Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation

Objective: To examine the phenotypic expression of CYP2E1 in liver transplant patients, as measured by the in vivo probe chlorzoxazone, and to evaluate CYP2E1 activity over me after transplantation. Methods: Thirty-three stable liver transplant: patients were given 250 mg chlorzoxazone within 1 year after transplantation as part of a multiprobe CYP cocktail; urine and blood were collected for 8 hours. Chlorzoxazone and 6-hydroxychlorzoxazone concentrations were determined by HPLC. Twenty-eight healthy control subjects, eight patients with moderate to severe liver disease, and four patients who had not received liver transplants were also studied for comparison. The chlorzoxazone metabolic ratio, calculated as the plasma concentration of 6-hydroxychlorzoxazone/chlorzoxazone at 4 hours after chlorzoxazone administration, was used as the phenotypic, index. In a subgroup of patients and control subjects, additional blood samples were obtained to allow for the calculation of chlorzoxazone pharmacokinetic parameters by noncompartmental methods. Results: The chlorzoxazone metabolic ratio for the liver transplant patients in the first month after transplantation (mean ± SD, 6.4 ± 5.1) was significantlp higher than that after 1 month after surgery (2.1 ± 2.0), when the chlorzoxazone metabolic ratio was not different from control subjects (0.8 ± 0.5). The chlorzoxazone metabolic ratios in the patients who had not received liver transplants (1.1 ± 0.7) were equivalent to those of healthy control subjects. The maximum observed 6-hydroxychlorzoxazone plasma concentration was 3046 ± 1848 ng/ml in seven liver transplant patients in the first month after surgery compared with 1618 ± 320 ng/ml in 16 healthy control subjects (p < 0.05). The maximum observed concentration of chlorzoxazone, the chlorzoxazone apparent oral clearance, and the formation clearance of 6-hydroxychlorzoxazone were also significantly different between the groups. Conclusions: We conclude that significant induction of CYP2E1, as indicated by the chlorzoxazone metabolic, ratio, occurs in the first month after surgery in liver transplant patients and that drugs that are substrates for CYP2E1 may require dosage alteration during that period. Contrary to expectations, drug metabolism is not uniformly depressed after liver transplantation

Thinking about a limited future enhances the positivity of younger and older adults’ recall: support for socioemotional selectivity theory

Compared with younger adults, older adults have a relative preference to attend to and remember positive over negative information. This is known as the “positivity effect,” and researchers have typically evoked socioemotional selectivity theory to explain it. According to socioemotional selectivity theory, as people get older they begin to perceive their time left in life as more limited. These reduced time horizons prompt older adults to prioritize achieving emotional gratification and thus exhibit increased positivity in attention and recall. Although this is the most commonly cited explanation of the positivity effect, there is currently a lack of clear experimental evidence demonstrating a link between time horizons and positivity. The goal of the current research was to address this issue. In two separate experiments, we asked participants to complete a writing activity, which directed them to think of time as being either limited or expansive (Experiments 1 and 2) or did not orient them to think about time in a particular manner (Experiment 2). Participants were then shown a series of emotional pictures, which they subsequently tried to recall. Results from both studies showed that regardless of chronological age, thinking about a limited future enhanced the relative positivity of participants’ recall. Furthermore, the results of Experiment 2 showed that this effect was not driven by changes in mood. Thus, the fact that older adults’ recall is typically more positive than younger adults’ recall may index naturally shifting time horizons and goals with age

Numerical simulation of blood flow and pressure drop in the pulmonary arterial and venous circulation

