Titanocene(III)-Catalyzed Precision Deuteration of Epoxides.

We describe a titanocene(III)-catalyzed deuterosilylation of epoxides that provides ß-deuterated anti-Markovnikov alcohols with excellent D-incorporation, in high yield, and often excellent diastereoselectivity after desilylation. The key to the success of the reaction is a novel activation method of Cp2 TiCl2 and (tBuC5 H4 )2 TiCl2 with BnMgBr and PhSiD3 to provide [(RC5 H4 )2 Ti(III)D] without isotope scrambling. It was developed after discovering an off-cycle scrambling with the previously described method. Our precision deuteration can be applied to the synthesis of drug precursors and highlights the power of combining radical chemistry with organometallic catalysis.

CIP2A regulates MYC translation (via its 5'UTR) in colorectal cancer.

BACKGROUND: Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that decreasing MYC expression may have significant therapeutic value. CIP2A is an oncogenic factor that regulates MYC expression. CIP2A is overexpressed in colorectal cancer (CRC), and its expression levels are an independent marker for long-term outcome of CRC. Previous studies suggested that CIP2A controls MYC protein expression on a post-transcriptional level. METHODS: To determine the mechanism by which CIP2A regulates MYC in CRC, we dissected MYC translation and stability dependent on CIP2A in CRC cell lines. RESULTS: Knockdown of CIP2A reduced MYC protein levels without influencing MYC stability in CRC cell lines. Interfering with proteasomal degradation of MYC by usage of FBXW7-deficient cells or treatment with the proteasome inhibitor MG132 did not rescue the effect of CIP2A depletion on MYC protein levels. Whereas CIP2A knockdown had marginal influence on global protein synthesis, we could demonstrate that, by using different reporter constructs and cells expressing MYC mRNA with or without flanking UTR, CIP2A regulates MYC translation. This interaction is mainly conducted by the MYC 5'UTR. CONCLUSIONS: Thus, instead of targeting MYC protein stability as reported for other tissue types before, CIP2A specifically regulates MYC mRNA translation in CRC but has only slight effects on global mRNA translation. In conclusion, we propose as novel mechanism that CIP2A regulates MYC on a translational level rather than affecting MYC protein stability in CRC.

Concentration distribution of more than 100 drugs and metabolites in forensic hair samples.

Drug testing in hair can complement conventional blood and urine analysis as it enlarges the window of detection and may allow a differentiation of heavy from moderate or rare use. Databases of drug concentrations in biological matrices are a valuable support in interpreting analytical results. In forensic toxicology, several databases exist especially for blood/serum samples. In the present paper, the concentration distributions of more than 100 legal and illegal drugs such as narcotic drugs, opioids, antidepressants, antipsychotics, benzodiazepines, and major metabolites detected in authentic Caucasian hair samples in our laboratory are summarized. Depending on availability, the proximal sections of 1-6 cm in length were analyzed by liquid chromatography/tandem mass spectrometry following extraction of the finely chopped specimens by ultrasound in methanol. The data may present a helpful basis also for other laboratories for an initial evaluation of their results. However, these statistical data should not be used uncritically without including the circumstances of the particular case and the analytical procedures used. In addition, each laboratory in charge of interpreting results from hair analysis should balance own results as far as available with this data base.

Ventilator autotriggering : An underestimated phenomenon in the determination of brain death.

BACKGROUND: Ventilator autotriggering (VAT) may induce uncertainty in diagnosing brain death because it may falsely suggest a central respiratory drive in brain-dead patients where no intrinsic respiratory efforts exist. Since the lack of international standardization of brain death criteria contributes to the loss of potential donor organs, it is important to be aware of this phenomenon, which is a not well-known confounder in the process of diagnosing brain death. METHODS: The national official recommendations or guidelines for the determination of brain death and organ transplantation of 15 selected European countries (including all 8 member states of the Eurotransplant network) were evaluated with respect to VAT. In addition, a literature search (PubMed, Google Scholar) using the term "ventilator autotriggering", synonyms or similar content-related wording was carried out. RESULTS: The VAT phenomenon was mentioned in 3 of the 15 official recommendations and guidelines on diagnosing brain death. The causes and management of VAT are presented in different ways in the reviewed official recommendations and guidelines. CONCLUSION: The phenomenon of VAT is inconsistently addressed in the national guidelines and recommendations for the determination of brain death and should, therefore, be included in future harmonized brain death codes. Detection and correction of VAT should be implemented as early as possible by a structured procedure. Additional training and information on this phenomenon should be made available to the entire intensive care unit staff.

