Effects of Rapid Increases of Desflurane and Sevoflurane to Concentrations of 1.5 MAC on Systemic Vascular Resistance and Catecholamine Response during Cardiopulmonary Bypass

Background: Airway irritation was hypothesized to trigger the transient cardiovascular stimulation associated with desflurane. The authors administered desflurane during cardiopulmonary bypass (CPB), thus avoiding airway contact, and compared the effects of rapid increases of desflurane to 1.5 MAC on systemic vascular resistance index (SVRI) and catecholamine response to those of 1.5 MAC sevoflurane.

Methods: Forty-eight patients, undergoing elective coronary bypass surgery, were randomly allocated to receive either desflurane or sevoflurane during hypothermic (32-33 [degree sign] Celsius) nonpulsatile CPB at exhaust gas concentrations of 1.5 MAC for 15 min. SVRI was calculated at baseline, 1, 2, 3, 4, 5, 7, 9, 12, and 15 min after starting volatile anesthetics' delivery. Plasma catecholamine concentrations were determined in 12 desflurane-treated patients and 12 sevoflurane-treated patients at baseline, 5, and 15 min.

Results: The time-course of Delta SVRI, (changes in SVRI from baseline), from baseline to 5 min was significantly different between desflurane- and sevoflurane-treated patients, whereas there was no difference from 7 to 15 min. In the desflurane group, SVRI from 1 to 7 min remained unchanged to baseline level, thereafter declining to significantly lower values at 9, 12, and 15 min compared with values from 0 to 5 min, whereas sevoflurane produced an immediate and significant reduction in SVRI. With desflurane, catecholamine concentrations remained unchanged to baseline level at 5 and 15 min; with sevoflurane, they decreased with time.     

Handling of computational in vitro/in vivo correlation problems by Microsoft Excel: IV. Generalized matrix analysis of linear compartment systems.

A linear system comprising n compartments is completely defined by the rate constants between any of the compartments and the initial condition in which compartment(s) the drug is present at the beginning. The generalized solution is the time profiles of drug amount in each compartment, described by polyexponential equations. Based on standard matrix operations, an Excel worksheet computes the rate constants and the coefficients, finally the full time profiles for a specified range of time values.     

Handling of computational in vitro/in vivo correlation problems by Microsoft Excel: III. Convolution and deconvolution.

Convolution and deconvolution are the classical in-vitro-in-vivo correlation tools to describe the relationship between input and weighting/response in a linear system, where input represents the drug release in vitro, weighting/response any body response in vivo. While functional treatment, e.g. in terms of polyexponential or Weibull distribution, is more appropriate for general survey or prediction, numerical algorithms are useful for treating actual experimental data. Deconvolution is not considered an algorithm by its own, but the inversion of a corresponding convolution. MS Excel is shown to be a useful tool for all these applications.     

The Effect of Presleep Focal Attention Load on Subsequent Sleep Patterns

The hypothesis that a load on focal attention prior to sleep results in subsequent changes in sleep patterns was investigated. Eight females and 2 males slept in the laboratory for 4 nights: 2 adaptation nights, 1 experimental night preceded by a focal attention load, and 1 control night preceded by relaxed activity. On the experimental night, time in bed, total sleep time, and stage REM sleep were significantly longer than on the control night. The results support the hypothesis and suggest that attention during REM sleep has a unique character.     

Differential vulnerability of male and female rats to the timing of various perinatal insults

The results of five experiments showed that exposure to diazepam, hypoxia and monosodium glutamate during the prenatal or early postnatal period of rapid brain development may result in different behavioral consequences depending on the timing of the exposure rather than the nature of the agent. Moreover, male and female offspring may be affected differently by the same agent at different periods of development. Prenatal insults of various kinds impair the later performance of males but not the females in a complex learning task, while postnatal insults seem to affect detrimentally this same behavior in both males and females. The effects of perinatal insults on maze learning and open field activity do not lend themselves to explanation by "feminization" or "masculinization" of behavior caused by interference with prenatal gonadal hormones.     

Short-term multiorgan metabolic benefits of rapid weight loss after sleeve gastrectomy in severely obese patients

BackgroundSleeve gastrectomy (SG) has become the most prevalent bariatric-metabolic surgical approach in the United States. Its popularity among surgeons and patients is mainly due to a better safety profile and less overall morbidity, with broad benefits from a systemic and metabolic perspective.ObjectiveComprehensively describe the short-term multiorgan metabolic effects of rapid weight loss after SG.SettingAcademic hospital, United States.MethodsWe retrospectively reviewed the charts of patients that underwent SG at our institution between 2012 and 2016. We analyzed the required variables to calculate multiple risk scores, such as cardiovascular, hypertension, and diabetes risk scores. Furthermore, the renal and hepatic functions and the metabolic and hematologic profiles were assessed at 12 months of follow-up.ResultsA total of 1002 patients were included in the analysis. The percentage of excess body mass index loss was, on average, 65% at 12 months of follow-up. We observed a positive cardio-renal-hepatic improvement, demonstrated by a substantial reduction of the 10-year cardiovascular risk. We noticed an improvement of renal function, which was more significant in chronic kidney disease (stage ≥2), and a significant improvement on liver function tests (measured by decreased aspartate aminotransferase and alanine transaminase) at 12 months of follow-up. Our data also show a positive impact on decreasing the risk of developing hypertension and type 2 diabetes. There was a positive impact on the lipid profile, with the exception of low-density lipoprotein.ConclusionThere are significant short-term benefits on multiorgan metabolic parameters after rapid weight loss in severely obese patients undergoing sleeve gastrectomy.     