A novel multiscale mathematical and computational model of the pulmonary circulation is presented and used to analyse both arterial and venous pressure and flow. This work is a major advance over previous studies by Olufsen et al. (Ann Biomed Eng 28:1281–1299, 2012) which only considered the arterial circulation. For the first three generations of vessels within the pulmonary circulation, geometry is specified from patient-specific measurements obtained using magnetic resonance imaging (MRI). Blood flow and pressure in the larger arteries and veins are predicted using a nonlinear, cross-sectional-area-averaged system of equations for a Newtonian fluid in an elastic tube. Inflow into the main pulmonary artery is obtained from MRI measurements, while pressure entering the left atrium from the main pulmonary vein is kept constant at the normal mean value of 2 mmHg. Each terminal vessel in the network of ‘large’ arteries is connected to its corresponding terminal vein via a network of vessels representing the vascular bed of smaller arteries and veins. We develop and implement an algorithm to calculate the admittance of each vascular bed, using bifurcating structured trees and recursion. The structured-tree models take into account the geometry and material properties of the ‘smaller’ arteries and veins of radii ≥ 50 μ m. We study the effects on flow and pressure associated with three classes of pulmonary hypertension expressed via stiffening of larger and smaller vessels, and vascular rarefaction. The results of simulating these pathological conditions are in agreement with clinical observations, showing that the model has potential for assisting with diagnosis and treatment for circulatory diseases within the lung

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Skin prick testing in patients using beta-blockers: a retrospective analysis

<p>Abstract</p> <p>Rationale</p> <p>The use of beta-blockers is a relative contraindication in allergen skin testing yet there is a paucity of literature on adverse events in this circumstance. We examined a population of skin tested patients on beta-blockers to look for any adverse effects.</p> <p>Methods</p> <p>Charts from 2004-2008 in a single allergy clinic were reviewed for any patients taking a beta-blocker when skin tested. Data was examined for skin test reactivity, type of skin test, concomitant asthma diagnosis, allergens tested, and adverse events.</p> <p>Results</p> <p>One hundred and ninety-one patients were taking beta-blockers when skin testing occurred. Seventy-two patients had positive skin tests. No tests resulted in an adverse event.</p> <p>Conclusions</p> <p>This data demonstrates the relative safety of administrating of skin prick tests to patients on beta-blocker treatment. Larger prospective studies are needed to substantiate the findings of this study.</p

Linking Microscopic Spatial Patterns of Tissue Destruction in Emphysema to Macroscopic Decline in Stiffness Using a 3D Computational Model

Pulmonary emphysema is a connective tissue disease characterized by the progressive destruction of alveolar walls leading to airspace enlargement and decreased elastic recoil of the lung. However, the relationship between microscopic tissue structure and decline in stiffness of the lung is not well understood. In this study, we developed a 3D computational model of lung tissue in which a pre-strained cuboidal block of tissue was represented by a tessellation of space filling polyhedra, with each polyhedral unit-cell representing an alveolus. Destruction of alveolar walls was mimicked by eliminating faces that separate two polyhedral either randomly or in a spatially correlated manner, in which the highest force bearing walls were removed at each step. Simulations were carried out to establish a link between the geometries that emerged and the rate of decline in bulk modulus of the tissue block. The spatially correlated process set up by the force-based destruction lead to a significantly faster rate of decline in bulk modulus accompanied by highly heterogeneous structures than the random destruction pattern. Using the Karhunen-Loève transformation, an estimator of the change in bulk modulus from the first four moments of airspace cell volumes was setup. Simulations were then obtained for tissue destruction with different idealized alveolar geometry, levels of pre-strain, linear and nonlinear elasticity assumptions for alveolar walls and also mixed destruction patterns where both random and force-based destruction occurs simultaneously. In all these cases, the change in bulk modulus from cell volumes was accurately estimated. We conclude that microscopic structural changes in emphysema and the associated decline in tissue stiffness are linked by the spatial pattern of the destruction process

Primary Phacoemulsification and Intraocular Lens Implantation for Acute Primary Angle-Closure

