The potential of a mindfulness-enhanced, integrative neuropsychotherapy program for treating fatigue following stroke: A preliminary Study

Fatigue is a frequently reported symptom after a stroke. Although the phenomenology of poststroke fatigue is well known, clear definitions as well as diagnostic and therapeutic guidelines are missing. Poststroke fatigue can be regarded as a multidimensional phenomenon that might be influenced by neurological, physical, psychological, and cognitive factors. It can range from mild to severe and can affect every area of the activities of daily life. The objective of our preliminary study was to outline aspects of a specific treatment program for the management of poststroke fatigue. Eight patients were recruited for a mindfulness-enhanced, integrative neuropsychotherapy program. The treatment was a combination of neuropsychological interventions, psychoeducation, cognitive-behavioral therapy, and mindfulness techniques. The main treatment foci were (a) to facilitate an increased awareness of fatigue symptoms, (b) to help the patient detect and manage triggers of fatigue, and (c) to equip the patient with multiple self-help tools. Measures were assessed at the beginning, during, and at the end of treatment using self-assessment questionnaire for mental fatigue and related symptoms after neurological disorders and injuries. Significant pre- to post-assessment differences were observed. These findings suggest that patients may benefit from a specific treatment program in order to better adapt to poststroke fatigue. These findings encourage further investigation of this integrative treatment in larger samples that include adequate control treatments.

Trauerverarbeitung und Anpassung nach einem Schlaganfall

Ein Schlaganfall ist einer der häufigsten Gründe für den Erwerb einer Behinderung im Erwachsenenalter. Die Anpassung an ein Leben mit dauerhaften Einschränkungen und Veränderungen in wichtigen Lebensbereichen stellt große Anforderungen an die Betroffenen. Viele Patienten entwickeln in der Folge depressive Symptome, die Teil einer Anpassungsstörung sein können. Anhand eines Fallbeispiels beschreiben wir die Anwendung einer integrativen Neuro-Psychotherapie. Integrative Neuro-Psychotherapie steht für die koordinierte Anwendung sowohl psychotherapeutischer als auch neuropsychologischer Interventionen. Ein Schwerpunkt stellt dabei eine auf die spezifischen Themen von Patienten nach einem Schlaganfall zugeschnittene Trauerarbeit, welche Betroffene in ihrem Anpassungsprozess an ein Leben mit Einschränkungen unterstützen soll.

Characterization of a novel CYP19A1 (aromatase) R192H mutation causing virilization of a 46,XX newborn, undervirilization of the 46,XY brother, but no virilization of the mother during pregnancies.

BACKGROUND P450 aromatase (CYP19A1) is essential for the biosynthesis of estrogens from androgen precursors. Mutations in the coding region of CYP19A1 lead to autosomal recessive aromatase deficiency. To date over 20 subjects have been reported with aromatase deficiency which may manifest during fetal life with maternal virilization and virilization of the external genitalia of a female fetus due to low aromatase activity in the steroid metabolizing fetal-placental unit and thus high androgen levels. During infancy, girls often have ovarian cysts and thereafter fail to enter puberty showing signs of variable degree of androgen excess. Moreover, impact on growth, skeletal maturation and other metabolic parameters is seen in both sexes. OBJECTIVE AND HYPOTHESIS We found a novel homozygous CYP19A1 mutation in a 46,XX girl who was born at term to consanguineous parents. Although the mother did not virilize during pregnancy, the baby was found to have a complex genital anomaly at birth (enlarged genital tubercle, fusion of labioscrotal folds) with elevated androgens at birth, normalizing thereafter. Presence of 46,XX karyotype and female internal genital organs (uterus, vagina) together with biochemical findings and follow-up showing regression of clitoral hypertrophy, as well as elevated FSH suggested aromatase deficiency. Interestingly, her older brother presented with mild hypospadias and bilateral cryptorchidism and was found to carry the same homozygous CYP19A1 mutation. To confirm the clinical diagnosis, genetic, functional and computational studies were performed. METHODS AND RESULTS Genetic analysis revealed a homozygous R192H mutation in the CYP19A1 gene. This novel mutation was characterized for its enzymatic activity (Km, Vmax) in a cell model and found to have markedly reduced catalytic activity when compared to wild-type aromatase; thus explaining the phenotype. Computational studies suggest that R192H disrupts the substrate access channel in CYP19A1 that may affect binding of substrates and exit of catalytic products. CONCLUSION R192H is a novel CYP19A1 mutation which causes a severe phenotype of aromatase deficiency in a 46,XX newborn and maybe hypospadias and cryptorchidism in a 46,XY, but no maternal androgen excess during pregnancy.

