[Catheterization of the subclavian vein and the risk of pneumothorax : Mechanical ventilation increases the risk of pneumothorax during infraclavicular landmark-guided subclavian vein puncture: a prospective randomized study]. / Vena-subclavia-Katheter und Pneumothoraxrisiko : Maschinelle Beatmung erhöht das Pneumothoraxrisiko während infraklavikulärer landmarkengestützter V.­subclavia-Punktion: eine prospektive randomisierte Studie.

BACKGROUND: Infraclavicular subclavian vein (SCV) catheterization is a standard procedure in anesthesia and intensive care. There is a lack of evidence on how mechanical ventilation during venipuncture of the SCV influences pneumothorax rates. OBJECTIVE: Primary hypothesis: non-inferiority of continuing vs. discontinuing mechanical ventilation during infraclavicular puncture of the SCV with respect to the pneumothorax rate. MATERIAL AND METHODS: This prospective, randomized and single-blinded study was approved by the local ethics committee. A total of 1021 eligible patients who underwent cranial neurosurgery in 2 different university hospitals were assessed between August 2014 and October 2017. Patients were randomly assigned to two groups directly before induction of anesthesia. Intervention groups for venipuncture of the SCV were mechanical ventilation: tidal volume 7 ml/kg ideal body weight, positive end expiratory pressure (PEEP) ideal body weight/10, n = 535, or apnea: manual/spontaneous, APL valve 0 mbar, n = 486. Patients and the physicians who assessed pneumothorax rates were blinded to the intervention group. Venipuncture was carried out by both inexperienced and experienced physicians. RESULTS: The pneumothorax rate was significantly higher in the mechanical ventilation group (2.2% vs. 0.4%; p = 0.012) with an odds ratio (OR) of 5.63 (95% confidence interval, CI: 1.17-27.2; p = 0.031). A lower body mass index (BMI) was associated with a higher pneumothorax rate, OR 0.89 (95% CI: 0.70-0.96; p = 0.013). CONCLUSION: In this study landmark-guided infraclavicular SCV catheterization was associated with a significantly higher rate of pneumothorax when venipuncture was performed during mechanical ventilation and not in apnea. If a short phase of apnea is justifiable in the patient, mechanical ventilation should be discontinued during the venipuncture procedure.

[Do residents and nurses communicate safety relevant concerns? : simulation study on the influence of the authority gradient]. / Äußern assistenzärzte und pflegekräfte sicherheitsrelevante bedenken? : simulatorstudie zum einfluss des "autoritätsgradienten"

BACKGROUND: Due to the negative impact on decision-making too steep authority gradients in teams represent a risk factor for patient safety. As residents and nursing staff may fear sanctions they may be reluctant to forward critical information to or challenge planned actions of attending physicians. In the setting of a simulation course it was investigated whether and to what extent team members would challenge decisions of familiar attending physicians. In each case where participants did not voice an opinion the underlying motives for the behavior were investigated. METHODS: A total of 59 physicians and 18 nursing staff participated in the scenario. During a rapid sequence induction they were confronted with 7 critical situations created by the attending physician who had been instructed by the simulation team. Recommendations of the German Society of Anaesthesiology were ignored as well as clinical standard operating procedures (SOPs) and two potentially fatal drug administrations were ordered. An attempt was made to determine whether team members were aware of the safety threat at all and if so how they would solve the resulting conflicts. The level of verbal challenge was scored. During debriefing participants were asked to verbalize the motives which they thought might account for their silence or level of challenge. RESULTS: In situations where non-verbal conflict resolution was possible 65% of the participants pursued that strategy whereas 35% voiced an opinion. Situations necessitating verbal intervention were identified in 66% but 72% of the participants chose to remain silent. Team members decided to challenge the attending physician in only 28% of the situations. In 35% their statement was oblique, in 25% the problem was addressed but not further pursued and only in 40% did participants show crisp advocacy and assertiveness and initiated discussion. Asked why they had refrained from challenging the attending physician 37% had no answer, in 35% of situations participants observed a discrepancy between their own knowledge and the intended course of action yet they decided not to address the problem, 12% explained their behavior with the perceived authority of the attending physician and 8% stated that in their opinion attending physicians violated SOPs on a daily basis. None of the participants had the feeling that the simulation setting had provoked a response different to what they might have done in everyday life. CONCLUSIONS: The authority gradient can have a major negative impact on perioperative patient care. Residents and nursing staff are seldom able to challenge the attending physicians when patient safety is at risk. However, even attending physicians who normally accept feedback and criticism from team members can fail to receive support.

