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.

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.

[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.

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.

[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.

Profile identification of disease-associated humoral antigens using AMIDA, a novel proteomics-based technology.

We describe AMIDA (autoantibody-mediated identification of antigens), a novel target identification technology based on the immunoprecipitation of disease-specific antigens by autologous serum antibodies followed by two-dimensional electrophoretic separation, and their identification via mass spectrometry. Twenty-seven potential carcinoma antigens were identified including proteins of hitherto unknown function. Validation of one of the identified antigens, cytokeratin 8, revealed its de novo expression in hyperplastic tissue, gradual overexpression with increasing malignancy, and ectopic localization on the cell surface. Furthermore, a strong prevalence of CK8-specific antibodies occurred in the serum of cancer patients already at early disease stages. In situ hybridization for one marker of unknown function, KIAA1273/TOB3, demonstrated its strong overexpression in head and neck carcinomas, thus making it a likely tumor antigen candidate. Eventually, AMIDA could foster significant improvements for the diagnosis and therapy of human diseases eliciting a humoral immune response, and allows for the rapid identification of new target molecules.

[Medical informatics in obstetrics and gynecology - the actual challenge?]. / Was sind die aktuellen Aufgaben? - Medizinische Informatik in der Frauenheilkunde.

There is common agreement about the importance of information management systems in obstetrics and gynecology. Those systems are necessary tools for medical quality management and are essential for the actual preparation for the age of the "diagnosis related groups" that will be introduced in Germany next year. Nevertheless there are only small scientifically activities to improve information management systems and to evaluate their performance. Great efforts are necessary to develop new features and not to loose the conflict between the needs of the physicians and their patients and the needs and demands of hospital administrative authorities.

Tumor necrosis factor alpha negatively regulates the expression of the carcinoma-associated antigen epithelial cell adhesion molecule.

BACKGROUND: The epithelial cell adhesion molecule (EpCAM) is a homophilic and Ca2+ independent adhesion molecule that is expressed de novo in squamous cell carcinoma (SCC) but is absent in the majority of healthy squamous epithelia. EpCAM expression correlates with cell proliferation and dedifferentiation along with a progression in tumorigenicity. To date, nothing is known about the molecular mechanisms responsible for the regulation of the EpCAM gene. METHODS: The authors analyzed the regulation of a fragment of the EpCAM promoter. RESULTS: The analyzed fragment has significant activity in EpCAM positive cells, and it is regulated negatively by tumor necrosis factor alpha (TNFalpha). This negative regulation results in diminished mRNA expression and in the down-regulation of EpCAM protein at the cell surface in SCC cells. Both effects can be mimicked by the treatment of cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). TNFalpha-induced inhibition of the EpCAM expression is mediated by TNF receptor 1 through the TNF receptor-associated death domain protein (TRADD) and by the activation of nuclear factor kappaB (NF-kappaB), and it can be blocked by dominant-negative variants of TRADD and the NF-kappaB inhibitor, IkappaB. The authors provide further evidence that NF-kappaB represses EpCAM expression by competing for the transcriptional coactivator p300/CREB binding protein (p300/CBP). CONCLUSIONS: The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects.

Total body and regional bone mineral densitometry (BMD) and soft tissue measurements: correlations of BMD parameter to lumbar spine and hip.