Antibody mediated CDCP1 degradation as mode of action for cancer targeted therapy

CUB-domain-containing-protein-1 (CDCP1) is an integral membrane protein whose expression is up-regulated in various cancer types. Although high CDCP1 expression has been correlated with poor prognosis in lung, breast, pancreas, and renal cancer, its functional role in tumor formation or progression is incompletely understood. So far it has remained unclear, whether CDCP1 is a useful target for antibody therapy of cancer and what could be a desired mode of action for a therapeutically useful antibody. To shed light on these questions, we have investigated the cellular effects of a therapeutic antibody candidate (RG7287). In focus formation assays, prolonged RG7287 treatment prevented the loss of contact inhibition caused by co-transformation of NIH3T3 cells with CDCP1 and Src. In a xenograft study, MCF7 cells stably overexpressing CDCP1 reached the predefined tumor volume faster than the parental MCF7 cells lacking endogenous CDCP1. This tumor growth advantage was abolished by RG7287 treatment. In vitro, RG7287 induced rapid tyrosine phosphorylation of CDCP1 by Src, which was accompanied by translocation of CDCP1 to a Triton X-100 insoluble fraction of the plasma membrane. Triggering these effects required bivalency of the antibody suggesting that it involves CDCP1 dimerization or clustering. However, this initial activation of CDCP1 was only transient and prolonged RG7287 treatment induced internalization and down-regulation of CDCP1 in different cancer cell lines. Antibody stimulated CDCP1 degradation required Src activity and was proteasome dependent. Also in three different xenograft models with endogenous CDCP1 expression RG7287 treatment resulted in significant tumor growth inhibition concomitant with substantially reduced CDCP1 levels as judged by immunohistochemistry and Western blotting. Thus, despite transiently activating CDCP1 signaling, the RG7287 antibody has a therapeutically useful mode of action.     

Over-expression of IGF-related peptides in stenoses of native arteriovenous fistulas in hemodialysis patients.

INTRODUCTION: Insulin-like growth factors (IGFs) are known to play an important role in atherogenesis. The aim of our study was to assess the local expression of IGF-related peptides in stenosed hemodialysis fistulas and compare these with their respective serum levels. METHODS: We investigated 15 stenosed vein segments of primary arteriovenous fistulas, 29 non-stenosed control vein segments from uremic patients and 15 non-stenosed control saphenous vein segments. Immunohistochemistry was performed for IGF-I, insulin, IGF-binding proteins (IGFBPs)-1, -2, -3 and -4, the acid labile subunit (ALS) and type 1 IGF-receptor (IGF-R). Serum levels were measured by specific radioimmunoassays. RESULTS: Compared to both control groups, a significantly higher expression of the following IGF-related peptides was seen in the stenotic (neo)intima: IGF-I, IGFBP-1, -2, -3, -4 and IGF-R; in the stenotic media: IGF-I and IGFBP-3 and in the endothelium of stenotic fistulas: IGF-I (all p<0.05). Staining against ALS and insulin was negative in all vessels. Serum IGF-I levels did not differ. Serum levels of IGFBP-1, -2, -3 and -4 were significantly higher in patients with renal disease (all p<0.05). There were no correlations between local and systemic IGF-related peptide levels. There were correlations of neointimal expression of IGF-I, IGFBP-1, -2, -3, -4 and IGF-R with both hypercellularity and the presence of inflammatory cells (p<0.05). CONCLUSION: In the stenotic arteriovenous fistula of hemodialysis patients, expression of the peptides IGF-I, IGFBP-1, -2, -3, -4 and IGF-R was significantly increased and showed a positive correlation with neointimal inflammation and hypercellularity (all p<0.05). IGF-related peptides are most likely synthesized locally and might be involved in the initiation and/or progression of neointimal thickening of primary arteriovenous fistulas.     

Self-expandable metallic stents for malignant duodenal obstruction caused by biliary tract cancer

BACKGROUND: Malignant duodenal obstruction is a common event in patients with advanced biliary tract cancer. Because bypass surgery is accompanied by significant morbidity, self-expandable metallic stents have emerged as a possible alternative for palliation. METHODS: Twenty patients with biliary tract cancer (7 gallbladder, 13 Klatskin tumors) and duodenal obstruction were treated with metallic stents at a single institution between 1999 and 2001. Survival, morbidity, and stent function were studied prospectively. The ability to eat was assessed by using a scoring system. RESULTS: Stent placement was technically successful in all patients. An additional stent was required in 6 cases (4 occlusions, 2 dislocations). Median survival was 20.5 weeks; there was no treatment-related death. Twenty-eight biliary stent exchanges were performed in 13 (65%) patients. Erosive reflux esophagitis improved in 11 of 12 (92%) cases. After 4 weeks, all 17 surviving patients tolerated soft or solid food, whereas 13 of 17 (77%) tolerated a more solid diet (p < 0.001, gastric outlet obstruction scoring system). Twelve of 17 (71%) patients gained a median of 1.5 kg of body weight (p = 0.001). The median Karnofsky scale increased from 50% to 60% in 13 of 17 (77%) patients. CONCLUSIONS: Self-expandable metallic stents are a safe, efficacious, and minimally invasive treatment option for palliation of patients with duodenal obstruction from biliary tract cancer. Technical complications can be managed endoscopically and the bile duct remains accessible for endoluminal treatment.