Phorbol ester-mediated suppression of cytochrome P450 Cyp1a-1 induction in murine skin: involvement of protein kinase C.

Epidermal 7-ethoxyresorufin O-deethylase (EROD) activity was elevated greater than 100-fold within 4 to 7 h of topical treatment of SENCAR mice with 100 nmol dibenz[a,c]anthracene (DB[a,c]A). Treatment of skin with 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) 2 to 8 h prior to DB[a,c]A application suppressed induction by 80%. Suppression was dose-dependent over the range of 0.01 to 5 micrograms TPA (ID50 approximately 0.6 nmol). EROD activities in normal and TPA-treated epidermis paralleled steady state P450 CYP1A1 mRNA content. Analogs of TPA incapable of activating or down-regulating protein kinase C (PKC) did not suppress induction. Pretreatment of skin with sn-1,2-didecanoylglycerol, an activator of PKC which causes translocation but no down-regulation, did not suppress EROD induction. However, induction was suppressed by chrysarobin, an anthralin analog that causes PKC down-regulation in the absence of prior activation. These studies suggest that PKC participates in the processes associated with Cyp1a-1 induction and that TPA effects Cyp1a-1 induction through its down-regulation of PKC.

Differential expression of basal and hydrocarbon-induced cytochrome P-450 monooxygenase and quinone reductase activities in subpopulations of murine epidermal cells differing in their stages of differentiation.

The activities of NAD(P)H-dependent quinone reductase (QR) and the cytochrome P-450 monooxygenases 7-ethoxycoumarin O-deethylase (7-ECD) and 7-ethoxyresorufin O-deethylase (7-ERD) were measured in four subpopulations of murine epidermal keratinocytes (MKs) that differed in their stages of differentiation. Noninduced per cell 7-ECD and 7-ERD activities were the lowest in basal cell MKs and progressively increased as the MKs underwent differentiation. In contrast, noninduced per cell QR activities in the three less differentiated MK subpopulations were very similar to one another and greater than the activities measured in the most differentiated subpopulation. Treatment of dorsal skin with 100 nmol of dibenz[a,c]anthracene (DB[a,c]A) increased CYPIA1 mRNA abundance and elevated 7-ERD activities to similar per cell levels in all MK subpopulations. This was achieved by differential inductions (200- to greater than or equal to 1850-fold) of 7-ERD in the different subpopulations. In contrast, QR induction by DB[a,c]A was similar (less than 3-fold) in all MK subpopulations. Consequently, the expressions of noninduced QR and 7-ERD activities in skin are regulated as a function of MK differentiation. However, the distributions of the noninduced activities of these two enzymes in MK subpopulations are the exact opposite. Furthermore, the relative inducibility of 7-ERD, but not QR, in skin is also regulated as a function of epidermal differentiation.

Short and long term effects of cytoskeleton-disrupting drugs on cytochrome P450 Cyp1a-1 induction in murine hepatoma 1c1c7 cells: suppression by the microtubule inhibitor nocodazole.

Cultured murine hepatoma 1c1c7 cells were treated with either the actin filament-disrupting drug cytochalasin D or the microtubule inhibitors colchicine and nocadazole (NOC) to assess the role of the cytoskeleton in the process of cytochrome P450 Cyp1a-1 induction. Indirect fluorescence analyses demonstrated that microtubule or actin networks were disrupted within 1 hr of treatment and remained altered as long as cultures were maintained in the presence of the drugs. Treatment of cultures with cytochalasin D, colchicine, or NOC for 1 hr before the addition of dibenz[a,c]anthracene had no effect of Cyp1a-1 induction, as monitored by measurements of CYP1A1 mRNA. Pretreatment with NOC for > or = 18 hr produced populations of cells that had either a flat or rounded morphology. Both populations, when isolated 20-24 hr after NOC treatment, were arrested in the G2/M phase of the cell cycle (83-98% in G2/M versus approximately 7-10% in nontreated or solvent-treated cultures). Cyp1a-1 induction was suppressed in both of these populations, as monitored by measurement of CYP1A1 mRNA content (reductions of > 68%), 7-ethoxyresorufin O-deethylase activity (reductions of > 80%), or microsomal CYP1A1 protein content (reductions of > 80%). In contrast, overall [3H]leucine incorporation into protein was not affected. Cytosol prepared from these NOC-treated cultures bound approximately 39% of the radiolabeled 2,3,7,8-tetrachlorodibenzo-p-dioxin bound by cytosol isolated from solvent-treated cultures. Nuclear extracts prepared from cultures treated with NOC for 20-24 hr before in vivo exposure to inducer and cytoplasmic extracts isolated from similarly NOC-treated cultures that were exposed to inducer in vitro demonstrated reductions of > or = 54% and > or = 55%, respectively, in their abilities to bind to DNA, when analyzed by gel retardation analyses using an oligonucleotide corresponding to dioxin-responsive element D of the Cyp1a-1 gene. These studies suggest that ligand-dependent induction of Cyp1a-1 transcription is unaffected by short term disruption of the microfilament or microtubule network. However, long term exposure to microtubule inhibitors causes cells to pause in the G2/M stage of the cell cycle and modulates processes involved in the induction of Cyp1a-1 in these cells.

