Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: A putative role for progesterone deficiency

This study explores the role of ovarian hormones in the phenotypic shaping of peripheral T-cell pool over the reproductive lifespan of rats. For this purpose, 2-month-old prepubertally ovariectomised (Ox) rats, showing oestrogen and progesterone deficiency, and 11-month-old Ox rats, exhibiting only progesterone deficiency, were examined for thymus output, and cellularity and composition of major TCRαβ+ peripheral blood lymphocyte (PBL) and splenocyte subsets. Although ovariectomy increased thymic output in both 2- and 11-month-old rats, the count of both CD4+ and CD8+ PBLs and splenocytes increased only in the former. In the blood and spleen of 11-month-old Ox rats only the count of CD8+ cells increased. Although ovariectomy affected the total CD4+ count in none of the examined compartments from the 11-month-old rats, it increased CD4+FoxP3+ PBL and splenocyte relative proportions over those in the age-matched controls. The age-related differences in the cellularity and the major subset composition in Ox rats were linked to the differences in the ovarian steroid hormone levels registered in 2- and 11-month-old rats. The administration of progesterone to Ox rats during the seven days before the sacrificing confirmed contribution of this hormone deficiency to the ovariectomy-induced changes in the TCRαβ+ PBL and splenocyte pool from 11-month-old rats. The expansion of the CD8+ splenocyte subset in the 11-month-old Ox rats reflected increases in cellularity of memory and, particularly, naïve cells. This was due to greater thymic output of CD8+ cells and homeostatic proliferation than apoptosis in 11-month-old Ox rats when compared with age-matched sham-Ox control rats. The homeostatic changes within CD8+ splenocyte pool from 11-month-old Ox rats, most likely, reflected the enhanced splenic IL-7 and TGF-β mRNA expression. Overall, in adult female rats, circulating oestrogen and progesterone provide maintenance of T-cell counts, a diversity of T-cell repertoire, and the main T-cell subset composition in the periphery. Progesterone deficiency affects mainly the CD8+ lymphocyte compartment through increasing thymic CD8+ cell export and upsetting homeostatic regulation within the CD8+ splenocyte pool. These alterations were reversible through progesterone supplementation.     

Vemurafenib and cobimetinib‐induced toxic epidermal necrolysis in a patient with metastatic melanoma

Combination therapy in the treatment of metastatic melanoma has been associated with more durable response rate compared to monotherapy. However, previous studies have shown that combined target therapy commonly causes a wide spectrum of adverse events. These adverse reactions are usually manageable, however, it is always necessary to compare drug efficacy with its potential adverse effects. Toxic epidermal necrolysis represents severe mucocutaneous reaction, usually triggered by medications and characterized by extensive necrosis and detachment of the epidermis. Here we present a first case of toxic epidermal necrolysis induced by combined target therapy (vemurafenib plus cobimetinib). The case was observed in a young patient with BRAF mutant melanoma who was started on first‐line metastatic immunotherapy with pembrolisumab.     

Do they teach what they need to? An analysis of the impact of curriculum mapping on the learning objectives taught in a lecture series in surgery

Abstract

Introduction: Curriculum mapping shows concordances and differences between the intended and the taught curriculum. To our knowledge, no previous studies describe the effects that this mapping has on the curriculum. The aim of the present study is to map the content of a lecture series in surgery to the National Catalogue of Learning Objectives in Surgery and analyze the effects this mapping has on the content of the following lecture series.

Methods: All lecturers in the lecture series were directly observed by a minimum of two reviewers and learning objectives and the level of competence were documented. After the lecture series, the results were visualized within the catalog of learning objectives and were sent to the lecturers. In the following lecture series, learning objectives were documented correspondingly.

Results: In the first lecture series, 47% of the learning objectives were taught. After the mapping, the number of learning objectives that were taught increased to 59% (p?<?0.001). The increase was found in all surgical disciplines and in all levels of competences without any changes in the average duration of the lectures.

Conclusions: The presented method for mapping a curriculum effectively increased the number of taught learning objectives without requiring longer lecture durations.     

Ammonium accumulation and chemokine decrease in culture media of Gcdh−/− 3D reaggregated brain cell cultures

Glutaric Aciduria type I (GA-I) is caused by mutations in the GCDH gene. Its deficiency results in accumulation of the key metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body tissues and fluids. Present knowledge on the neuropathogenesis of GA-I suggests that GA and 3-OHGA have toxic properties on the developing brain.We analyzed morphological and biochemical features of 3D brain cell aggregates issued from Gcdh^?/? mice at two different developmental stages, day-in-vitro (DIV) 8 and 14, corresponding to the neonatal period and early childhood. We also induced a metabolic stress by exposing the aggregates to 10 mM l-lysine (Lys).Significant amounts of GA and 3-OHGA were detected in Gcdh^?/? aggregates and their culture media. Ammonium was significantly increased in culture media of Gcdh^?/? aggregates at the early developmental stage. Concentrations of GA, 3-OHGA and ammonium increased significantly after exposure to Lys. Gcdh^?/? aggregates manifested morphological alterations of all brain cell types at DIV 8 while at DIV 14 they were only visible after exposure to Lys. Several chemokine levels were significantly decreased in culture media of Gcdh^?/? aggregates at DIV 14 and after exposure to Lys at DIV 8.This new in vitro model for brain damage in GA-I mimics well in vivo conditions. As seen previously in WT aggregates exposed to 3-OHGA, we confirmed a significant ammonium production by immature Gcdh^?/? brain cells. We described for the first time a decrease of chemokines in Gcdh^?/? culture media which might contribute to brain cell injury in GA-I.     

Hemostatic problems before, during and after delivery.

