Decrease in penbutolol central response as a cause of changes in its serum protein binding

Penbutolol is a beta-adrenoceptor antagonist that is extensively bound to alpha 1-acid glycoprotein (alpha 1-AGP), a protein that increases in inflammatory diseases thereby binding more drug in such conditions. Changes in serum binding can lead to modifications in the pharmacokinetics and pharmacodynamics of a drug, therefore, the central effect (as the anticonvulsant response) and brain uptake of penbutolol given intravenously to mice with experimental inflammation have been measured. A significant decrease of the central effect of penbutolol and its brain uptake was seen in diseased when compared with control animals (P less than 0.01). A parallel decrease in free fraction of penbutolol in diseased vs normal animals was detected. These results suggest that there is an increase in serum binding of basic drugs related to increments in alpha 1-AGP concentration, which reduces their central pharmacological effect.     

A novel logistic model based on clinicopathological features predicts microsatellite instability in colorectal carcinomas.

High-frequency microsatellite instability has been reported to be associated with good prognosis in colorectal adenocarcinoma. However, methods to assess microsatellite instability (MIN) are based on genetic assays and are not ideally suited to most histopathology laboratories. The aim of the present study was to develop a model for prediction of MIN status in colorectal cancer based on phenotypic characteristics. Clinicopathological features of a cohort of 204 patients with primary colon cancer were retrospectively reviewed following predetermined criteria. Genetic assessment of MIN status was performed on DNA extracted from sections of formalin-fixed, paraffin-embedded specimens by testing a panel of 11 microsatellite markers. Logistic regression analysis generated a mathematical tool capable of identifying colorectal tumors displaying MIN status with a sensitivity of 77.8% and a specificity of 96.8%. Features associated with instability included the proximal location of the lesions, occurrence of solid and/or mucinous differentiation, absence of cribriform structures, presence of peritumoral Crohn-like reaction, expansive growth pattern, high Ki67 proliferative index, and p53-negative phenotype. This approach predicts microsatellite instability in colorectal carcinoma with an overall assigned accuracy of 95.1% and a negative predictive value of 97.8%. Implementation of this tool to routine histopathological studies could improve the management of patients with colorectal cancer, especially those presenting with stage II and III of the disease. It will also assist in identifying a subset of patients likely to benefit from adjuvant chemotherapy.     

Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole‐exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca²⁺ sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca²⁺ levels and store‐operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single‐gene defect, which is consistent with Mendelian‐dominant inheritance.     

The effectiveness of memory rehabilitation following neurological disabilities: A qualitative inquiry of patient perspectives

The evidence for the effectiveness of memory rehabilitation following neurological conditions, mainly studied through quantitative methodologies, has been equivocal. This study aimed to examine feedback from participants who had been through a randomised controlled trial (RCT) comparing two types of memory rehabilitation with a self-help control. It was envisaged that this information would offer a detailed understanding of patient experience of going through a trial and the perceived effects of having attended group sessions. Through 31 in-depth interviews, data collected were thematically analysed. The seven themes identified highlighted improvements in insight and awareness of memory problems and their neurological conditions, knowledge and skills about using memory aids; and as a consequence, improvements in cognitive functions, mood, and confidence, assertiveness and control over their condition. Participants also reported an altered perspective of life that helped them deal with their problems, and the therapeutic effects of attending group sessions. While these improvements were mainly reported in the intervention groups, even those in the control group reported some benefits. This study highlights that it is both feasible and advantageous to embed qualitative research within the traditional RCT methodology to arrive at a more nuanced understanding of patient experiences and intervention outcomes.     

Experiences of combined visual training and arm activation in the rehabilitation of unilateral visual neglect: A clinical study

This study reports a rehabilitation training for unilateral visual neglect combining a visual training programme and arm activation. Four cases of left visual neglect are presented with differing arm use. Neglect impairment was assessed using seven neuropsychological tests at weekly intervals for nine weeks: three weeks before, during and after the treatment period. In addition, one patient was followed over a longer time period. The treatment consisted of both a visual training programme and simultaneous arm activation. Considerable improvement in three of the four patients was observed in article reading. Moreover, all patients showed some improvement on three cancellation tests, whereas there was no improvement on other tests. In particular, the patients who had full hand or shoulder movement showed improvement in their performance. These results point out the usefulness of combined visual training and arm activation in the rehabilitation of visual neglect.     

A Critical Role for Thioredoxin-Interacting Protein in Diabetes-Related Impairment of Angiogenesis

Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose–mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose–induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.