Establishing the Feasibility of Face Transplantation in Granulomatosis With Polyangiitis.

Granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis) is a rare vasculitis that commonly starts in the craniofacial region. We report a case that was masked by prior facial trauma and associated with pyoderma gangrenosum (PG). Disease progression and aggressive debridements led to severe facial tissue loss. The decision to perform a face transplant was controversial because of the risk of disease relapse on the facial allograft. We reviewed renal transplant outcomes in GPA for possible relevance. A PubMed search retrieved 29 studies. Patient and graft survival, relapse, morbidity, mortality, rejection and immunosuppression were assessed. Ten-year patient survival and graft survival were 84.4% and 72.6%, respectively. GPA relapse occurred in 31.5%, and upper airway/ocular relapse occurred in 17.8% (resolved in 76.9%). Mortality was 12.3%. Acute and chronic rejection rates were 14.9% and 6.8%, respectively. Traditional posttransplant immunosuppression was effective. Our review suggests that GPA renal transplant outcomes are comparable to general renal transplant cohorts. Furthermore, transplanted GPA patients exhibit lower disease relapse secondary to lifelong immunosuppression. This supported our decision to perform a face transplant in this patient, which has been successful up to the present time (1-year posttransplantation). Untreated GPA and PG are potential causes of worse surgical outcomes in the craniofacial region.

Highly Active Titanocene Catalysts for Epoxide Hydrosilylation: Synthesis, Theory, Kinetics, EPR Spectroscopy.

A catalytic system for titanocene-catalyzed epoxide hydrosilylation is described. It features a straightforward preparation of titanocene hydrides that leads to a reaction with low catalyst loading, high yields, and high selectivity of radical reduction. The mechanism was studied by a suite of methods, including kinetic studies, EPR spectroscopy, and computational methods. An unusual resting state leads to the observation of an inverse rate order with respect to the epoxide.

Micro-topography influences blood platelet spreading.

Injuries in blood vessels are accompanied by disrupted endothelial cell layers. Missing or destroyed endothelial cells lead to rough, structured surfaces on the micrometer scale. The first cells to arrive at the site of injury and to cover the wound are platelets, which subsequently drive blood clot formation. Therefore, investigating the interactions of platelets with structured surfaces is essential for the understanding of blood clotting. Here, we study the effects of underlying topography on platelet spreading using microstructured model substrates with varying area fractions of protein coating. We thereby distinguish the effects of (physical) topography and of (biochemical) protein availability. By analyzing the cell area and morphology, we find that the extent of protrusion formation - but not the total spread area - is determined by the area fractions of coating. The extent of filopodia formation is influenced by the availability of binding sites and the reaction of cells to the substrate's topography. The cells react to the structured substrate by avoiding topographic holes at the cell periphery and thus adapting their outer shape. This finding leads us to the conclusion that both chemically blocked and fibrinogen-coated holes represent "energetic obstacles" to the cells. Thus, the shape of the cell is governed by the interplay between spreading to an optimized area and adaption to the substrate topography.

Remifentanil target-controlled infusion during second stage labour in high-risk parturients: a case series.

BACKGROUND: Providing adequate analgesia and appropriate sedation to high-risk parturients during late second stage labour without compromising foetal safety remains a major challenge, especially in situations when neuraxial block is not applicable. Remifentanil emerged as an option for labour analgesia during the last decade but may be suitable for the facilitation of complicated vaginal deliveries as well. METHODS: A retrospective chart review of nine labouring women with significant medical and/or obstetrical risk factors was conducted. According to the assessment of an experienced obstetrician, vaginal delivery could only be achieved with profound analgesia, and neuraxial block was not possible because of contraindications, technical failure, or shortage of time. Mode of delivery, need for neonatal resuscitation, maternal and neonatal vital parameters, drug consumption, and personnel resource expenses were recorded. RESULTS: Remifentanil target-controlled infusion (TCI) facilitated vaginal delivery in eight out of nine women. No serious adverse events were observed, but three newborns needed initial respiratory support for a few minutes. The total cost of remifentanil TCI administration to facilitate vaginal delivery compared with the estimated additional cost of an emergency caesarean section was negligible. CONCLUSION: This case series suggests that remifentanil TCI may be used to facilitate vaginal delivery in high-risk parturients when other forms of analgesia are limited. However, the small number of patients studied does not allow generalisation of the results; neither can safety concerns be dispelled yet.

