Epileptogenic actions of xanthines in relation to their affinities for adenosine A1 receptors in CA3 neurons of hippocampal slices (guinea pig)

In order to analyze the epileptogenic mechanisms of caffaine and related xanthines, putative effects of these drugs were studied on adenosine receptors of CA3 neurons in hippocampal slices. Epileptogenic concentrations of different xanthine derivatives strongly correlated with their affinities for the inhibitory A₁ adenosine receptor subtype. The A₁ receptor agonists adenosine and R-PIA reversibly depressed xanthine-induced epileptic activity without effects on the resting membrane potential or on spontaneously occuring action potentials. These findings suggest that the epileptogenic potency of xanthines is primarily due to the blockade of the A₁ receptors through an abnormal rise of intracellular cAMP and to the excessive transmembrane calcium fluxes underlying paroxysmal depolarization shifts.     

The use of three different mesh materials in the treatment of abdominal wall defects

Abstract Abstract. Various prosthetic materials have been proposed for the repair of abdominal wall defects. These materials offer tension-free repair and significantly lower recurrence rate. Their respective properties are related to such complications as seroma, infection, fistula formation, intestinal adhesions and removal. We compared the final outcome in treating abdominal wall defects in 56 patients with three different prosthetic materials: conventional polypropylene in a preperitoneal location, expanded polytetrafluoroethylene mesh, and hydrophilic membrane coated polyester mesh in an intraperitoneal location. The hydrophilic coated polyester group exhibited the lowest complication rate and the polypropylene group the highest. Electronic Publication     

Metalloproteinase expression after desflurane preconditioning in hepatectomies: A randomized clinical trial

BACKGROUNDHepatectomy with inflow occlusion results in ischemia-reperfusion injury; however, pharmacological preconditioning can prevent such injury and optimize the postoperative recovery of hepatectomized patients. The normal inflammatory response after a hepatectomy involves increased expression of metalloproteinases, which may signal pathologic hepatic tissue reformation. AIMTo investigate the effect of desflurane preconditioning on these inflammatory indices in patients with inflow occlusion undergoing hepatectomy.METHODSThis is a single-center, prospective, randomized controlled trial conducted at the 4^th Department of Surgery of the Medical School of Aristotle University of Thessaloniki, between August 2016 and December 2017. Forty-six patients were randomized to either the desflurane treatment group for pharmacological preconditioning (by replacement of propofol with desflurane, administered 30 min before induction of ischemia) or the control group for standard intravenous propofol. The primary endpoint of expression levels of matrix metalloproteinases and their inhibitors was determined preoperatively and at 30 min posthepatic reperfusion. The secondary endpoints of neutrophil infiltration, coagulation profile, activity of antithrombin III (AT III), protein C (PC), protein S and biochemical markers of liver function were determined for 5 d postoperatively and compared between the groups.RESULTSThe desflurane treatment group showed significantly increased levels of tissue inhibitor of metalloproteinases 1 and 2, significantly decreased levels of matrix metalloproteinases 2 and 9, decreased neutrophil infiltration, and less profound changes in the coagulation profile.  During the 5-d postoperative period, all patients showed significantly decreased activity of AT III, PC and protein S (vs baseline values, P < 0.05). The activity of AT III and PC differed significantly between the two groups from postoperative day 1 to postoperative day 5 (P < 0.05), showing a moderate drop in activity of AT III and PC in the desflurane treatment group and a dramatic drop in the control group. Compared to the control group, the desflurane treatment group also had significantly lower international normalized ratio values on all postoperative days (P < 0.005) and lower serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase values on postoperative days 2 and 3 (P < 0.05).   Total length of stay was significantly less in the desflurane group (P = 0.009).CONCLUSIONDesflurane preconditioning can lessen the inflammatory response related to ischemia-reperfusion injury and may shorten length of hospitalization.     

