Preparation of monopodal and bipodal aluminum surface species by selective protonolysis of highly reactive [AlH3(NMe2Et)] on silica.

The synthesis and characterization of silica-grafted monopodal and bipodal aluminum hydrides has been achieved starting from 200 °C- and 700 °C-annealed silica and [AlH3(NMe2Et)]. The mechanism by which aluminum trishydride reacts with isolated and vicinal silanols, assisted by the amine, has been investigated computationally at the ωB97XD-DFT level.

KCa3.1 (IK) modulates pancreatic cancer cell migration, invasion and proliferation: anomalous effects on TRAM-34.

In the recent decades, ion channels became the focus of cancer biologists, as many channels are overexpressed in tumour tissue and functionally they are linked to abnormal cell behaviour with processes including apoptosis, chemo- and radioresistance, proliferation and migration. KCa3.1 is a Ca2+-activated K+ channel that plays a central role in tumour progression in many cancer types. Therefore, the aim of the present study was to investigate KCa3.1 expression in pancreatic cancer cells and assess possible implications to disease progression. Using qPCR technique, we found abundant expression of KCa3.1 in pancreatic cancer cell lines. Patch clamp measurements on MiaPaCa-2 cells revealed a Ca2+-activated K+ current that matched biophysical characteristics as described for KCa3.1. Moreover, the current was sensitive to the commonly used channel modulators TRAM-34, clotrimazole and DC-EBIO, and it was abolished following transient gene knockdown of KCa3.1. We utilized both pharmacology and RNAi to assess a possible role of the channel in tumour cell behaviour. We found that the channel supported MiaPaCa-2 cell proliferation. Using RNAi protocols, we also identified KCa3.1 as important entity in cell invasion. However, TRAM-34 had unexpected stimulatory effects on cell migration and invasion estimated in various assays. Moreover, TRAM-34 increased intracellular Ca2+. In conclusion, we found prominent functional expression of KCa3.1 in pancreatic cancer cells. We provide evidence that the channel has a key role in cell proliferation and for the first time identify KCa3.1 as important entity in PDAC cell migration. We further reveal anomalous effects of TRAM-34.

[Personnel resources for psychiatric institutions. Needs assessment exemplified by the nursing profession in Germany]. / Personalressourcen für psychiatrische Einrichtungen. Bedarfsermittlung am Beispiel der Pflegefachberufe in Deutschland.

BACKGROUND: The Psychiatry Personnel Act (Psych-PV) as the basis for personnel assessment in psychiatry becomes invalid on 1 January 2019. Because the Psych-PV previously coupled the personnel quota with the intensity of services provided, current efforts are required to develop an instrument to adapt the extent of financed personnel resources to the manifold new legal requirements and advances in treatment in terms of guideline-based care. OBJECTIVES: Based on a literature search and the additional use of a databank of routine data, an example of a calculation was made to estimate the additional personnel resources which would be necessary for psychoeducation and fulfill the legal requirements from 2019 onwards. An investigation was also carried out to identify which psychiatry guidelines contain time values which can be used for calculation of personnel requirements. MATERIAL AND METHODS: A three-step approach was used: (1) screening of the current guidelines and determination of the average intervention times with respect to nursing staff, (2) exemplary comparison between the times for guideline-based psychoeducation for patients in the diagnosis groups F32-F33 with the times allocated by the Psych-PV and (3) determination of times between education measures prescribed by law and necessary training for which no (sufficient) time contingents are provided in the Psych-PV. RESULTS: Times for individual activities (e.g. psychoeducation), which are also appropriate for nursing personnel can be found in the primary literature on guidelines; however, these include only a small proportion of tasks undertaken by nursing personnel. For psychoeducation it could be shown that additional time contingents would be necessary in the Psych-PV. Furthermore, there are new mandatory but disregarded schooling measures and instructions for nursing staff, the duration of which can be conservatively calculated as 21 min per case per hospital stay. CONCLUSION: The empirical approach presented in this study shows the possibility to identify time resources needed for nursing personnel to provide guideline-based interventions; however, these represent only partial aspects of nursing activities. Further research and analytical methods are needed to calculate the currently needed personnel resources for all nursing activities and other professional groups involved in treatment in inpatient psychiatry.

ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC).

