Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease

Intestinal mucosal damage in the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) involves reactive oxygen metabolites (ROMs). ROMs are neutralized by endogenous antioxidant enzymes in a carefully balanced two-step pathway. Superoxide dismutases (SODs) convert superoxide anion to hydrogen peroxide (H(2)O(2)), which is subsequently neutralized to water by catalase (CAT) or glutathione peroxidase (GPO). Remarkably changed expression levels of the three isoforms of SOD in paired non-inflamed and inflamed mucosae from CD and UC patients have been previously reported in comparison to normal control mucosa. Most notable was the strong up-regulation of Mn-SOD in inflamed epithelium. It was hypothesized that in order to provide optimal protection against ROM-mediated damage, these changes should be coordinately counterbalanced by an increased H(2)O(2)-neutralizing capacity. Therefore, the same tissue samples were used to assess the levels, activities, and/or localization of the most prominent mucosal H(2)O(2)-related antioxidants CAT, GPO, glutathione (GSH), myeloperoxidase (MPO), and metallothionein (MT). Quantitative measurements showed that in both CD and UC patients, intestinal inflammation was associated with increased activities of CAT, GPO, and MPO, whereas the mucosal GSH content was unaffected and the concentration of MT was decreased. Despite this overall increase in mucosal H(2)O(2)-metabolizing enzyme capacity, immunohistochemical analysis revealed a differentially disturbed antioxidant balance in IBD epithelium and lamina propria. In the lamina propria, the risk of direct H(2)O(2)-mediated damage seemed to be restrained by the increasing numbers of CAT- and MPO-positive monocytes/macrophages and neutrophils that infiltrated the inflamed areas. On the other hand, MPO overexpression might increase the lamina propria levels of hypochlorous acid, a stable ROM with multiple pro-inflammatory effects. In the epithelium, the number of cells that expressed CAT remained unchanged during inflammation and GPO was found in only a very low and constant number of epithelial cells. In addition, the inflamed epithelium displayed decreased expression of the hydroxyl radical (OH(*)) scavenger MT. In view of the high epithelial SOD levels in inflamed IBD epithelium, it is speculated that the efficient removal of excess H(2)O(2) is hampered in these cells, thereby increasing not only the risk of detrimental effects of H(2)O(2) directly, but also those of its extremely reactive derivatives such as OH(*). Taken together, the results suggest an imbalanced and inefficient endogenous antioxidant response in the intestinal mucosa of IBD patients, which may contribute to both the pathogenesis and the perpetuation of the inflammatory processes.     

Cost-Effectiveness Assessment of Monitoring Abiraterone Levels in Metastatic Castration-Resistant Prostate Cancer Patients

ObjectivesAbiraterone acetate is registered for the treatment of metastatic castration-sensitive and resistant prostate cancer (mCRPC). Treatment outcome is associated with plasma trough concentrations (C_min) of abiraterone. Patients with a plasma C_min below the target of 8.4 ng/mL may benefit from treatment optimization by dose increase or concomitant intake with food. This study aims to investigate the cost-effectiveness of monitoring abiraterone C_min in patients with mCRPC.MethodsA Markov model was built with health states progression-free survival, progressed disease, and death. The benefits of monitoring abiraterone C_min followed by a dose increase or food intervention were modeled via a difference in the percentage of patients achieving adequate C_min taking a healthcare payer perspective. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainties and their impac to the incremental cost-effectiveness ratio (ICER).ResultsMonitoring abiraterone followed by a dose increase resulted in 0.149 incremental quality-adjusted life-years (QALYs) with €22 145 incremental costs and an ICER of €177 821/QALY. The food intervention assumed equal effects and estimated incremental costs of €7599, resulting in an ICER of €61 019/QALY. The likelihoods of therapeutic drug monitoring (TDM) with a dose increase or food intervention being cost-effective were 8.04%and 81.9%, respectively.ConclusionsMonitoring abiraterone followed by a dose increase is not cost-effective in patients with mCRPC from a healthcare payer perspective. Monitoring in combination with a food intervention is likely to be cost-effective. This cost-effectiveness assessment may assist decision making in future integration of abiraterone TDM followed by a food intervention into standard abiraterone acetate treatment practices of mCRPC patients.     

