis (AgP; 896 cases, 7,104 controls) and chronic periodontitis (CP; 2,746 cases, 1,864 controls) of northwest European and European American descent, respectively. In the mouse genome, QTL mapping revealed 2 significant loci (-log P = 5.3; false discovery rate = 0.06) on chromosomes 1 ( Perio3) and 14 ( Perio4). The mapping resolution ranged from ~1.5 to 3 Mb. Perio3 overlaps with a previously reported QTL associated with residual bone volume in F2 cross and includes the murine gene Ccdc121. Its human orthologue showed previously a nominal significant association with CP in humans. Use of variation data from the genomes of the CC founder strains further refined the QTL and suggested 7 candidate genes ( CAPN8, DUSP23, PCDH17, SNORA17, PCDH9, LECT1, and LECT2). We found no evidence of association of these candidates with the human orthologues. In conclusion, the CC populations enabled mapping of confined QTL that confer susceptibility to alveolar bone loss in mice and larger human phenotype-genotype samples and additional expression data from gingival tissues are likely required to identify true positive signals.

[Pharmacokinetics and pharmacodynamics of antibiotics in intensive care]. / Pharmakokinetik und Pharmakodynamik von Antibiotika in der Intensivmedizin.

Optimized dosage regimens of antibiotics have remained obscure since their introduction. During the last two decades pharmacokinetic(PK)-pharmacodynamic(PD) relationships, originally established in animal experiments, have been increasingly used in patients. The action of betalactams is believed to be governed by the time the plasma concentration is above the minimum inhibitory concentration (MIC). Aminoglycosides act as planned when the peak concentration is a multiple of the MIC and vancomycin seems to work best when the area under the plasma vs. time curve (AUC) to MIC has a certain ratio. Clinicians should be aware that these relationships can only be an indication in which direction dosing should go. Larger studies with sufficiently high numbers of patients and particularly severely sick patients are needed to prove the concepts. In times where all antibiotics can be measured with new technologies, the introduction of therapeutic drug monitoring (TDM) is suggested for ICUs (Intensive Care Unit). The idea of a central lab for TDM of antibiotics such as PEAK (Paul Ehrlich Antibiotika Konzentrationsmessung) is supported.

The PF4/PPBP/CXCL5 Gene Cluster Is Associated with Periodontitis.

Periodontitis is a common dysbiotic inflammatory disease with an estimated heritability of 50%. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWAS) of chronic periodontitis (CP) have been unsuccessful in discovering susceptibility factors. A strategy that combines agnostic GWAS with a well-powered candidate-gene approach has the potential to discover novel loci. We combined RNA-seq data from gingival tissues with quantitative trait loci (QTLs) that were identified in a F2-cross of mice resistant and susceptible to infection with oral bacterial pathogens. Four genes, which were located within the mapped QTLs, showed differential expression. The chromosomal regions across the human orthologous were interrogated for putative periodontitis-associated variants using existing GWAS data from a German case-control sample of aggressive periodontitis (AgP; 651 cases, 4,001 controls), the most severe and early onset form of periodontitis. Two haplotype blocks, one upstream to the coding region of UGT2A1 (rs146712414, P = 9.1 × 10-5; odds ratio [OR], 1.34; 95% confidence interval [CI], 1.16-1.56) and one downstream of the genes PF4/PPBP/CXCL5 (rs1595009, P = 1.3 × 10-4; OR, 1.32; 95% CI, 1.15-1.52), were associated with AgP. The association of rs1595009 was validated in an independent cohort of CP of European Americans (1,961 cases and 1,864 controls; P = 0.03; OR, 1.45; 95% CI, 1.01-1.29). This association was further replicated in another sample of 399 German CP cases (disease onset <60 y of age) and 1,633 controls ( P = 0.03; OR, 1.75; 95% CI, 1.06-2.90). The combined estimates of association from all samples were P = 2.9 × 10-5 (OR, 1.2; 95% CI, 1.1-1.3). This study shows the strength of combining QTL mapping and RNA-Seq data from a mouse model with association studies in human case-control samples to identify genetic risk variants of periodontitis.

Functional activity of rat brainstem neurons regenerating axons along peripheral nerve grafts.

To investigate activation and discharge patterns of central nervous system neurons that regenerate lengthy axons along peripheral nerve grafts we inserted a 4 cm long autologous segment of sciatic nerve into the dorsolateral medulla oblongata of adult rats. Two to 6 months after grafting, the distribution of the cells of origin of the regenerating axons in many nuclei of the brainstem was documented by retrograde horseradish peroxidase labelling from the cut end of the grafts. Functional properties of neurons regenerating axons into the grafts were studied by recording from single regenerated fibers teased from the grafts. Conduction velocities of graft fibers ranged from less than 1 m/s to 25 m/s (30 degrees C). Spontaneous centrifugal impulse traffic in the grafts included units firing in bursts synchronously with the respiratory cycle. Activity in other units was either elicited or inhibited by natural or electrical stimulation of the periphery. Most units recorded in the grafts were neither spontaneously active nor responsive to stimulation of primary afferents. We conclude that: there are central nervous system neurons projecting into the grafts that respond to both excitatory and inhibitory transsynaptic influences; at least some of the spontaneous and induced activity recorded from axons in the grafts resembles that known for normal nerve cells in the regions of the brainstem from which axonal growth arises; and it is possible that many central neurons regenerating axons into peripheral nerve grafts have significantly reduced or altered synaptic inputs.