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst survival rates of all cancers. ANO1 (TMEM16A) is a recently identified Ca(2+)-activated Cl(-) channel (CaCC) that is upregulated in several tumors. Although ANO1 was subject to extensive studies in the recent years, its pathophysiological function has only been poorly understood. The aim of the present study is to establish the significance of ANO1 in PDAC behavior and demarcate its roles in PDAC from those of the volume-regulated anion channel (VRAC). We performed qPCR and Western blot measurements on different PDAC cell lines (Panc-1, Mia PaCa 2, Capan-1, AsPC-1, BxPC-3) and compared the results to those obtained in a human pancreatic ductal epithelium (HPDE) cell line. All cancer cell lines showed an upregulation of ANO1 on mRNA and protein levels. Whole-cell patch-clamp recordings identified large Ca(2+) and voltage-dependent Cl(-) currents in PDAC cells. Using siRNA knockdown of ANO1 and three ANO1 inhibitors (T16Ainh-A01, CaCCinh-A01, and NS3728), we found that ANO1 is the main constituent of CaCC current in PDAC cells. We further characterized these three inhibitors and found that they had unspecific effects on the free intracellular calcium concentration. Functional studies on PDAC behavior showed that surprisingly inhibition of ANO1 did not influence cellular proliferation. On the other hand, we found ANO1 channel to be pivotal in PDAC cell migration as assessed in wound healing experiments.

Individual differences in laughter perception reveal roles for mentalizing and sensorimotor systems in the evaluation of emotional authenticity.

Humans express laughter differently depending on the context: polite titters of agreement are very different from explosions of mirth. Using functional MRI, we explored the neural responses during passive listening to authentic amusement laughter and controlled, voluntary laughter. We found greater activity in anterior medial prefrontal cortex (amPFC) to the deliberate, Emitted Laughs, suggesting an obligatory attempt to determine others' mental states when laughter is perceived as less genuine. In contrast, passive perception of authentic Evoked Laughs was associated with greater activity in bilateral superior temporal gyri. An individual differences analysis found that greater accuracy on a post hoc test of authenticity judgments of laughter predicted the magnitude of passive listening responses to laughter in amPFC, as well as several regions in sensorimotor cortex (in line with simulation accounts of emotion perception). These medial prefrontal and sensorimotor sites showed enhanced positive connectivity with cortical and subcortical regions during listening to involuntary laughter, indicating a complex set of interacting systems supporting the automatic emotional evaluation of heard vocalizations.

Early assessment of minimal residual disease in AML by flow cytometry during aplasia identifies patients at increased risk of relapse.

In acute myeloid leukemia (AML), assessment of minimal residual disease (MRD) by flow cytometry (flow MRD) after induction and consolidation therapy has been shown to provide independent prognostic information. However, data on the value of earlier flow MRD assessment are lacking. Therefore, the value of flow MRD detection was determined during aplasia in 178 patients achieving complete remission after treatment according to AMLCG (AML Cooperative Group) induction protocols. Flow MRD positivity during aplasia predicted poor outcome (5-year relapse-free survival (RFS) 16% vs 43%, P<0.001) independently from age and cytogenetic risk group (hazard ratio for MRD positivity 1.71; P=0.009). Importantly, the prognosis of patients without detectable MRD was neither impacted by morphological blast count during aplasia nor by MRD status postinduction. Early flow MRD was also evaluated in the context of existing risk factors. Flow MRD was prognostic within the intermediate cytogenetic risk group (5-year RFS 15% vs 37%, P=0.016) as well as for patients with normal karyotype and NPM1 mutations (5-year RFS 13% vs 49%, P=0.02) or FLT3-ITD (3-year RFS rates 9% vs 44%, P=0.016). Early flow MRD assessment can improve current risk stratification approaches by prediction of RFS in AML and might facilitate adaptation of postremission therapy for patients at high risk of relapse.

The role of TMEM16A (ANO1) and TMEM16F (ANO6) in cell migration.