Fibrinolysis for patients with intermediate-risk pulmonary embolism

BACKGROUND The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Determination of Δ9-tetrahydrocannabinolic acid A (Δ9-THCA-A) in whole blood and plasma by LC–MS/MS and application in authentic samples from drivers suspected of driving under the influence of cannabis

Delta-9-tetrahydrocannabinolic acid A (THCA-A) is the biosynthetic precursor of delta-9-tetrahydrocannabinol (THC) in cannabis plants, and has no psychotropic effects. THCA-A can be detected in blood and urine, and several metabolites have been identified. THCA-A was also shown to be incorporated in hair by side stream smoke to a minor extent, but incorporation via blood stream or sweat seems unlikely. The detection of THCA-A in biological fluids may serve as a marker for differentiating between the intake of prescribed THC medication – containing only pure THC – and cannabis products containing THC besides THC-acid A and other cannabinoids. However, the knowledge about its usefulness in forensic cases is very limited. The aim of the present work was the development of a reliable method for THCA-A determination in human blood or plasma using LC–MS/MS and application to cases of driving under the influence of drugs. Fifty eight (58) authentic whole blood and the respective plasma samples were collected from drivers suspected of driving under the influence of cannabis from the region of Bern (Switzerland). Samples were first tested for THC, 11-OH-THC and THC-COOH, and then additionally for THCA-A. For this purpose, the existing LC–MS/MS method was modified and validated, and found to be selective and linear over a range of 1.0 to 200 ng/mL (the correlation coefficients were above 0.9980 in all validation runs). Limit of detection (LOD) and limit of quantification (LOQ) were 0.3 ng/mL and 1.0 ng/mL respectively. Intra- and inter-assay accuracy were equal or better than 90% and intra- and inter-assay precision were equal or better than 11.1%. The mean extraction efficiencies were satisfactory being equal or higher than 85.4%. THCA-A was stable in whole blood samples after 3 freeze/thaw cycles and storage at 4 °C for 7 days. Re-injection (autosampler) stability was also satisfactory. THC was present in all blood samples with levels ranging from 0.7 to 51 ng/mL. THCA-A concentrations ranged from 1.0 to 496 ng/mL in blood samples and from 1.4 to 824 ng/mL in plasma samples. The plasma:blood partition coefficient had a mean value of 1.7 (±0.21, SD). No correlation was found between the degree of intoxication or impairment stated in the police protocols or reports of medical examinations and the detected THCA-A-concentration in blood.

Negative density dependence of seed dispersal and seedling recruitment in a Neotropical palm

Negative density dependence (NDD) of recruitment is pervasive in tropical tree species. We tested the hypotheses that seed dispersal is NDD, due to intraspecific competition for dispersers, and that this contributes to NDD of recruitment. We compared dispersal in the palm Attalea butyracea across a wide range of population density on Barro Colorado Island in Panama and assessed its consequences for seed distributions. We found that frugivore visitation, seed removal and dispersal distance all declined with population density of A. butyracea, demonstrating NDD of seed dispersal due to competition for dispersers. Furthermore, as population density increased, the distances of seeds from the nearest adult decreased, conspecific seed crowding increased and seedling recruitment success decreased, all patterns expected under poorer dispersal. Unexpectedly, however, our analyses showed that NDD of dispersal did not contribute substantially to these changes in the quality of the seed distribution; patterns with population density were dominated by effects due solely to increasing adult and seed density.

Local and general anaesthesia do not influence outcome of transfemoral aortic valve implantation.