Chronic electrical stimulation of the gasserian ganglion for the relief of pain in a series of 34 patients.

The use of an implanted system for chronic electrical stimulation of the gasserian ganglion for relief of facial pain was described in 1980 by Meyerson and Håkansson. Between 1982 and 1995, the senior author (R.R.T.) performed gasserian ganglion stimulation in 34 patients for the relief of chronic medically intractable facial pain. The etiology of pain was peripheral damage to the trigeminal nerve in 22 patients (65%), central (stroke) damage in seven (21%), postherpetic neuralgia in four (12%), and unclassifiable cause in one (3%). All patients received a trial of transcutaneous stimulation (Stage 1). Successful trials in 19 patients (56%) were followed by implantation of a permanent system (Stage II). Trial and postimplantation stimulation were deemed successful when there was a reduction of pain by at least 50% whenever the stimulator was on. Success rates varied from five (71%) of seven patients for central pain to five (23%) of 22 for peripheral pain and none (0%) of four for postherpetic neuralgia. The median follow-up duration in successful cases was 22.5 months. Infections occurred in seven patients, all of whom had undergone Stage II treatment. Infections were more frequent when the stimulating electrode from Stage I was left in place for Stage II (six [43%] of 14) than when completely new hardware was used and prophylactic antibiotic drugs were administered (one [20%] of five). Other complications included iatrogenic injury to the trigeminal nerve or ganglion in three cases (9%), transient diplopia in two (6%), increased pain in two (6%), and various technical problems in 10 (29%). It is concluded that pain of central origin (stroke) is the type most likely to be relieved by this procedure. This finding is new, as the few other clinical series reported to date contain no patients with this type of pain. The risk of infection seems to be lower when completely new hardware is used for Stage II and prophylactic antibiotic drugs are administered.

Spinal synovial cyst: case report using magnetic resonance imaging.

The case of a 65-year-old woman who developed a spinal synovial cyst at the L4-5 disk space is reported. Her clinical signs and symptoms are presented. A comparison among her preoperative myelogram, computed tomography scan, and magnetic resonance imaging showed magnetic resonance imaging to be more accurate in detailing both the intraoperative and pathological findings.

Deep brain stimulation and thalamotomy for tremor compared.

Deep brain stimulation (DBS) and thalamotomy are both capable of abolishing tremor. However, no technique is perfect and if thalamotomy proves inadequate so that tremor recurs, presumably because of suboptimal lesion location, the only option is to repeat the thalamotomy. With DBS all that has been necessary to date is to change the parameters of stimulation. Similarly with complications such as the "cerebellar" ones and paraesthesiae. If these occur after thalamotomy one can only wait and hope that they will subside and they do not always do so. With DBS, changing the parameters in the authors' patients has so far been successful in eliminating them. DBS, like thalamotomy is very effective for controlling tremor in Parkinson's disease (PD) and essential tremor (ET) and for improving dexterity in ET, but both techniques are less useful for the control of dopa dyskinesia, Parkinsonian rigidity, or impaired dexterity in PD, though DBS may be better than thalamotomy for the latter condition. On the other hand, both DBS and thalamotomy are very effective in improving dexterity in PD and ET may depend upon the fact that in PD bradykinesia is a major component, whereas in ET only the tremor is. The advantages of DBS over thalamotomy have to be weighed against the peculiar risks of DBS and of course, its cost.

Interurban migration and the dynamics of a system of cities: 1. The stochastic framework with an application to the French urban system.

"A stochastic framework for the modelling of interurban migration is presented. The model is an extension of a recently developed master-equation approach to interregional migration. The population dynamics of the French urban system, described by a set of 78 cities, is investigated within the period 1954-82. The importance of synergy effects (self-reinforcing collective effects) as well as socioeconomic macrovariables for the understanding of urban dynamics becomes obvious. A forecasting of urban dynamics...[up to the year 2002 confirms] this result and [gives] further insight into the nested structure of urban systems."

[Allergic transfusion reactions in a patient with multiple food allergies]. / Allergische Transfusionsreaktionen bei einer Patientin mit multiplen Nahrungsmittelallergien.

