16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Screening for complex healing processes and psychological intervention in injured individuals

Introduction Injured individuals face a high risk for the development of psychological symptoms such as depression or anxiety, which influences early return to work after an accident. So far, it is unclear to which extent early psychological interventions can improve the ability to return to work. Purpose of the study The aim of the study was to investigate whether an improvement of the treatment-triage (by the screening questionnaire work and health [FAB]) influences early return to work and well being in injured individuals. Methods The study sample consists of injured individuals with different mental health-related or work-related disabilities after an accident. Participants are included eight weeks after an accident. Participants are randomly assigned to the intervention or to the control group. The intervention is an individualized psychotherapy consisting of cognitive-behavioral therapy and work related topics in an individual setting. Well being and work related actors are assessed at baseline and after six months. Results The recruitment is still ongoing. The preliminary results of this randomized controlled study will be presented at the conference. Conclusion An individualized psychotherapy might have the potential to improve the rehabilitation process in injured individuals and improve the ability to return to work.

Psychological intervention in injured individuals

Aim: Injured individuals face a high risk for the development of psychological symptoms such as depression or anxiety, which influences early return to work after an accident. So far, it is unclear to which extent early psychological interventions can improve the ability to return to work. The aim of the study was to investigate whether an improvement of the treatment‐triage influences early return to work and well being in injured individuals. Method: The study sample consists of injured individuals with different mental health-related or work-related disabilities after an accident. Participants are included eight weeks after an accident. Participants are randomly assigned to the intervention or to the control group. The intervention is an individualized psychotherapy consisting of cognitive‐behavioral therapy and work related topics in an individual setting. Wellbeing and work related factors are assessed at baseline and after six months. Result: The recruitment is still ongoing. The preliminary results of this randomized controlled study will be presented at the conference. Discussion: An individualized psychotherapy might have the potential to improve the rehabilitation process in injured individuals and improve the ability to return to work.

Controlled assembly and single electron charging of monolayer protected Au 144 clusters: an electrochemistry and scanning tunneling spectroscopy study

Single gold particles may serve as room temperature single electron memory units because of their size dependent electronic level spacing. Here, we present a proof-of-concept study by electrochemically controlled scanning probe experiments performed on tailor-made Au particles of narrow dispersity. In particular, the charge transport characteristics through chemically synthesized hexane-1-thiol and 4-pyridylbenzene-1-thiol mixed monolayer protected Au144 clusters (MPCs) by differential pulse voltammetry (DPV) and electrochemical scanning tunneling spectroscopy (EC-STS) are reported. The pyridyl groups exposed by the Au-MPCs enable their immobilization on Pt(111) substrates. By varying the humidity during their deposition, samples coated by stacks of compact monolayers of Au-MPCs or decorated with individual, laterally separated Au-MPCs are obtained. DPV experiments with stacked monolayers of Au144-MPCs and EC-STS experiments with laterally separated individual Au144-MPCs are performed both in aqueous and ionic liquid electrolytes. Lower capacitance values were observed for individual clusters compared to ensemble clusters. This trend remains the same irrespective of the composition of the electrolyte surrounding the Au144-MPC. However, the resolution of the energy level spacing of the single clusters is strongly affected by the proximity of neighboring particles.

Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib

The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 × 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 × 10(9)/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier:00055874).

Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV

The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874

Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV

PURPOSE Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival. PATIENTS AND METHODS Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival. RESULTS Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression. CONCLUSION MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.

Physiologie und Musik in ihrer Bedeutung für die Grammatik, besonders die hebräische : eine akademische Rede. Mit drei physikal. Abb. u. e. musikal. Beil.

von Franz Delitzsch

Die Tötung Ungläubiger nach talmudisch-rabbinischen Recht

quellenmäßig dargest. von Gustaf Marx [d.i. Gustaf Herman Dalman]

Attributional styles and stress-related atherogenic plasma lipid reactivity in essential hypertension.

OBJECTIVE Hypertension and an atherogenic lipid profile are known risk factors for coronary heart disease (CHD). Hypertensives show greater changes in atherogenic plasma lipids to acute stress than normotensives. In this study, we investigated whether attribution of failure is associated with lipid stress reactivity in hypertensive compared with normotensive men. METHODS 18 normotensive and 17 hypertensive men (mean±SEM; 45±2.2 years) underwent an acute standardized psychosocial stress task that can be viewed as a situation of experimentally induced failure. We assessed external-stable (ES), external-variable (EV), internal-stable (IS), and internal-variable (IV) attribution of failure and psychological control variables (i.e. extent of depression and neuroticism). Moreover, total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and norepinephrine were measured immediately before and several times after stress. RESULTS ES moderated TC- and LDL-C-stress reactivity in hypertensives as compared to normotensives (interaction mean arterial pressure [MAP]-by-ES for TC: F=3.71, p=.015; for LDL-C: F=3.61, p=.016). TC and LDL-C levels were highest in hypertensives with low ES immediately after stress (p≤.039). In contrast, hypertensives with high ES did not differ from normotensives in TC and LDL-C immediately after stress (p's>.28). Controlling for norepinephrine, depression, and neuroticism in addition to age and BMI did not significantly change results. There were no significant associations between lipid baseline levels or aggregated lipid secretion and IS, IV, or EV (p's>.23). CONCLUSION Our data suggest that ES may independently protect from elevated lipid stress reactivity in hypertensive individuals. ES thus might be a protective factor against CHD in hypertension.

Norepinephrine infusion with and without alpha-adrenergic blockade by phentolamine increases salivary alpha amylase in healthy men

BACKGROUND: Mental stress reliably induces increases in salivary alpha amylase (sAA), a suggested surrogate marker for sympathetic nervous system (SNS) reactivity. While stress-induced sAA increases correlate with norepinephrine (NE) secretion, a potential mediating role of noradrenergic mechanisms remains unclear. In this study, we investigated for the first time in humans whether a NE-stress-reactivity mimicking NE-infusion with and without alpha-adrenergic blockade by phentolamine would induce changes in sAA. METHODS: In a single-blind placebo-controlled within-subjects design, 21 healthy men (29-66 years) took part in three different experimental trials varying in terms of substance infusion with a 1-min first infusion followed by a 15-min second infusion: saline-infusion (trial-1), NE-infusion (5 μg/min) without alpha-adrenergic blockade (trial-2), and with phentolamine-induced non-selective blockade of alpha1- and alpha2-adrenergic receptors (trial-3). Saliva samples were collected immediately before, during, and several times after substance infusion in addition to blood pressure and heart rate readings. RESULTS: Experimental trials significantly differed in sAA reactivity to substance-infusion (p=.001) with higher sAA reactivity following NE-infusion with (trial-3; p=.001) and without alpha-adrenergic-blockade (trial-2; p=.004) as compared to placebo-infusion (trial-1); sAA infusion reactivity did not differ between trial-2 and trial-3 (p=.29). Effective phentolamine application was verified by blood pressure and heart rate infusion reactivity. Salivary cortisol was not affected by NE, either with or without alpha-adrenergic-blockade. CONCLUSIONS: We found that NE-infusion stimulates sAA secretion, regardless of co-administered non-selective alpha-adrenergic blockade by phentolamine, suggesting that the mechanism underlying stress-induced sAA increases may involve NE.