Heelkundige behandeling van morbide obesitas (extreem overgewicht)

Background and aims: The population with a BMI of 70kg/m² or greater has been described and categorized as mega-obese. Mega-obese patients weighing more than 250kg constitute a special group of mega-obese patients that present more intra-and post-operative problems than other suprasuperobese.

Material and Methods: This is a retrospective analysis of 7 mega-obese patients weighing more than 250 kg, who underwent bariatric surgery. Patients’ medical records were reviewed for length of stay, complications, co-morbidities, and weight loss.

Results: Five patients were men and 2 were women. Co-morbidities included sleep apnoea syndrome (7 patients [100%]), venous ulcers (4 patients [57.1%]), post-thrombotic venous syndrome (3 patients [42.9%]), symptomatic cholelithiasis (3 patients [42.9%]), cellulites (3 patients [42.9%]), hypertension (4 patients [57.1%]), cardiac insufficiency (3 patients [42.9%]), and diabetes mellitus (1 patient [14.3%]). The length of stay averaged 15.3 days. Three patients presented short-term complications, 2 with long-term complications. Overall weight loss was 42.8% of excess body weight 6 months after surgery and 80.8% 2 years after surgery (when follow-up was completed). Conclusions: Bariatric operations are safe and effective in the mega-obese population weighing more than 250 kg. Some minor modifications to the traditional techniques may be necessary, especially concerning equipment. Treatment of patients weighing more than 250 kg is problematic, presenting a relatively high percentage of short-and long-term complications, together with various intra-operative problems.     

Validation of the Expressions of Moral Injury Scale‐Military version‐Short Form

Military personnel may encounter morally injurious events that lead to emotional, social, and spiritual suffering that transcend and/or overlap with mental health diagnoses (e.g., post‐traumatic stress disorder [PTSD]). Advancement of scientific research and potential clinical innovation for moral injury (MI) requires a diversity of measurement approaches. Drawing on results from the bifactor model in Currier et al.'s (2017) psychometric evaluation of the Expressions of Moral Injury Scale‐Military version (EMIS‐M), this study validated a four‐item short form of the instrument with two samples of veterans with a history of war‐zone service. Namely, despite the reduced number of items, the EMIS‐M‐Short Form (SF) yielded favourable internal consistency and comparable levels of convergent validity with theoretically related constructs (e.g., PTSD and struggles with morality and ultimate meaning) as the full‐length version. Notwithstanding the possible utility of distinguishing between self‐ and other‐directed forms of MI, factor analytic results further revealed that the EMIS‐M‐SF was best conceptualized with a unidimensional factorial model that might allow for a general assessment of MI‐related outcomes. Overall, these initial results suggest that the EMIS‐M‐SF may hold promise as a short, reliable, and valid assessment of overall outcomes related to a possible MI.     

Applicability and Dosimetric Impact of Ultrasound-Based Preplanning in High-Dose-Rate Brachytherapy of Prostate Cancer

BACKGROUND AND PURPOSE: Analyses of permanent brachytherapy seed implants of the prostate have demonstrated that the use of a preplan may lead to a considerable decrease of dosimetric implant quality. The authors aimed to determine whether the same drawbacks of preplanning also apply to high-dose-rate (HDR) brachytherapy. PATIENTS AND METHODS: 15 patients who underwent two separate HDR brachytherapy implants in addition to external-beam radiation therapy for advanced prostate cancer were analyzed. A pretherapeutic transrectal ultrasound was performed in all patients to generate a preplan for the first brachytherapy implant. For the second brachytherapy, a subset of patients were treated by preplans based on the ultrasound from the first brachytherapy implant. Preplans were compared with the respective postplans assessing the following parameters: coverage index, minimum target dose, homogeneity index, and dose exposure of organs at risk. The prostate geometries (volume, width, height, length) were compared as well. RESULTS: At the first brachytherapy, the matching between the preplan and actual implant geometry was sufficient in 47% of the patients, and the preplan could be applied. The dosimetric implant quality decreased considerably: the mean coverage differed by -0.11, the mean minimum target dose by -0.15, the mean homogeneity index by -0.09. The exposure of organs at risk was not substantially altered. At the second brachytherapy, all patients could be treated by the preplan; the differences between the implant quality parameters were less pronounced. The changes of prostate geometry between preplans and postplans were considerable, the differences in volume ranging from -8.0 to 13.8 cm(3) and in dimensions (width, height, length) from -1.1 to 1.0 cm. CONCLUSION: Preplanning in HDR brachytherapy of the prostate is associated with a substantial decrease of dosimetric implant quality, when the preplan is based on a pretherapeutic ultrasound. The implant quality is less impaired in subsequent implants of fractionated brachytherapy.     