HISTORY AND CLINICAL PRESENTATION: A 13-year-old girl with an osteosarcoma was treated by surgery and chemotherapy. During three transfusions of apheresis platelet concentrates allergic reactions occurred, partly in spite of premedication with an antihistamine and a corticoid. INVESTIGATIONS: As the patient declared to be allergic to some foods, in-vitro tests for allergen-specific IgE antibodies were performed and showed markedly positive results for specific IgE to carrot and celery, less so to hazelnut, peanut and a lot of other food antigens. The donor of one of the unsuitable platelet concentrates remembered when questioned, that he had eaten carrots and chocolate with hazelnuts during the evening before platelet donation. TREATMENT AND COURSE: Two washed platelet concentrates were transfused without any problem. Furthermore, transfusions of nine red blood cell concentrates and one unit of virus-inactivated frozen pooled plasma were well tolerated. CONCLUSION: Patients should be asked for allergies previous to transfusions to be alert to allergic reactions in patients with a positive history of food or drug allergies. If premedication with antihistamines does not prevent severe allergic transfusion reactions, transfusion of washed platelet concentrates and of virus-inactivated frozen pooled plasma can be considered.

A failure of conflict to modulate dual-stream processing may underlie the formation and maintenance of delusions.

BACKGROUND: Dual-stream information processing proposes that reasoning is composed of two interacting processes: a fast, intuitive system (Stream 1) and a slower, more logical process (Stream 2). In non-patient controls, divergence of these streams may result in the experience of conflict, modulating decision-making towards Stream 2, and initiating a more thorough examination of the available evidence. In delusional schizophrenia patients, a failure of conflict to modulate decision-making towards Stream 2 may reduce the influence of contradictory evidence, resulting in a failure to correct erroneous beliefs. METHOD: Delusional schizophrenia patients and non-patient controls completed a deductive reasoning task requiring logical validity judgments of two-part conditional statements. Half of the statements were characterized by a conflict between logical validity (Stream 2) and content believability (Stream 1). RESULTS: Patients were significantly worse than controls in determining the logical validity of both conflict and non-conflict conditional statements. This between groups difference was significantly greater for the conflict condition. CONCLUSIONS: The results are consistent with the hypothesis that delusional schizophrenia patients fail to use conflict to modulate towards Stream 2 when the two streams of reasoning arrive at incompatible judgments. This finding provides encouraging preliminary support for the Dual-Stream Modulation Failure model of delusion formation and maintenance.

Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication.

BACKGROUND: The "Lister family complex," an extensive Swedish family with autosomal dominant Parkinson disease, was first described by Henry Mjönes in 1949. On the basis of clinical, molecular, and genealogic findings on a Swedish and an American family branch, we provide genetic evidence that explains the parkinsonism in this extended pedigree. METHODS: Clinical methods included a detailed neurologic exam of the proband of the Swedish family branch, MRI, and ([123]I)-beta-CIT SPECT imaging. Genomic analysis included alpha-synuclein sequencing, SNCA real-time PCR dosage, chromosome 4q21 microsatellite analysis, and high-resolution microarray genotyping. The geographic origin and ancestral genealogy of each pedigree were researched in the medical literature and Swedish Parish records. RESULTS: The proband of the Swedish family branch presented with early dysautonomia followed by progressive parkinsonism suggestive of multiple system atrophy. Molecular analysis identified a genomic duplication of <0.9 Mb encompassing alpha-synuclein and multimerin 1 (SNCA-MMRN1), flanked by long interspersed repeat sequences (LINE L1). Microsatellite variability within the genomic interval was identical to that previously described for a Swedish American family with an alpha-synuclein triplication. Subsequent genealogic investigation suggested that both kindreds are ancestrally related to the Lister family complex. CONCLUSION: Our findings extend clinical, genetic, and genealogical research on the Lister family complex. The genetic basis for familial parkinsonism is an SNCA-MMRN11 multiplication, but whereas SNCA-MMRN1 duplication in the Swedish proband (Branch J) leads to late-onset autonomic dysfunction and parkinsonism, SNCA-MMRN1 triplication in the Swedish American family (Branch I) leads to early-onset Parkinson disease and dementia.

A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa.

Presented is a pedigree with infancy-onset benign hereditary chorea (BHC) caused by a novel nonsense mutation in exon 3 (523G-->T, E175X) of the TITF-1 (Nkx2.1) gene. Four confirmed mutation carriers showed the typical movement disorder of BHC and congenital hypothyroidism. Surprisingly, treatment with levodopa improved gait dramatically and reduced chorea in two patients. Dopaminergic drugs should be considered a useful therapeutic option in BHC.

Settlement formation. Part I: a dynamic theory.

"The dynamic process of settlement formation is a fundamental issue in regional science. Our proposed model integrates the economic and migratory sectors in terms of endogenous variables in order to describe the evolution of continuous population distributions as a self-organising process.... The purpose...is to show that under strongly idealised conditions, a population consisting of different subpopulations with different economic activities will evolve into a differentiated population pattern. Each member of the subpopulations has the possibility to migrate between locations stimulated by rational economic reasons. This idea, which seems almost self-evident on the level of qualitative argumentation, [will] be cast into a mathematically self-contained quantitative dynamic model."