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.     

Care delivery among refugees and internally displaced persons affected by complex emergencies: a systematic review of the literature

Journal of Public Health - This study reviews the empirical evidence on care delivery in complex emergencies (CEs) to better understand ways of improving care delivery and mitigating inequity in...     

The Psychology of Kink: A Cross-Sectional Survey Study Investigating the Roles of Sensation Seeking and Coping Style in BDSM-Related Interests

Archives of Sexual Behavior - Despite the gaining popularity in mainstream media of the phenomenon that is BDSM, empirical research on the motives and underlying psychological mechanisms driving...     

Synchrony levels during evoked seizure-like bursts in mouse neocortical slices

Slices (n = 45) from the somatosensory cortex of mouse (P8-13) generated spontaneous bursts of activity (0.10 +/- 0.05 Hz) that were recorded extracellularly. Multiunit action potential (AP) activity was integrated and used as an index of population activity. In this experimental model, seizure-like activity (SLA) was evoked with bicuculline (5-10 microM) or N-methyl-d-aspartate (NMDA, 5 microM). SLA was an episode with repetitive bursting at a frequency of 0.50 +/- 0.06 Hz. To evaluate whether SLA was associated with a change in synchrony, we obtained simultaneous intracellular and extracellular recordings (n = 40) and quantified the relationship between individual cells and the surrounding population of neurons. During the SLA there was an increase in population activity and bursting activity was observed in neurons and areas that were previously silent. We defined synchrony as cellular activity that is consistently locked with the population bursts. Signal-averaging techniques were used to determine this component. To quantitatively assess change in synchronous activity at SLA onset, we estimated the entropy of the single cell's spike trains and subdivided this measure into network burst-related information and noise-related entropy. The burst-related information was not significantly altered at the onset of NMDA-evoked SLA and slightly increased when evoked with bicuculline. The signal-to-noise ratio determined from the entropy estimates showed a significant decrease (instead of an expected increase) during SLA. We conclude that the increased population activity during the SLA is attributed to recruitment of neurons rather than to increased synchrony of each of the individual elements.     

Phase I clinical study of LL-D49194α1 with retrospective pharmacokinetic investigations in mice and humans

Summary LL-D491941 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m². One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D491941 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.     

Comparison of non-invasive approaches to red marrow dosimetry for radiolabelled monoclonal antibodies

Red marrow is usually the dose-limiting organ during radioimmunotherapy. Several non-invasive approaches to calculate the red marrow dose have been proposed. We compared four approaches to analyse the differences in calculated red marrow doses. The data were obtained from immunoscintigraphy of two antibodies with different red marrow kinetics [iodine-131-16.88 IgM and indium- 111-OV-TL-3 F(ab)₂]. The approaches are based on, respectively, homogeneously distributed activity in the body, a red marrow-blood activity concentration ratio of 0.3, scintigraphic quantification, and a combination of the second and third approaches. This fourth approach may be more adequate because of its independence from the chosen antibody. In addition, the influence of activity accumulation in liver, kidneys or cancellous bone on red marrow dose was studied. The calculated red marrow dose varied between 0.14 and 0.42 mGy/MBq for ¹¹¹ In-OV TL-3 and between 0.13 and 0.68 mGy/MBq for ¹³¹I-16-88. If the radiopharmaceutical shows high affinity for cancellous bone or another organ situated near the red marrow, the activity in these organs must be included in dose calculations. This study shows a large variation in calculated red marrow dose and selection of the definitive non-invasive approach awaits validation. Correspondence to: M.A.B.D. Plaizier     

Laser energy threshold for thermal vascular injury in a port-wine stain skin model

Monte Carlo simulation of laser energy deposition in a port-wine stain (PWS) skin model and numerical solution of the thermal diffusion equation have been used to calculate threshold energies for thermal injury of PWS blood vessels for different vessel sizes and laser pulse durations. It has been assumed that an average vessel temperature rise of 65 C causes thermal injury to the blood vessel. The result is that for a certain combination of wavelength, pulse duration and incident energy density, only a limited range of blood vessel sizes can be injured optimally. Higher energy densities are required to injure smaller vessels with the same pulse duration, spot size and wavelength. This gives support to the mechanisms of selective photothermolysis suggested previously by Anderson and Parrish, although their model was based on the cooling behaviour of instantaneously heated vessels. The authors hypothesize that different laser parameter settings that match the individual PWS vessel anatomy during treatment will be used in the future, instead of many treatments with the same laser parameters. This could lead to less treatment sessions and to an improved predictability of clinical results.     

When Asthma Interrupts Sleep in Children

black triangle Levosalbutamol is a chirally pure beta(2)-adrenoceptor agonist developed from racemic salbutamol. black triangle The therapeutically inactive (S)-enantiomer in racemic salbutamol may be associated with increased airway hyperreactivity in patients with asthma. Levosalbutamol aims to provide equivalent control of symptoms to salbutamol but without this potential unfavourable effect. black triangle The pharmacodynamic and pharmacokinetic profiles of levosalbutamol were similar to those of racemic salbutamol and no additional effects were reported. Levosalbutamol was bronchoprotective following a methacholine challenge. black triangle A large clinical study demonstrated that inhaled levosalbutamol, 0.625mg or 1.25mg 3 times daily, provided effective relief from the symptoms of asthma. Levosalbutamol 0.625mg was at least as effective as racemic salbutamol 2.5mg. black triangle Levosalbutamol was well tolerated in clinical trials and the risk/benefit ratio was reported to be superior to that of racemic salbutamol.     

Variability of Clinical and Pressure-Flow Study Variables After 6 Months of Watchful Waiting in Patients with Lower Urinary Tract Symptoms and Benign Prostatic Enlargement

Purpose

We quantified the physiological variability of clinical and pressure-flow study variables in patients with symptomatic benign prostatic enlargement.

Materials and Methods

Symptom scores were measured, and advanced urodynamic studies with pressure-flow analysis were performed in 178 patients before and 6 months after a period of watchful waiting.

Results

Patients without bladder outlet obstruction experienced significant symptomatic improvement. Symptoms in patients with obvious bladder outlet obstruction did not improve significantly. The reproducibility of mean pressure-flow variables was evident. However, there was an important intra-individual variability. Patients with obvious bladder outlet obstruction showed a significant decrease in detrusor pressure at maximal flow of 14 cm. water, a significant decrease in the urethral resistance factor of 7 cm. water and a significant decrease of 1 obstruction class on the linear passive urethral resistance relation nomogram, indicating less severe bladder outlet obstruction.

Conclusions

Mean differences among therapy groups must be regarded critically, especially when the differences are slight and possibly within physiological variability.