Members of the TMEM16 family have recently been described as Ca(2+)-activated Cl(-) channels. They have been implicated in cancer and appear to be associated with poor patient prognosis. Here, we investigate the role of TMEM16 channels in cell migration, which is largely unknown. We focused on TMEM16A and TMEM16F channels that have the highest expression of TMEM16 channels in Ehrlich Lettre ascites (ELA) cells. Due to the lack of specific pharmacological modulators, we employed a miRNA approach and stably knocked down the expression of TMEM16A and TMEM16F channels, respectively. Migration analysis shows that TMEM16A KD clones are affected in their directional migration, whereas TMEM16F KD clones show a 40 % reduced rate of cell migration. Moreover, TMEM16A KD clones have a smaller projected cell area, and they are rounder than TMEM16F KD clones. The morphological changes are linearly correlated with the directionality of cells. TMEM16A and TMEM16F, thus, have an important function in cell migration-TMEM16A in directional migration, TMEM16F in determination of the speed of migration. We conclude that TMEM16A and TMEM16F channels have a distinct impact on the steering and motor mechanisms of migrating ELA cells.

Measuring the effects of alexithymia on perception of emotional vocalizations in autistic spectrum disorder and typical development.

BACKGROUND: The results from recent studies suggest that alexithymia, a disorder characterized by impairments in understanding personal experiences of emotion, is frequently co-morbid with autism spectrum disorder (ASD). However, the extent that alexithymia is associated with primary deficits in recognizing external emotional cues, characteristic in ASD, has yet to be determined. METHOD: Twenty high-functioning adults with ASD and 20 age- and intelligence-matched typical controls categorized vocal and verbal expressions of emotion and completed an alexithymia assessment. RESULTS: Emotion recognition scores in the ASD group were significantly poorer than in the control group and performance was influenced by the severity of alexithymia and the psycho-acoustic complexity of the presented stimuli. For controls, the effect of complexity was significantly smaller than for the ASD group, although the association between total emotion recognition scores and alexithymia was still strong. CONCLUSIONS: Higher levels of alexithymia in the ASD group accounted for some, but not all, of the group difference in emotion recognition ability. However, alexithymia was insufficient to explain the different sensitivities of the two groups to the effects of psycho-acoustic complexity on performance. The results showing strong associations between emotion recognition and alexithymia scores in controls suggest a potential explanation for variability in emotion recognition in non-clinical populations.

[Therapy-refractory thrombocytopenia in a 28-year-old patient]. / Therapierefraktäre Thrombozytopenie bei einem 28-jährigen Patienten.

We report a case of a patient with thrombocytopenia. A sporadic MYH9-associated disease, May Hegglin anomaly, was identified by giant platelets, leucocyte inclusion bodies and the typical distribution of NMMHC-IIA in granulocytes in the absence of impaired renal function, cataract and hearing loss. MYH9-associated diseases are an underestimated differential diagnosis of idiopathic thrombocytopenia. The correct diagnosis is important to prevent unnecessary treatment of a patient with thrombocytopenia and to provide sufficient patient information and genetic counseling. Therefore, careful examination of the blood smear has to be the first diagnostic step in a case of unexplained thrombocytopenia.

New aspects of an anti-tumour drug: sorafenib efficiently inhibits HCV replication.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and is associated with significant morbidity and mortality. Since there is evidence for an interaction of NS5A with c-Raf we studied whether the c-Raf inhibitor sorafenib affects HCV replication. METHODS: HCV replicating HuH7.5 cells were treated with sorafenib and examined for HCV RNA titres by northern blotting or real time polymerase chain reaction (PCR), for core, NS3 and NS5A expression by immunostaining, and for replication by luciferase reporter assays. RESULTS: Here we demonstrate that in cells replicating infectious HCV particles, NS5A recruits c-Raf to the replicon complex resulting in the activation of c-Raf. Therefore, we studied the effect of inhibition of c-Raf on HCV replication using the anti-tumour drug sorafenib that is known to inhibit c-Raf with high specificity. Sorafenib efficiently blocks HCV replication and viral gene expression. In addition, in HCV-replicating cells sorafenib decreased the hyperphosphorylated form of NS5A and resulted in the formation of additional hypophosphorylated forms. Further, sorafenib caused a rapid dissociation of lipid droplets. We provide evidence that the antiviral effect of sorafenib indeed is caused by inhibition of c-Raf. By contrast, inhibition of targets downstream of c-Raf or inhibition of tyrosine kinases by sunitinib did not affect HCV replication. CONCLUSION: Our data demonstrate that the well-characterised anti-tumour drug sorafenib efficiently blocks HCV replication in vitro. This novel effect of sorafenib should be further explored as an antiviral strategy for patients with chronic HCV infection.