Background: To investigate the effect of primary phacoemulsification on intraocular pressure (IOP) in patients with acute primary angle-closure (PAC) and coexisting cataract. Methodology: Sixteen eyes of 14 patients with acute PAC received phacoemulsification and intraocular lens implantation as initial management for medically uncontrolled IOP in a retrospective chart review. The effects on IOP, vision, anterior chamber depth (ACD), and number of antiglaucoma medications were evaluated. Principal Findings: The postoperative IOP was reduced in 16 eyes (100%). The mean 6 standard deviation preoperative IOP was 48.81616.83 mm Hg, which decreased postoperatively to 16.46610.67 mm Hg at 1 day, 9.4363.03 mm Hg at 1 week

Impact of leg lengthening on viscoelastic properties of the deep fascia

<p>Abstract</p> <p>Background</p> <p>Despite the morphological alterations of the deep fascia subjected to leg lengthening have been investigated in cellular and extracellular aspects, the impact of leg lengthening on viscoelastic properties of the deep fascia remains largely unknown. This study aimed to address the changes of viscoelastic properties of the deep fascia during leg lengthening using uniaxial tensile test.</p> <p>Methods</p> <p>Animal model of leg lengthening was established in New Zealand white rabbits. Distraction was initiated at a rate of 1 mm/day and 2 mm/day in two steps, and preceded until increases of 10% and 20% in the initial length of tibia had been achieved. The deep fascia specimens of 30 mm × 10 mm were clamped with the Instron 1122 tensile tester at room temperature with a constant tensile rate of 5 mm/min. After 5 load-download tensile tests had been performed, the specimens were elongated until rupture. The load-displacement curves were automatically generated.</p> <p>Results</p> <p>The normal deep fascia showed typical viscoelastic rule of collagenous tissues. Each experimental group of the deep fascia after leg lengthening kept the properties. The curves of the deep fascia at a rate of 1 mm/day with 20% increase in tibia length were the closest to those of normal deep fascia. The ultimate tension strength and the strain at rupture on average of normal deep fascia were 2.69 N (8.97 mN/mm²) and 14.11%, respectively. The increases in ultimate tension strength and strain at rupture of the deep fascia after leg lengthening were statistically significant.</p> <p>Conclusion</p> <p>The deep fascia subjected to leg lengthening exhibits viscoelastic properties as collagenous tissues without lengthening other than increased strain and strength. Notwithstanding different lengthening schemes result in varied viscoelastic properties changes, the most comparable viscoelastic properties to be demonstrated are under the scheme of a distraction rate of 1 mm/day and 20% increase in tibia length.</p

Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells

<p>Abstract</p> <p>Background</p> <p>Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells.</p> <p>Methods</p> <p>Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured <it>in vivo </it>with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed <it>ex vivo </it>with fluorescence imaging.</p> <p>Results</p> <p>We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells.</p> <p>Conclusion</p> <p>The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives.</p

25th RCOphth Congress, President's Session paper:25 years of progress in medical retina

The quarter century since the foundation of the Royal College of Ophthalmologists has coincided with immense change in the subspecialty of medical retina, which has moved from being the province of a few dedicated enthusiasts to being an integral, core part of ophthalmology in every eye department. In age-related macular degeneration, there has been a move away from targeted, destructive laser therapy, dependent on fluorescein angiography to intravitreal injection therapy of anti-growth factor agents, largely guided by optical coherence tomography. As a result of these changes, ophthalmologists have witnessed a marked improvement in visual outcomes for their patients with wet age-related macular degeneration (AMD), while at the same time developing and enacting entirely novel ways of delivering care. In the field of diabetic retinopathy, this period also saw advances in laser technology and a move away from highly destructive laser photocoagulation treatment to gentler retinal laser treatments. The introduction of intravitreal therapies, both steroids and anti-growth factor agents, has further advanced the treatment of diabetic macular oedema. This era has also seen in the United Kingdom the introduction of a coordinated national diabetic retinopathy screening programme, which offers an increasing hope that the burden of blindness from diabetic eye disease can be lessened. Exciting future advances in retinal imaging, genetics, and pharmacology will allow us to further improve outcomes for our patients and for ophthalmologists specialising in medical retina, the future looks very exciting but increasingly busy