Ethanol-induced gastric damage in the rat: Lack of a correlation with oxygen-derived free radicals

The present study investigated the role of oxygen-derived free radicals as mediators of acute damage to rat gastric mucosae exposed to topically applied absolute ethanol. Although a hydroxyl radical scavenger, Dimethylthiourea, was noted to exhibit profound gastroprotective properties, other pretreatment regimens employing a host of known free radical scavengers, and enzyme inhibitors failed to confirm this hypothesis. Furthermore, no change in mucosal malondialdehyde, an indicator of free radical attack to cell membranes, could be detected in ethanol exposed tissues. Taken together, the present study fails to confirm that oxygen-derived free radicals mediate the gastric damaging effects of topically applied absolute ethanol. ^

Effect of continuous gastric enteral feeding on tonometric measurement of gastric intramucosal carbon dioxide levels in healthy volunteers

Purpose. The aim of this research was to evaluate the effect of enteral feeding on tonometric measurement of gastric regional carbon dioxide levels (PrCO2) in normal healthy volunteers. Design and methods. The sample included 12 healthy volunteers recruited by the University Clinical Research Center (UCRC). An air tonometry system monitored PrCO2 levels using a tonometer placed in the lumen of the stomach via orogastric intubation. PrCO2 was automatically measured and recorded every 10 minutes throughout the five hour study period. An oral dose of famotidine 40 mg was self-administered the evening prior to and the morning of the study. Instillation of Isocal® High Nitrogen (HN) was used for enteral feeding in hourly escalating doses of 0, 40, 60, and 80 ml/hr with no feeding during the fifth hour. Results . PrCO2 measurements at time 0 and 10 minutes (41.4 ± 6.5 and 41.8 ± 5.7, respectively) demonstrated biologic precision (Levene's Test statistic = 0.085, p-value 0.774). Biologic precision was lost between T130 and T140 40 when compared to baseline TO (Levene's Test statistic = 1.70, p-value 0.205; and 3.205, p-value 0.042, respectively) and returned to non-significant levels between T270 and T280 (Levene's Test statistic = 3.083, p-value 0.043; and 2.307, p-value 0.143, respectively). Isocal® HN significantly affected the biologic accuracy of PrCO2 measurements (repeated measures ANOVA F 4.91, p-value <0.001). After 20 minutes of enteral feeding at 40 ml/hr, PrCO2 significantly increased (41.4 ± 6.5 to 46.6 ± 4.25, F = 5.4, p-value 0.029). Maximum variance from baseline (41.4 ± 6.5 to 61.3 ± 15.2, F = 17.22, p-value <0.001) was noted after 30 minutes of Isocal® HN at 80 ml/hr or 210 minutes from baseline. The significant elevations in PrCO2 continued throughout the study. Sixty minutes after discontinuation of enteral feeding, PrCO2 remained significantly elevated from baseline (41.4 ± 6.5 to 51.8 ± 9.2, F = 10.15, p-value 0.004). Conclusion. Enteral feeding with Isocal® HN significantly affects the precision and accuracy of PrCO2 measurements in healthy volunteers. ^

THE ROLE OF ADRENAL AND THYROID HORMONES IN GASTRIC DEVELOPMENT (THYROXINE, PARIETAL CELL, CORTICOSTERONE)

The role of adrenal and thyroid hormones on the development of chief and parietal cells was studied in the rat. Administration of corticosterone or thyroxine in the first and second postnatal weeks resulted in the precocious appearance of pepsinogen in the oxyntic gland mucosa and an increase in basal acid output. When pups were adrenalectomized or made hypothyroid, both pepsinogen and basal acid secretion were lowed. Corticosterone injection increased pepsinogen content and acid secretion to levels higher than those of control in hypothyroid and adrenalectomized rats while thyroxine had no such effect in adrenalectomized rats. Morphologically, chief cells responded to corticosterone or thyroxine with increases in both zymogen granules and RER. Chief cells, however, contained less zymogen granules and RER in adrenalectomized and hypothyroid rats. Corticosterone was effective in restoring the normal morphological appearance of chief cells in the hypothyroid rats while thyroxine had no effect in the adrenalectomized rats. In response to corticosterone or thyroxine, parietal cells in normal animals appeared to contain more mitochondria, tubulovesicles and intracellular canaliculi than those of control. Unlike chief cells, parietal cells retained normal ultrastructure in the absence of adrenal and thyroid hormones. These data indicate that (1) corticosterone is necessary for the functional and morphological development of chief cells; (2) the morphological development of parietal cells does not appear to depend upon corticosterone, (3) the effect of thyroxine on the development of chief and parietal cells is due to corticosterone. ^