[Transcranial cerebral oxymetry in interventional neuroradiology. Sources of error in interpretation of measurement data]. / Transkranielle zerebrale Oxymetrie in der interventionellen Neuroradiologie. Fehlerquellen der Dateninterpretation.

Transcranial cerebral oximetry is a non-invasive method to support the estimation of the balance in cerebral oxygen metabolism status during interventional neuroradiological procedures. The simple data acquisition can lead to errors by oversimplification in interpretation of the displayed data. To avoid fatal mistakes of the acquired data the complex interactions of the examined substrate with physiological and pathophysiological interactions have to be critically judged as well as the procedural approach and methodological limitations.

[Onset of a fulminant malignant hyperthermia crisis. Case report of a 74-year-old patient with previously subclinical central core disease]. / Erstmanifestation einer fulminanten malignen-hyperthermie-krise. Fall eines 74-jährigen patienten mit bislang subklinischer "central core disease".

Malignant hyperthermia (MH) is a latent, autosomal dominant inherited syndrome of skeletal musculature which results in excessive hypermetabolism induced by halogenated anesthetic agents and depolarizing muscle relaxants and is caused by an uncontrolled intramuscular calcium release. This case report focuses on the description of symptoms of a fulminant MH crisis. A possible link between central core disease (CCD) and the clinical severity of MH crisis is postulated in this paper.

Whole-brain diffusion tensor imaging predicts 6-month functional outcome in acute intracerebral haemorrhage.

INTRODUCTION: Small vessel disease (SVD) causes most spontaneous intracerebral haemorrhage (ICH) and is associated with widespread microstructural brain tissue disruption, which can be quantified via diffusion tensor imaging (DTI) metrics: mean diffusivity (MD) and fractional anisotropy (FA). Little is known about the impact of whole-brain microstructural alterations after SVD-related ICH. We aimed to investigate: (1) association between whole-brain DTI metrics and functional outcome after ICH; and (2) predictive ability of these metrics compared to the pre-existing ICH score. METHODS: Sixty-eight patients (38.2% lobar) were retrospectively included. We assessed whole-brain DTI metrics (obtained within 5 days after ICH) in cortical and deep grey matter and white matter. We used univariable logistic regression to assess the associations between DTI and clinical-radiological variables and poor outcome (modified Rankin Scale > 2). We determined the optimal predictive variables (via LASSO estimation) in: model 1 (DTI variables only), model 2 (DTI plus non-DTI variables), model 3 (DTI plus ICH score). Optimism-adjusted C-statistics were calculated for each model and compared (likelihood ratio test) against the ICH score. RESULTS: Deep grey matter MD (OR 1.04 [95% CI 1.01-1.07], p = 0.010) and white matter MD (OR 1.11 [95% CI 1.01-1.23], p = 0.044) were associated (univariate analysis) with poor outcome. Discrimination values for model 1 (0.67 [95% CI 0.52-0.83]), model 2 (0.71 [95% CI 0.57-0.85) and model 3 (0.66 [95% CI 0.52-0.82]) were all significantly higher than the ICH score (0.62 [95% CI 0.49-0.75]). CONCLUSION: Our exploratory study suggests that whole-brain microstructural disruption measured by DTI is associated with poor 6-month functional outcome after SVD-related ICH. Whole-brain DTI metrics performed better at predicting recovery than the existing ICH score.

ICG lymphographic findings following immediate lymphatic reconstruction in breast cancer patients.

BACKGROUND: Immediate lymphatic reconstruction (ILR), performed at the time of axillary lymph node dissection (ALND), has demonstrated promising reductions in breast cancer-associated lymphedema. However, questions remain over the effects of adjuvant therapies on the continued patency of the lymphaticovenous anastomosis. Our study aimed to assess lymphographic outcomes, including ICG pattern and LVB patency, in patients at high risk for breast cancer-associated lymphedema following axillary ILR. METHODS: Baseline ICG lymphography studies performed during ILR of 15 patients were compared to repeat ICG studies obtained during second-stage breast reconstructive procedures to assess for changes in lymphatic flow patterns through the at-risk arm and transit into the axilla. RESULTS: All 15 patients in this study demonstrated linear lymphatic flow in baseline lymphography. Repeat lymphographic studies showed linear lymphatic transit in 12/15 patients. Of these 12 patients, 10 received chemotherapy, and all 12 received post-mastectomy radiation (PMRT). Dermal backflow patterns were recorded in 3/15 patients. All 3 patients received chemotherapy and 2/3 underwent PMRT. Additionally, repeat ICG studies of 7/12 lymphedema-free patients demonstrated clear visualization of linear ICG flow from the lymphatics of the arm into the axilla. CONCLUSION: We have demonstrated that ICG lymphography can be implemented as a postoperative tool to assess lymphatic function in patients who have undergone ILR in the axilla. Repeat ICG studies in the majority of patients demonstrated linear ICG flow similar to baseline studies. Additionally, ICG flow patterns through the axilla in repeat lymphography provided visual evidence supporting sustained LVB patency, despite axillary irradiation.