Normal pregnancy and childbirth are known to be associated with marked changes in the coagulation and fibrinolytic systems. Generally, enhancement of clotting activity persists to prevent the risk of major hemorrhage. Hemostatic problems, either associated with a specific complication of pregnancy and labor or due to a hereditary or acquired bleeding diathesis or thrombophilias, present a significant cause of maternal and neonatal morbidity and mortality. This article reviews hemostatic disorders in pregnancy and the peripartal period from the standpoint of the obstetrician.     

Epoetin treatment improves red blood cell and plasma antioxidant capacity in hemodialysis patients

The efficiency of human recombinant epoetin in alleviating anemia in hemodialyzed patients has been well documented. However, the effects of rhEPO therapy in correction of antioxidant capacity are not completely explained. In this study we examined both extracellular (plasma) and intracellular (red blood cells) antioxidant potential in hemodialyzed patients before and after three and six months of epoetin treatment by evaluating markers of oxidative stress (malondialdehyde) and antioxidant capacity (thiol groups, superoxide dismutase, and glutathione peroxidase). Six months of treatment with epoetin was followed by significant increases in thiol groups, superoxide dismutase and glutathione peroxidase activities in both plasma and red blood cells of hemodialyzed patients. Hence, during accelerated erythropoiesis, an increase in the number of young hematopoietic cells may replenish erythrocyte superoxide dismutase and glutathione peroxidase activity. However, the consequences of an imbalance between enzymatic antioxidant system (higher superoxide dismutase and lower glutathione peroxidase activity) that exists in these patients are the very high red blood cell and plasma malondialdehyde levels. These results suggest that, in spite of epoetin treatment and improvement in red blood cells and plasma antioxidant capacity, the production of reactive oxygen species overwhelms the intracellular and extracellular antioxidant capacity.     

Factors associated with dysmorphic concern and psychiatric morbidity in plastic surgery outpatients

OBJECTIVES: To compare new referrals to a plastic surgery clinic for cosmetic (non-medically explained) reasons with a control group of equal size with medically explained symptoms. METHOD: Patients attending for cosmetic (non-medically explained) reasons were compared with the controls using the general health questionnaire (GHQ), and dysmorphic concern questionnaire (DCQ). Patients were divided into high and low DCQ scores on the basis of their median scores. RESULTS: Ninety subjects were approached of whom 84 (93%) participated giving 42 patients each in the cosmetic (non-medically explained) and control groups. Forty-four per cent were referred for mammoplasty (n = 37) and 8% for rhinoplasty (n = 7). The other 40 cases (48%) were for other procedures including excision, abdominoplasty and blepharoplasty. Thirty-two per cent of the sample were GHQ cases (n = 27). Patients presenting for cosmetic (non-medically explained) reasons were 13 times more likely to be female (95% CI = 4.3-41), nine times more likely to have high DCQ scores (95% CI = 3.3-24), six times more likely to be GHQ cases (95% CI = 2.1-17), and seven times more likely to present for mammoplasty. The same factors were associated with high DCQ scores. Patients with high DCQ scores were 32 times as likely to be GHQ cases (95% CI = 6.8-151). On multivariate analysis, dysmorphic concern emerged as the only independent predictor of GHQ caseness rather than sex, surgical diagnosis or procedure (adjusted OR = 32.0, 95 % CI = 6.5-156). Similarly, only GHQ caseness and presentation for cosmetic (non-medically explained) surgery independently predicted DCQ score. CONCLUSIONS: Patients presenting for cosmetic (non-medically explained) surgery have high rates of dysmorphic concern and psychiatric morbidity     

Development and Mechanical Characterization of Bioadhesive Semi-Solid,Polymeric Systems Containing Tetracycline for the Treatment of Periodontal Diseases

Purpose. This study examined the mechanical characteristics and release of tetracycline from bioadhesive, semi-solid systems which were designed for the treatment of periodontal diseases. Methods. Tetracycline release into phosphate buffered saline (pH 6.8, 0.03 M) was examined using a Caleva 7ST dissolution apparatus at 37°C. The mechanical properties of each formulation (hardness, compressibility, adhesiveness, elasticity and cohesiveness) were determined using texture profile analysis. Syringeability was measured using the texture analyser in compression mode as the work of syringeability i.e. the force required to express the product from a periodontal syringe over a defined distance. Results. Tetracycline release from all formulations was zero-order for 24–54 h and ranged from 1.59 ± 0.20 to 15.80 ± 0.50 mg h^–1. Increased concentrations of hydroxyethylcellulose (HEC) decreased the rate of release of tetracycline, due to the concomitant increase in product viscosity and the subsequent decreased rate of penetration of dissolution fluid into the formulation. Conversely, an increased polyvinylpyrrolidone (PVP) concentration increased tetracycline release rates, due to an increased formulation porosity following dissolution of this polymer. Increased concentrations of HEC and PVP increased the hardness, compressibility and work of syringeability of the semi-solid formulations, due to increased product viscosity. An increase in formulation adhesiveness, a parameter related to bioadhesion, was observed as the concentrations of HEC and PVP were increased, illustrating the adhesive nature of these polymers. Increased concentrations of HEC and PVP enhanced the semi-solid nature of the product, resulting in decreased product elasticity and cohesiveness. Several statistically significant interactions between polymeric formulation components were observed within the factorial design, with respect to rate of release and all mechanical properties. These interactions arose because of variations in the physical states (dissolved or dispersed) of polymeric formulation components. Conclusions. The optimal choice of bioadhesive formulation for use in periodontal disease will involve a compromise between achieving the necessary release rate of tetracycline and the mechanical characteristics of the formulation, as these factors will affect clinical efficacy and the ease of product application into the periodontal pocket.