Effect of ticagrelor on the outcomes of patients with prior coronary artery bypass graft surgery: insights from the PLATelet inhibition and patient outcomes (PLATO) trial

BACKGROUND Patients with prior coronary artery bypass graft surgery (CABG) who present with an acute coronary syndrome have a high risk for recurrent events. Whether intensive antiplatelet therapy with ticagrelor might be beneficial compared with clopidogrel is unknown. In this substudy of the PLATO trial, we studied the effects of randomized treatment dependent on history of CABG. METHODS Patients participating in PLATO were classified according to whether they had undergone prior CABG. The trial's primary and secondary end points were compared using Cox proportional hazards regression. RESULTS Of the 18,613 study patients, 1,133 (6.1%) had prior CABG. Prior-CABG patients had more high-risk characteristics at study entry and a 2-fold increase in clinical events during follow-up, but less major bleeding. The primary end point (composite of cardiovascular death, myocardial infarction, and stroke) was reduced to a similar extent by ticagrelor among patients with (19.6% vs 21.4%; adjusted hazard ratio [HR], 0.91 [0.67, 1.24]) and without (9.2% vs 11.0%; adjusted HR, 0.86 [0.77, 0.96]; P(interaction) = .73) prior CABG. Major bleeding was similar with ticagrelor versus clopidogrel among patients with (8.1% vs 8.7%; adjusted HR, 0.89 [0.55, 1.47]) and without (11.8% vs 11.4%; HR, 1.08 [0.98, 1.20]; P(interaction) = .46) prior CABG. CONCLUSIONS Prior-CABG patients presenting with acute coronary syndrome are a high-risk cohort for death and recurrent cardiovascular events but have a lower risk for major bleeding. Similar to the results in no-prior-CABG patients, ticagrelor was associated with a reduction in ischemic events without an increase in major bleeding.

Climatic conditions as a risk factor in canine gastric dilatation-volvulus

Canine acute gastric dilatation-volvulus (GDV) is a life-threatening condition of multifactorial origin. The risk of developing GDV is influenced by a variety of factors, including breed, age, gender, temperament, diet and management. A relationship between seasonal variations and the frequency of GDV has been previously documented although no association was found with any specific climatic event. Variables in weather conditions within a defined geographic region were investigated in a retrospective study of 287 client-owned dogs diagnosed with GDV between 1992 and 1999. Monthly incidences were evaluated and differences in atmospheric temperature, humidity and pressure between days in which GDV cases were observed and days in which no case was presented were examined. Although temperature was significantly associated with the occurrence of GDV, the difference in temperatures between days with and days without GDV cases was so small that it is unlikely to be of clinical relevance. Moreover, no significant association was found between GDV occurrence and atmospheric pressure or humidity, and a seasonal variation in GDV incidence was not observed.

Antioxidant supplementation attenuates oxidative stress in patients undergoing coronary artery bypass graft surgery.

Ischemia-reperfusion has been reported to be associated with augmented oxidative stress in the course of surgery, which might be causally involved in the onset of atrial fibrillation (AF), the most common arrhythmia after cardiac surgery. We hypothesized that supplementation of antioxidants and n-3 polyunsaturated fatty acids (n-3 PUFAs) might lower the incidence of AF following coronary artery bypass graft (CABG) surgery. In the present study, by monitoring oxidative stress in the course of CABG surgery, we analyzed the efficacy of vitamins (ascorbic acid and α-tocopherol) and/or n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid). Subjects (n = 75) were divided into 4 subgroups: control, vitamins, n-3 PUFAs, and a combination of vitamins and n-3 PUFAs. Fluorescent techniques were used to measure the antioxidative capacity, i.e. ability to inhibit oxidation. Total peroxides, endogenous peroxidase activity, and antibodies against oxidized LDL (oLAb) were used as serum oxidative stress biomarkers. Post-operative increase in oxidative stress was associated with the consumption of antioxidants and a simultaneous onset of AF. This was confirmed through an increased peroxide level and a decreased oLAb titer in control and n-3 PUFAs groups, indicating the binding of antibodies to oxidative modified epitopes. In both subgroups that were supplemented with vitamins, total peroxides decreased, and the maintenance of a constant IgG antibody titer was facilitated. However, treatment with vitamins or n-3 PUFAs was inefficient with respect to AF onset and its duration. We conclude that the administration of vitamins attenuates post-operative oxidative stress in the course of CABG surgery.