[Nonsymptomatic leukocytosis]. / Leukozytose ohne weitere Symptome. Im Zweifelsfall ein Differenzialblutbild.

Leukocytosis is a condition often met with in the clinical and ambulatory setting. Although it is usually caused by an increase in the numbers of neutrophilic granulocytes, an increase in other leukocytes populations may also account for leukocytosis. Etiologically, both primary pathological conditions affecting the white blood cells, such as various forms of leukemia and lymphomas, and also rare genetic disorders must be considered. Decidedly more common, however, are reactive changes caused by infections, cigarette smoking, chronic inflammation, necrotic tissue or certain drugs. Although moderate leukocytosis in the absence of a clinical correlate and/or an apparent trigger, requires no diagnostic clarification, it should be kept under observation. If the etiology is uncertain, or a treatment-requiring disorder is suspected, the differential blood count is at the focus of the further diagnostic work-up. Depending upon the findings, this is supplemented by additional laboratory parameters, bone marrow examination, microbiological investigations and imaging procedures. Leukostasis resulting from vasoocclusion in the presence of very high numbers of leukocytes represents an emergency situation, and is an indication for leukapheresis.

Sensor fault diagnosis based on energy balance evaluation: application to a metal processing.

This paper deals with the design of a residual generator for fault detection and isolation in the dynamic closed-loop systems based on the balance of energy which "enters" and "leaves" plants. The main contribution of this paper consists in developing a suitable fault detection and isolation technique to detect faults in single-input single-output closed-loop system based on major signals without the requirement of an accurate static or dynamic model. Indeed, in the absence of conventional input-output models, the proposed method involves the on-line energy balance evaluation to detect a sensor fault. The application to the monitoring of a galvanizing line in steel industry shows the effectiveness of the suggested approach when a sensor fault occurs.

Long-term effects of vasopressin on the subcellular localization of ENaC in the renal collecting system.

Previous studies revealed that chronic (days) vasopressin treatment stimulates amiloride-sensitive sodium transport in isolated renal cortical collecting ducts and increases the abundance of beta- and gamma-subunits of the epithelial sodium channel (ENaC) in the kidney. The aim of the present work was to investigate in vivo the cellular basis of these effects. The long-term effect of V2 vasopressin agonist (1-deamino-8-D-arginine vasopressin (dDAVP)) on the abundance and subcellular localization of ENaC along the rat renal collecting system was determined by immunohistochemistry and laser confocal microscopy. Moreover, we studied by real-time reverse transcriptase-polymerase chain reaction the effect of vasopressin on proteins implicated in the regulation of ENaC (Nedd4-2, prostasin, Sgk1). After 5 days of administration, dDAVP markedly increased the intracellular pool of the beta- and gamma-ENaC subunits in the principal cells, with an increasing gradient from connecting tubule to the outer medullary collecting duct, but did not increase any subunit at the cell surface. The apical immunostaining of ENaC increased in response to sodium restriction, as expected, but dDAVP did not further enhance this apical labelling. dDAVP increased the gene expression of prostasin in the cortex but not that of Nedd4-2 and Sgk1. These findings suggest that the previously reported increase in sodium transport induced by sustained stimulation of vasopressin V2 receptor is probably mediated by other mechanism than an increase in the apical density of ENaC.

Association between reported use of inhaled triamcinolone and differential short-term responses to aerosolized albuterol in asthmatics in an emergency department setting.

Forty-four adult patients with acute asthma were treated with albuterol at a rate of 15 mg/h over 2 h. Analysis of covariance showed a significantly higher baseline adjusted mean for both percent predicted forced expiratory volume in 1 s (PFEV1) (p = 0.045) and percent predicted forced vital capacity (PFVC) (p = 0.022) at 50 and 110 min for the patients who reported triamcinolone use. Although heart rates decreased overall during the first hour of albuterol treatment, a rise in mean heart rate occurred during the second hour of treatment only in patients reporting triamcinolone use (p = 0.005). After accounting for the effects of parenteral corticosteroids, the effect of reported triamcinolone use remained significant. These data suggest that use of inhaled corticosteroids in this context may be associated with enhanced local and systemic beta-responsiveness, and if a causal relationship could be confirmed, this may constitute yet another advantage of early inhaled corticosteroid treatment in asthma. These data also suggest that chronotropic effects of high-dose albuterol should be monitored in patients using inhaled triamcinolone.