BACKGROUND There is great variability for the type of anaesthesia used during TAVI, with no clear consensus coming from comparative studies or guidelines. We sought to detect regional differences in the anaesthetic management of patients undergoing transcatheter aortic valve implantation (TAVI) in Europe and to evaluate the relationship between type of anaesthesia and in-hospital and 1year outcome. METHODS Between January 2011 and May 2012 the Sentinel European TAVI Pilot Registry enrolled 2807 patients treated via a transfemoral approach using either local (LA-group, 1095 patients, 39%) or general anaesthesia (GA-group, 1712 patients, 61%). RESULTS A wide variation in LA use was evident amongst the 10 participating countries. The use of LA has increased over time (from a mean of 37.5% of procedures in the first year, to 57% in last 6months, p<0.01). MI, major stroke as well as in-hospital death rate (7.0% LA vs 5.3% GA, p=0.053) had a similar incidence between groups, confirmed in multivariate regression analysis after adjusting for confounders. Dividing our population in tertiles according to the Log-EuroSCORE we found similar mortality under LA, whilst mortality was higher in the highest risk tertile under GA. Survival at 1year, compared by Kaplan-Meier analysis, was similar between groups (log-rank: p=0.1505). CONCLUSIONS Selection of anaesthesia appears to be more influenced by national practice and operator preference than patient characteristics. In the absence of an observed difference in outcomes for either approach, there is no compelling argument to suggest that operators and centres should change their anaesthetic practice.

Drei Legenden

von Martin Buber ; H. H. Cohn ; Ch. Z. Klötzel

FGFR3 expression in primary invasive bladder cancers and matched lymph node metastases

PURPOSE FGFR3 is considered a good therapeutic target for bladder cancer. However, to our knowledge it is unknown whether the FGFR3 status of primary tumors is a surrogate for related metastases, which must be targeted by FGFR targeted systemic therapies. We assessed FGFR3 protein expression in primary bladder tumors and matched nodal metastases. MATERIALS AND METHODS We examined matched primary tumor and nodal metastases from 150 patients with bladder cancer clinically staged as N0M0. Four samples per patient were incorporated into a tissue microarray and FGFR3 expression was assessed by immunohistochemistry. FGFR3 expression was tested for an association with categorical clinical data using the Fisher exact test, and with overall and recurrence-free survival by Kaplan-Meier analysis. RESULTS Duplicate spots from primary tumors and lymph node metastases were highly concordant (OR 8.6 and 16.7, respectively, each p <0.001). Overall FGFR protein expression levels did not differ between primary and metastatic lesions (p = 0.78). Up-regulated expression was recorded in 53 of 106 evaluable primary tumor spots and 56 matched metastases. Concordance of FGFR3 expression levels in 79 matched primary tumor and metastasis specimens was high (OR 8.45, p <0.001). In 15 and 12 patients expression was up-regulated in only metastasis and in only the primary tumor, respectively. Overall and recurrence-free survival was not related to FGFR3 expression. CONCLUSIONS FGFR3 expression in matched primary and metastasized bladder cancer specimens showed good but not absolute concordance. Thus, in most patients primary tumor FGFR3 status can guide the selection of FGFR targeted therapy.

Repeated electrical stimulations as a tool to evoke temporal summation of nociceptive inputs in healthy, non-medicated experimental sheep.

The nociceptive withdrawal reflex (NWR) model is used in animal pain research to quantify nociception. The aim of this study was to evaluate the NWR evoked by repeated stimulations in healthy, non-medicated standing sheep. Repeated electrical stimulations were applied at 5Hz for 2s to the digital nerves of the right thoracic and the pelvic limbs of 25 standing sheep. The stimulation intensities applied were fractions (0.5, 0.6, 0.7, 0.8, 0.9 and 1) of the individual previously determined nociceptive threshold (It) after single stimulation. Surface-electromyographic activity (EMG) was recorded from the deltoid, the femoral biceps or the peroneus tertius muscles. The repeated stimulation threshold (RS It) was reached if at least one stimulus in the train was followed by a reflex with a minimal root-mean-square-amplitude (RMSA) of 20μV. The behavioural reaction following each series of stimulations was scored on a scale from 0 (no reaction) to 5 (vigorous whole-body reaction). For the deltoid muscle, RS It was 2.3mA (1.6-3mA) with a reaction score of 2 (1-2) and at a fraction of 0.6 (0.5-0.8)×It. For the biceps femoris muscle, RS It was 2.9mA (2.6-4mA) with a reaction score of 1 (1-2) at a fraction of and 0.55 (0.4-0.7)×It while for the peroneus tertius muscle RS It was 3mA (2.8-3.5mA) with a reaction score of 1 (1-2) and at a fraction of 0.8 (0.8-0.95)×It. Both, RMSA and reaction scores increased significantly with increasing stimulation intensities in all muscles (p<0.001). The repeated application of electrical stimuli led to temporal summation of nociceptive inputs and therefore a reduction of the stimulus intensity evoking a withdrawal reaction in healthy, standing sheep. Data achieved in this study can now serve as reference for further clinical or experimental applications of the model in this species.