A retrospective comparative exploratory study on two methylentetrahydrofolate reductase (MTHFR) polymorphisms in esophagogastric cancer: the A1298C MTHFR polymorphism is an independent prognostic factor only in neoadjuvantly treated gastric cancer patients.

BACKGROUND Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas. METHODS 569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression). RESULTS Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact. CONCLUSIONS The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6th or 7th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome.

Minimized extracorporeal circulation does not impair cognitive brain function after coronary artery bypass grafting

OBJECTIVES Objective evaluation of the impact of minimized extracorporeal circulation (MECC) on perioperative cognitive brain function in coronary artery bypass grafting (CABG) by electroencephalogram P300 wave event-related potentials and number connection test (NCT) as metrics of cognitive function. METHODS Cognitive brain function was assessed in 31 patients in 2013 with a mean age of 65 years [standard deviation (SD) 10] undergoing CABG by the use of MECC with P300 auditory evoked potentials (peak latencies in milliseconds) directly prior to intervention, 7 days after and 3 months later. Number connection test, serving as method of control, was performed simultaneously in all patients. RESULTS Seven days following CABG, cognitive P300 evoked potentials were comparable with preoperative baseline values [vertex (Cz) 376 (SD 11) ms vs 378 (18) ms, P = 0.39; frontal (Fz) 377 (11) vs 379 (21) ms, P = 0.53]. Cognitive brain function at 3 months was compared with baseline values [(Cz) 376 (11) ms vs 371 (14 ms) P = 0.09; (Fz) 377 (11) ms vs 371 (15) ms, P = 0.04]. Between the first postoperative measurement and 3 months later, significant improvement was observed [(Cz) 378 (18) ms vs 371 (14) ms, P = 0.03; (Fz) 379 (21) vs 371 (15) ms, P = 0.02]. Similar clearly corresponding patterns could be obtained via the number connection test. Results could be confirmed in repeated measures analysis of variance for Cz (P = 0.05) and (Fz) results (P = 0.04). CONCLUSIONS MECC does not adversely affect cognitive brain function after CABG. Additionally, these patients experience a substantial significant cognitive improvement after 3 months, evidentiary proving that the concept of MECC ensures safety and outcome in terms of brain function.

A novel blood-sparing agent in cardiac surgery? First in-patient experience with the synthetic serine protease inhibitor MDCO-2010: a phase II, randomized, double-blind, placebo-controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass

BACKGROUND Antifibrinolytics have been used for 2 decades to reduce bleeding in cardiac surgery. MDCO-2010 is a novel, synthetic, serine protease inhibitor. We describe the first experience with this drug in patients. METHODS In this phase II, double-blind, placebo-controlled study, 32 patients undergoing isolated primary coronary artery bypass grafting with cardiopulmonary bypass were randomly assigned to 1 of 5 increasing dosage groups of MDCO-2010. The primary aim was to evaluate pharmacokinetics (PK) with assessment of plasmatic concentrations of the drug, short-term safety, and tolerance of MDCO-2010. Secondary end points were influence on coagulation, chest tube drainage, and transfusion requirements. RESULTS PK analysis showed linear dosage-proportional correlation between MDCO-2010 infusion rate and PK parameters. Blood loss was significantly reduced in the 3 highest dosage groups compared with control (P = 0.002, 0.004 and 0.011, respectively). The incidence of allogeneic blood product transfusions was lower with MDCO-2010 4/24 (17%) vs 4/8 (50%) in the control group. MDCO-2010 exhibited dosage-dependent antifibrinolytic effects through suppression of D-dimer generation and inhibition of tissue plasminogen activator-induced lysis in ROTEM analysis as well as anticoagulant effects demonstrated by prolongation of activated clotting time and activated partial thromboplastin time. No systematic differences in markers of end organ function were observed among treatment groups. Three patients in the MDCO-2010 groups experienced serious adverse events. One patient experienced intraoperative thrombosis of venous grafts considered possibly related to the study drug. No reexploration for mediastinal bleeding was required, and there were no deaths. CONCLUSIONS This first-in-patient study demonstrated dosage-proportional PK for MDCO-2010 and reduction of chest tube drainage and transfusions in patients undergoing primary coronary artery bypass grafting. Antifibrinolytic and anticoagulant effects were demonstrated using various markers of coagulation. MDCO-2010 was well tolerated and showed an acceptable initial safety profile. Larger multi-institutional studies are warranted to further investigate the safety and efficacy of this compound.

Off-pump compared to minimal extracorporeal circulation surgery in coronary artery bypass grafting.