Acute corticospinal tract diffusion tensor imaging predicts 6-month functional outcome after intracerebral haemorrhage.

INTRODUCTION: Diffusion tensor imaging (DTI) can assess the structural integrity of the corticospinal tract (CST) in vivo. We aimed to investigate whether CST DTI metrics after intracerebral haemorrhage (ICH) are associated with 6-month functional outcome and can improve the predictive performance of the existing ICH score. METHODS: We retrospectively included 42 patients with DTI performed within 5 days after deep supratentorial spontaneous ICH. Ipsilesional-to-contralesional ratios were calculated for fractional anisotropy (rFA) and mean diffusivity (rMD) in the pontine segment (PS) of the CST. We determined the most predictive variables for poor 6-month functional outcome [modified Rankin Scale (mRS) > 2] using the least absolute shrinkage and selection operator (LASSO) method. We calculated discrimination using optimism-adjusted estimation of the area under the curve (AUC). RESULTS: Patients with 6-month mRS > 2 had lower rFA (0.945 [± 0.139] vs 1.045 [± 0.130]; OR 0.004 [95% CI 0.00-0.77]; p = 0.04) and higher rMD (1.233 [± 0.418] vs 0.963 [± 0.211]; OR 22.5 [95% CI 1.46-519.68]; p = 0.02). Discrimination (AUC) values were: 0.76 (95% CI 0.61-0.91) for the ICH score, 0.71 (95% CI 0.54-0.89) for rFA, and 0.72 (95% CI 0.61-0.91) for rMD. Combined models with DTI and non-DTI variables offer an improvement in discrimination: for the best model, the AUC was 0.82 ([95% CI 0.68-0.95]; p = 0.15). CONCLUSION: In our exploratory study, PS-CST rFA and rMD had comparable predictive ability to the ICH score for 6-month functional outcome. Adding DTI metrics to clinical-radiological scores might improve discrimination, but this needs to be investigated in larger studies.

Experimental model of laryngotracheal stenosis in infants: effects of different high-frequency jet ventilation patterns on pulmonary parameters.

BACKGROUND: Supraglottic high-frequency jet ventilation (HFJV) in laryngotracheal surgery in infants with modified jet laryngoscopes offers the surgeon an unimpaired operating field. However, supraglottic HFJV is associated with the development of high airway pressures, inadvertent positive end-expiratory pressure (PEEP) levels, and barotrauma. METHODS: We investigated the total lung volumes (TLV) and tidal volume variations at peak inspiratory pressure levels (PIP) and at PEEP levels along with the pulmonary pressures (PIP and PEEP) during two conventional methods of supraglottic HFJV in an infant trachea-lung model without stenosis and with different degrees of stenosis. RESULTS: With augmentation of the driving pressure in the experiment without stenosis, the TLV plus the pulmonary pressures increased. With narrowing of the stenosis, TLV reduced at PIP level and increased at PEEP level. Volume shifts were significantly higher during superimposed HFJV compared with monofrequent HFJV at equivalent stenosis diameter (P < 0.05) except for the setting with 0.3 bar driving pressure (P > 0.05). The pulmonary PIP was in none of the test series higher than 20 mbar, and the pulmonary PEEP did not exceed 14 mbar. CONCLUSIONS: The results from our experimental model support the safe and effective clinical use of supraglottic HFJV in infants with tracheal stenosis. Moderate driving pressures provide acceptable pulmonary pressures in normal compliant lungs.

MRI-related anxiety can induce slow BOLD oscillations coupled with cardiac oscillations.