Bone loss in men and women seems to differ according to the skeletal regions or particular areas being evaluated. Dual energy X-ray absorptiometry (DXA) is the method of choice for measuring total body and regional bone mineral area density (BMD). The aim of the study was to evaluate the importance of DXA measurements of total body in relation to lumbar spine and hip in different scan beam designs. In 300 patients, ages 43-80 years, lumbar spine, hip, total body and regional bone mineral area density, and soft tissue measurements were performed on all subjects in the supine position on a QDR 2000 using single beam (SB) and fan beam (FB). Short-term precision errors were 0.7% (SB) and 1.2% (FB) for BMD total of the total body and between 1.2% and 8.0% for soft tissue measurements. All mid-term precision errors of BMD total, right and left leg, and pelvis were below 2.0% with SB and FB, whereas precision errors of thoracic and lumbar spine varied depending on the scan mode being applied. In contrast, all mid-term precision errors of soft tissue measurements were greater (2.6-11.0%). All SB values of BMD and soft tissue measurement were significantly higher than FB values, except for BMD values of the head, thoracic spine, and pelvis. Furthermore, BMD total of the total body scan correlated significantly (P < 0. 001) with all subregional parameters with best "r"-values (0.86-0. 92) for the right and left leg in SB and FB design. In addition, there were excellent correlations (r > 0.94, P < 0.001) between the right and left legs (SB and FB) or arms (SB). There were also highly significant correlations between the lumbar spine (or hip) and total body, being best for the subregional thorax. Our data demonstrate short-and mid-term precision errors of BMD with reproducible results for most areas in SB and FB design, whereas soft tissue measurements vary depending on the area being measured. Furthermore, there is a close relationship between BMD values of total body total and subregional parameters and lumbar spine and hip scans, respectively.

Placement of deep brain stimulators into the subthalamic nucleus.

We present our technique for deep brain stimulation (DBS) of the subthalamic nucleus (STN) and include information which may be helpful in general DBS. With the patient in a stereotactic head frame, the anterior and posterior commissures are identified on SPGR-sequence magnetic resonance imaging (MRI). STN coordinates are based on a stereotactic brain atlas at 12 mm lateral, 2 mm posterior and 5 mm caudal to the midcommissural point. Surgical navigation software allows for planning of the trajectory. Electromyography is used to quantitatively measure tremor responses to macrostimulation. Permanent lead placement is confirmed with intraoperative fluoroscopy and postoperative MRI.

Vocal tremor reduction with deep brain stimulation.

We present a case illustration of the significant effect that deep brain stimulation (DBS) of the thalamus can have on vocal tremor. A 72-year-old female with a history of essential tremor was noted preoperatively to have a moderate vocal tremor (3 on a scale of 1-5). Following bilateral DBS of the thalamus, the vocal tremor rating improved to 1. Acoustic analysis demonstrated her vocal tremor to be affecting the amplitude of her voice at 5.58 Hz preoperatively, at 1. 93 Hz postoperatively with both leads on and at 1.54 Hz with only the left lead on. A videotaped endoscopic view of the patient's vocal cords (presented at the 1999 ASSFN meeting) clearly illustrated the dramatic changes apparent in the vocal tremor when the stimulators were turned on and off.

Inhibition of voluntary activity by thalamic stimulation in humans: relevance for the control of tremor.

The motor effects of stimuli delivered through four-channel, quadripolar macroelectrodes chronically implanted in the ventrolateral thalamus were studied in 20 awake cooperating human subjects. Single stimuli could inhibit voluntary contraction of the contralateral first dorsal interosseous muscle (FDI) for up to 200 ms. The inhibition was often followed by a rebound facilitation or by oscillatory activity. This inhibition appeared to arise from the ventrolateral thalamus and could not be obtained in other patients by stimulation of the periventricular grey matter (PVG), the globus pallidus internus (GPI), or the subthalamic nucleus (STN). The neural elements activated by the stimulus had a short chronaxie and a short refractory period, implying that they were large-diameter axons. Similar effects were obtained from each of the four electrodes in the row, suggesting that this fiber system lay parallel rather than perpendicular to the implanted macroelectrode. The inhibition resulting from a single stimulus was diminished by a prior stimulus or train of stimuli. A continuous train of stimuli produced inhibition for only the first 200 ms. We propose that the thalamic stimulus activates a neural network which includes thalamic relay cells and neurons of the thalamic reticular nucleus and that the inhibition of thalamic relay cells habituates with repeated stimuli. It has been suggested that parkinsonian rest tremor results from synchronization of the oscillatory activity of this network. If this is the case, continuous thalamic stimulation might disrupt this oscillation by diminishing the inhibitory phase.