Triplications of chromosome 1p36.3, including the genes GABRD and SKI,are associated with a developmental disorder and a facial gestalt

Triplication of chromosomal region 1p36.3 is a rare genomic rearrangement. In this report, we delineate the phenotypic spectrum associated with 1p36.3 triplications. We describe four patients with microtriplications of variable size, but with a strong phenotypic overlap, and compare them to previously described patients with an isolated triplication or duplication of this region. The 1p36.3 triplication syndrome is associated with a distinct phenotype, characterized by global developmental delay, moderate intellectual disability, seizures, behavioral problems, and specific facial dysmorphic features, including ptosis, hypertelorism, and arched eyebrows. The de novo occurrence of these microtriplications demonstrates the reduced reproductive fitness associated with this genotype, in contrast to 1p36.3 duplications which are mostly inherited and can be associated with similar facial features but with a less severe developmental phenotype. The shared triplicated region encompasses four disease-related genes of which GABRD and SKI are most likely to contribute to the phenotype.     

Iridocorneal adhesions in patients with the Marfan syndrome

Marfan syndrome is an autosomal dominant connective tissue disorder characterized by skeletal, cardiovascular, and ocular anomalies. Ectopia lentis is the most common ocular manifestation. We report an ocular sign not previously described in Marfan syndrome, iridocorneal adhesions secondary to anterior lens subluxation. Three patients with the Marfan syndrome had iridocorneal adhesions on slit-lamp examination. One patient developed adhesions following treatment with pilocarpine. She underwent pars plana vitrectomy and lensectomy in both eyes due to progression of the iridocorneal adhesions. Treatment with miotics rotates the lens-iris diaphragm anteriorly and may contribute to the formation of such adhesions. The two other patients remained stable and did not received lensectomy or vitrectomy. Careful slit-lamp examination of the anterior segment should be conducted in patients with dislocated lenses.     

Fractures of the orbital floor. Apropos of a homogeneous series of 70 patients]

The authors report their experience based on a homogeneous series of 70 fractures of the orbital floor. Different anatomo-clinical forms were defined in particular fractures of the orbital floor, accompanying an "internal pivoting" of the cheek bone, which by their incarceration mechanism resemble the trap-door fractures. The blow-out fracture associated with the lower orbital margin also raises therapeutic problems. After a clinical and CT study, the authors recommend treatment via the lower orbital approach using silastic implants. The different sequelae are described clinically and are appraised medically and legally.     

The pharmacokinetics of anesthetic drugs and adjuvants during cardiopulmonary bypass

The institution of cardiopulmonary bypass during cardiac surgery has profound effects on the plasma concentration of drugs and thus their therapeutic effectiveness. These changes occur through acute hemodilution, altered plasma protein binding, hypotension, as well as the use of hypothermia and heparin administration. Isolation of the lungs from the circulation and the possible sequestration of drugs in the bypass circuit also affect drug plasma concentrations on bypass. The individual characteristics of the drug in question are also important in determining the final plasma concentration: Lipid soluble drugs with a high volume of distribution may be more readily taken up by bypass equipment, but the initial fall in concentration at the start of cardiopulmonary bypass may be more readily counteracted by back diffusion into plasma, if large tissue stores have accumulated. The extent of the drug's plasma protein binding is of importance as the effective free fraction in plasma for highly bound drugs will be sensitive to changes in plasma protein binding brought on by factors such as hemodilution, heparin administration as well as alpha, acid-glycoprotein binding. Clearly the fate of drugs administered before or on bypass is complex and can only be accurately determined by specific studies evaluating drug plasma concentrations. This review updates the available data on anesthetics and drugs used during cardiac surgery in order that anesthetists may predict better the likely effect of drugs administered before or during cardiopulmonary bypass.     

Interventions to enhance the Quality of Life of older people in residential long-term care: A systematic review

PurposeIn residential long-term care (LTC), a growing interest exists in the older residents’ Quality of Life (QoL). The Active Ageing-concept (AA) extended this focus, since AA has the aim to enhance QoL by optimising the opportunities for health, participation and security. In LTCs, AA can be outlined by 9 determinants. This systematic review aimed at identifying interventions to improve the QoL of LTC-residents. These interventions were organised according to the AA-determinants.MethodsPubMed, Web of Science, Psychinfo and Sociological Abstracts were screened systematically. Articles were excluded when they only concerned a specific group of LTC-residents.ResultsThirty five relevant articles, encompassing 3910 subjects were found. These concerned interventions concentrating on one or more of the 9 AA-determinants. The largest proportion of interventions regarded the physical activity level or the psychological factors of the residents. Overall, no systematic effects on QoL could be found and a low methodological quality was generally present.ConclusionCurrently, studies aimed at enhancing the QoL of older LTC-resident are limited and often directed to physical and psychological interventions. The lack of a systematic effect on QoL is possibly related to the fact that these interventions were often not multidimensional, whereas QoL is a multidimensional concept.