Suppression of cytochrome P450 Cyp1a-1 induction in murine hepatoma 1c1c7 cells by 12-O-tetradecanoylphorbol-13-acetate and inhibitors of protein kinase C.

Treatment of murine hepatoma 1c1c7 cultures with dibenz[a,c]anthracene (DB[a,c]A)-induced P450 Cyp1a-1, as indicated by analyses of CYP1A1 mRNA and 7-ethoxyresorufin O-deethylase (EROD) activity. Pretreatment of cultures with 12-O-tetradecanoylphorbol-13-acetate (TPA) for as short as 1 h reduced protein kinase C (PKC) activity and resulted in a temporary suppression of EROD induction. The dose-response curves defining the TPA-dependent suppression of EROD induction and PKC down-regulation were very similar, as were the initial kinetics of PKC loss and the times of TPA pretreatment required for suppression of EROD induction. The effects of TPA could not be mimicked by 4 alpha-TPA, an analog incapable of activating and down-regulating PKC. Pretreatment of cultures with the protein kinase inhibitors staurosporine, calphostin C, or H7 resulted in dose-dependent suppressions of EROD induction. However, the suppressive and cytotoxic effects of these agents could be separated from one another in the case of only H7. HA1004, an analog of H7 that inhibits the same spectrum of protein kinases as H7 except for PKC, did not inhibit DB[a,c]A induction of EROD. Pretreatment of cultures with H7, but not HA1004, suppressed the accumulation of CYP1A1 mRNA that normally occurred following treatment with DB[a,c]A. Collectively, these studies suggest that PKC plays a role in the processes involved in the induction of Cyp1a-1.

Expression of the aryl hydrocarbon receptor (AhR) and the aryl hydrocarbon receptor nuclear translocator (ARNT) in fetal, benign hyperplastic, and malignant prostate.

BACKGROUND: Androgen-dependent tissue has been reported to be affected by chemical ligands of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, which heterodimerizes with the aryl hydrocarbon receptor nuclear translocator protein (ARNT). METHODS: Fetal (n = 3), benign hyperplastic (BPH) (n = 10), and carcinomatous (CaP) (n = 19) prostate tissues were analyzed using immunohistochemistry. Western blot analysis was used to confirm the identity of the recognized proteins. RESULTS: Immunoblotting of enriched prostatic epithelial cells (EC) and stromal cells revealed constitutive expression of bands at around 110 kDa and 90 kDa, using anti-AhR and anti-ARNT, respectively. Immunohistology of the fetal specimens revealed heterogeneous cytoplasmic and nuclear AhR expression of immature EC and mesenchymal cells. Constitutive expression of AhR (primarily cytoplasmic) and ARNT (nuclear and cytoplasmic) by the majority of adult basal and secretory EC, CaP, and smooth muscle cells was confirmed in situ. The most intense anti-AhR/-ARNT reactivity was found on smooth muscle cells, followed by EC and fibrocytes. Secretory BPH-EC revealed significantly decreased AhR expression when compared to normal tissue segments. By contrast, anti-AhR reactivity was frequently increased in the more dedifferentiated tumor areas. CONCLUSIONS: These findings suggest that an undefined physiologic AhR ligand(s) as well as environmental factors may exert effects on EC and smooth muscle cells in the prostate through binding to these receptors.