OBJECTIVE Coronary artery bypass grafting (CABG) using extracorporeal circulation (ECC) is still the gold standard. However, alternative techniques have been developed to avoid ECC and its potential adverse effects. These encompass minimal extracorporeal circulation (MECC) or off-pump coronary artery bypass grafting (OPCAB). However, the prevailing potential benefits when comparing MECC and OPCABG are not yet clearly established. METHODS In this retrospective study we investigated the potential benefits of MECC and OPCABG in 697 patients undergoing CABG. Of these, 555 patients had been operated with MECC and 142 off-pump. The primary endpoint was Troponin T level as an indicator for myocardial damage. RESULTS Study groups were not significantly different in general. However, patients undergoing OPCABG were significantly older (65.01 years ± 9.5 vs. 69.39 years ± 9.5; p value <0.001) with a higher Logistic EuroSCORE I (4.92% ± 6.5 vs. 5.88% ± 6.8; p value = 0.017). Operating off pump significantly reduced the need for intra-operative blood products (0.7% vs. 8.6%; p-value <0.001) and the length of stay in the intensive care unit (ICU) (2.04 days ± 2.63 vs. 2.76 days ± 2.79; p value <0.001). Regarding other blood values a significant difference could not be found in the adjusted calculations. The combined secondary endpoint, major cardiac or cerebrovascular events (MACCE), was equal in both groups as well. CONCLUSIONS Coronary artery bypass grafting using MECC or OPCABG are two comparable techniques with advantages for OPCABG regarding the reduced need for intra-operative blood products and shorter length of stay in the ICU. However serological values and combined endpoint MACCE did not differ significantly in both groups.

Stabilization of subcritical bypass transition in the leading-edge boundary layer by suction

This work investigates the subcritical spatial transition in the swept Hiemenz boundary layer by means of direct numerical simulations (DNS). A pair of steady co-rotating vortices located at the attachment line is enforced as a primary disturbance leading to streaks which are stable. A small secondary, time-dependent disturbance interacts with these streaks such that instability and breakdown to turbulence may occur. The instability only occurs for a certain band of secondary disturbance frequencies. Positive secondary instability growth rates could be observed for Reynolds numbers as low as , whereas the linear critical Reynolds number is. Uniform wall suction is shown to stabilise this transition mechanism, analogously to results from linear stability theory. The effects of suction on the formation of primary streaks and on the secondary growth rate are decoupled. For streaks of different suction whose amplitude is held constant by adjusting the Reynolds number, the suction is shown to increase the growth rate of the secondary instability. The stabilising influence of wall suction consists in decreasing the streak amplitude only. Depending on the Reynolds number and the suction strength, breakdown may either occur locally and may be convected along the far-field streamlines, or occur globally and cover broad regions in the downstream direction.

Prediction of Post-Weaning Fibrinogen Status during Cardiopulmonary Bypass: An Observational Study in 110 Patients.

BACKGROUND After cardiac surgery with cardiopulmonary bypass (CPB), acquired coagulopathy often leads to post-CPB bleeding. Though multifactorial in origin, this coagulopathy is often aggravated by deficient fibrinogen levels. OBJECTIVE To assess whether laboratory and thrombelastometric testing on CPB can predict plasma fibrinogen immediately after CPB weaning. PATIENTS / METHODS This prospective study in 110 patients undergoing major cardiovascular surgery at risk of post-CPB bleeding compares fibrinogen level (Clauss method) and function (fibrin-specific thrombelastometry) in order to study the predictability of their course early after termination of CPB. Linear regression analysis and receiver operating characteristics were used to determine correlations and predictive accuracy. RESULTS Quantitative estimation of post-CPB Clauss fibrinogen from on-CPB fibrinogen was feasible with small bias (+0.19 g/l), but with poor precision and a percentage of error >30%. A clinically useful alternative approach was developed by using on-CPB A10 to predict a Clauss fibrinogen range of interest instead of a discrete level. An on-CPB A10 ≤10 mm identified patients with a post-CPB Clauss fibrinogen of ≤1.5 g/l with a sensitivity of 0.99 and a positive predictive value of 0.60; it also identified those without a post-CPB Clauss fibrinogen <2.0 g/l with a specificity of 0.83. CONCLUSIONS When measured on CPB prior to weaning, a FIBTEM A10 ≤10 mm is an early alert for post-CPB fibrinogen levels below or within the substitution range (1.5-2.0 g/l) recommended in case of post-CPB coagulopathic bleeding. This helps to minimize the delay to data-based hemostatic management after weaning from CPB.