Continuous versus intermittent albuterol nebulization in the treatment of acute asthma.

STUDY OBJECTIVES: To compare bronchodilation, chronotropic effects, and side effects of the same dose of nebulized albuterol when given by either intermittent or continuous administration. DESIGN: A randomized assignment of patients to one of the two methods of albuterol nebulization. SETTING: Adult emergency department in an urban public hospital. TYPE OF PARTICIPANTS: Adult patients with acute exacerbations of asthma. INTERVENTIONS: Administration of 30 mg albuterol given over 110 minutes by either continuous or intermittent aerosolization. MEASUREMENTS: FEV1, forced vital capacity, heart rate, and systolic and diastolic blood pressures were measured immediately before treatment and then hourly for two hours. Side effects, symptoms, subsequent admission, and discharge also were noted. MAIN RESULTS: An overall significant decrease in heart rate was observed, indicating the lack of significant chronotropic effects with this dose of albuterol. Both treatments resulted in significant spirometric improvement without a significant treatment difference for the entire group. A difference, however, was found in the relative rates of FEV1 improvement with the two treatments depending on whether patients had an initial FEV1 less than or more than 50% predicted (P = .05). A secondary analysis on patients with an initial FEV1 less than percent predicted demonstrated a higher rate of percent predicted FEV1 increase with the continuously nebulized albuterol group (P = .03). CONCLUSION: This study demonstrates that albuterol can be given safely at this dose by either intermittent or continuous nebulization. Future studies should examine whether continuous nebulization has a reproducible advantage over intermittent nebulization in patients with more severe obstruction.

Acquired traumatic pulmonary arteriovenous fistula: case report.

Post-traumatic pulmonary arteriovenous fistula, a rare entity, was treated in a 35-year-old HIV-positive man by transcatheter embolization. When seen 4 months later, the patient had florid Pneumocystis carinii pneumonia. Generally, pulmonary angiography demonstrates such fistulae when they are not visible on chest roentgenograms. This diagnosis should be considered in patients with penetrating chest trauma when suggestive clinical or radiologic signs are present.

Hypersensitivity to common indoor aeroallergens in asthmatic patients.

To study whether inhalant allergy to specific allergens is associated with inner city asthma, adult emergency room asthmatic patients (n = 41), and controls (n = 34) were examined for immediate hypersensitivity to six common indoor allergens using both skin tests and serologic tests. A highly significant association was observed between cat epidermis-specific IgE and asthma (P < .01) and this constituted the strongest association for a single allergen. The pooled variable of IgE to cat and/or dog epidermis had an even stronger disease association (P < .001). The presence of IgE to other allergens and the presence of two or more positive IgE tests did not enhance this association. After inclusion of three other significant covariates (elevated serum total IgE, longer duration of residence in the New York City area, and family history of atopic disease) in a logistic prediction model for asthma, skin test-detected IgE to cat and/or dog remained significantly associated with asthma (odds ratio 8.4, P = .019). A higher proportion of asthmatic patients had both IgE to cat and/or dog allergen and ongoing historical exposure to pets and/or rodents compared with controls (P < .005). Skin testing in general distinguished asthmatic patients better than serologic tests. These results suggest that inner city asthma in adults during a nonpeak pollen period is associated with hypersensitivity to specific indoor allergens. The potential to use environmental control to ameliorate disease in such patients may have significant health care implications.

Dyslexia in the workplace: Implications of the Americans with disabilities act.

The Americans with Disabilities Act of 1990 (ADA) insures greater accessibility of disabled persons to the workplace. This includes persons with dyslexia and other learning disabilities. The ADA requires reasonable accommodations for persons with disabilities, yet it is different in its mandates from many other federal laws addressing disability-related issues.This article reviews some of the critical provisions of the ADA as it applies to persons with dyslexia, outlines a procedure through which the employer and employee negotiate accommodations, and offers examples of typical workplace problems and corresponding modifications. Finally, some of the talents and strengths often associated with dyslexia are described, as is their potential value in the workplace.