Prevention of irritant contact dermatitis.

The prevention of skin diseases is accepted as an important part of occupational dermatology. Irritant dermatitis in particular, is a skin disease which can be avoided by preventional measures. Hence, an early introduction of trainees to preventional measures seems to be necessary to avoid bad habits which then become a matter of routine. The role of the dermatologist is not only the identification of individuals with a higher risk for developing irritant dermatitis, he should also inform his patients about the relevant irritants in their occupation (or of irritants in the household or leisure activities). Prevention by collective measures must be combined with individual measures (like gloves and protective clothing, correct skin cleaning and external creams). Periodical training and motivation of individuals at most risk is of utmost importance, because the best preventive measures are of no effect when they are not used regularly.     

Food Effect Projections via Physiologically Based Pharmacokinetic Modeling: Predictive Case Studies

Food can alter the absorption of orally administered drugs. Biopharmaceutics physiologically based pharmacokinetic (PBPK) modeling offers the possibility to simulate a compound's pharmacokinetics under fasted or fed states. To advance the utility of PBPK modeling, with a view to regulatory impact, we have pooled our experience across 4 pharmaceutical companies to propose a general multistep PBPK workflow leveraging pre-existing clinical data for immediate-release formulations of Biopharmaceutics Classification System I and II compounds. With this strategy, we wish to promote pragmatic PBPK approaches for compounds where absorption is well understood, that is, compounds with moderate-to-high permeability that are not substrates for uptake transporters. Five case studies demonstrate how food effect can be well predicted using appropriately established and validated models. The case studies integrate solubility and dissolution data for initial model development and apply a “middle-out” validation with clinical data in one prandial state. Then, whenever possible, a validation against both fasted and fed state data is recommended before application of the models prospectively for to-be-marketed formulations. Thus, when combined with limited clinical data, PBPK models could be used to simulate outcomes for new doses, formulations, or active pharmaceutical ingredient forms, in lieu of a clinical food-effect study.     

Dissolution and Translational Modeling Strategies Enabling Patient-Centric Drug Product Development: the M-CERSI Workshop Summary Report

On May 15th–17th, 2017, the US FDA and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) held a workshop at the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI), to discuss the role of dissolution testing and translational modeling and simulation in enabling patient-centric solid oral drug product development. This 3-day event was attended by scientists from regulatory agencies, pharmaceutical companies, and academia. The workshop included podium presentations followed by breakout session discussions. The first day of the meeting focused on the challenges in dissolution method development and the role of dissolution testing throughout drug product development. On the second day, approaches to establish a link between in vitro testing and in vivo drug product performance (e.g., systemic exposure) were presented. Overall success rates and challenges in establishing IVIVCs via traditional and modern physiologically based pharmacokinetic (PBPK) modeling and simulation approaches were discussed. Day 3 provided an opportunity to discuss the expectations for establishing clinically relevant drug product specifications (CRDPS). It was recognized that understanding the impact of formulation and process variations on dissolution and in vivo performance is critical for most drug products formulated with poorly soluble drugs to ensure consistent product performance. The breakout sessions served as platforms for discussing controversial topics such as the clarification of dissolution terminology, PBPK model development and validation expectations, and approaches to set CRDPS. The meeting concluded with a commitment to continue the dialog between regulators, industry, and academia to advance overall product quality understanding.