OBJECTIVE: Although about 1-2% of MRI examinations must be aborted due to anxiety, there is little research on how MRI-related anxiety affects BOLD signals in resting states. METHODS: We re-analyzed cardiac beat-to beat interval (RRI) and BOLD signals of 23 healthy fMRI participants in four resting states by calculation of phase-coupling in the 0.07-0.13 Hz band and determination of positive time delays (pTDs; RRI leading neural BOLD oscillations) and negative time delays (nTDs; RRI lagging behind vascular BOLD oscillations). State anxiety of each subject was assigned to either a low anxiety (LA) or a high anxiety (HA, with most participants exhibiting moderate anxiety symptoms) category based on the inside scanner assessed anxiety score. RESULTS: Although anxiety strongly differed between HA and LA categories, no significant difference was found for nTDs. In contrast, pTDs indicating neural BOLD oscillations exhibited a significant cumulation in the high anxiety category. CONCLUSIONS: Findings may suggest that vascular BOLD oscillations related to slow cerebral blood circulation are of about similar intensity during low/no and elevated anxiety. In contrast, neural BOLD oscillations, which might be associated with a central rhythm generating mechanism (pacemaker-like activity), appear to be significantly intensified during elevated anxiety. SIGNIFICANCE: The study provides evidence that fMRI-related anxiety can activate a central rhythm generating mechanism very likely located in the brain stem, associated with slow neural BOLD oscillation.

Anti-inflammatory effects of atorvastatin on peripheral blood mononuclear cells and synovial fibroblasts in rheumatoid arthritis.

OBJECTIVE: Statins, such as atorvastatin (ATV), are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known to exert lipid-lowering but also anti-inflammatory, effects. In this study, we analysed the in vitro effects of ATV on peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA), a chronic inflammatory joint disease. METHODS: PBMCs isolated from 25 RA patients and 20 healthy blood donors were stimulated in vitro with 0.1 microM ATV for 24 h. PBMC cultures were analysed for cell surface markers to characterize T-cell subtypes (CD4, CD8, CD69, HLA-DR) by flow cytometry and for T helper cell type 1 (Th1) and type 2 (Th2) cytokines [interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-10] in culture supernatants by enzyme-linked immunosorbent assay (ELISA). Furthermore, RNA isolated from ATV-stimulated RA-FLS pre- and post-ATV stimulation was analysed by microarray and quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Flow cytometric analysis of T-cell subsets revealed no significant differences for CD4, CD8, CD69, and HLA-DR surface marker expression of PBMCs in RA patients and healthy controls after ATV stimulation. However, the proportion of IFN-gamma expressing CD4+ T cells and the IFN-gamma cytokine concentrations in culture supernatants were significantly reduced in T-cell cultures from RA patients. In ATV-stimulated FLS a significant downregulation of proinflammatory cytokine (IL-6) and chemokine (IL-8) expression was detected (p<0.001). CONCLUSIONS: Our study demonstrates a marked in vitro anti-inflammatory activity of ATV in RA including a systemic effect on a pathogenic CD4+ T-cell population (Th1) and a local effect on FLS. These findings may provide a scientific rationale for statins as add-on therapy in RA.

[The authorization of clinical trials by the federal authorities]. / Das Genehmigungsverfahren klinischer Prüfungen von Arzneimitteln bei den Bundesoberbehörden.

Since 2004, clinical trials of medicinal products have to be approved by the federal authorities in Germany. Authorization is necessary in addition to the favorable opinion of the concerned ethics committee. This procedure has undoubtedly resulted in larger expenditures with respect to time and costs of planning and conducting of clinical trials. However, the implementation of Good Clinical Practice has also increased both safety for the trial subjects and validity of the data. The most important laws and regulations, definitions, the procedures for submitting a clinical trial application as well as subsequent amendments are described and further information is provided.

Search for long-term radiation trends in the environs of Swiss nuclear power plants.

Annually since 1989, biannually since 1994 the sites of the Swiss nuclear facilities are surveyed flying the same survey lines by airborne gamma ray spectrometry. The equipment and the data processing software used for those surveys were built and developed at the Institute of Geophysics, ETH Zurich. For mapping the ground radiation around the nuclear facilities, a pixel representation and a modified spectrum dose index (SDI) method are used. In the search for long-term trends, the local dose rates are calculated first and in turn the net dose rates. So far, no change in the radiation levels was detected over the last 13 years outside of the fenced sites of the nuclear facilities and, especially, no artificial radioactivity was present that could not be explained by nuclear weapon tests or by the Chernobyl event.