Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model

Single-dose administration of beta-adrenoceptor agonists produces bronchodilation and inhibits airway hyperresponsiveness (AHR), and is the standard treatment for the acute relief of asthma. However, chronic repetitive administration of beta-adrenoceptor agonists may increase AHR, airway inflammation, and risk of death. Based upon the paradigm shift that occurred with the use of beta-blockers in congestive heart failure, we previously determined that chronic administration of beta-blockers decreased AHR in a murine model of asthma. To elucidate the mechanisms for the beneficial effects of beta-blockers, we examined the effects of chronic administration of several beta-adrenoceptor ligands in a murine model of allergic asthma. Administration of beta-blockers resulted in a reduction in total cell counts, eosinophils, and the cytokines IL-13, IL-10, IL-5, and TGF-beta1 in bronchoalveolar lavage, and attenuated epithelial mucin content and morphologic changes. The differences in mucin content also occurred if the beta-blockers were administered only during the ovalbumin challenge phase, but administration of beta-blockers for 7 days was not as effective as administration for 28 days. These results indicate that in a murine model of asthma, chronic administration of beta-blockers reduces inflammation and mucous metaplasia, cardinal features of asthma that may contribute to airflow obstruction and AHR. Similar to heart failure, our results provide a second disease model in which beta-blockers producing an acutely detrimental effect may provide a therapeutically beneficial effect with chronic administration.     

Predicting disability and quality of life in a community-based sample of women with migraine headache

Migraine is a significant pain problem for almost one third of women in the United States. Little previous research has been conducted regarding the effects of migraine headache on the lives of women migraineurs. The purpose of this report is to determine the contribution of coping, depressive symptomatology, and the chronic pain experience on disability and quality of life in women with migraine. Two hundred and forty-seven women responded to a mailed survey about migraine headache, the chronic pain experience, coping, depressive symptomatology, and quality of life. Data were collected with the following: the Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias, and Facial Pain; the McGill Pain Questionnaire; the Chronic Pain Experience Instrument-Headache; the Coping Strategies Questionnaire; the Center for Epidemiologic Studies-Depression Scale; the Henry Ford Hospital Disability Inventory; and the Migraine-Related Quality of Life Questionnaire. Multiple regression analyses were conducted to determine the amount of variance that could be explained by selected predictor variables. Women ranged in age from 18 to 66 years and migraineurs reported suffering from migraine from 1 to 54 years. Nearly half of the migraineurs (41.5%) reported migraine headaches occurring monthly, and almost a quarter of the sample reported weekly migraines. Migraines were reported to last for several hours (53.4%). Results indicate that migraine headache pain was typically severe and throbbing, lasting for hours to days. The coping, depressive symptomatology, disability, and quality-of-life variables were all significantly correlated. Two separate regression analyses that examined predictor variables and the criterion variables, disability and quality of life, showed that a significant amount of both constructs could be explained by the predictor variables in the model tested. In the first regression analysis, depressive symptomatology, the chronic pain experience, and migraine headache pain accounted for 62.9% of the variance in disability. In the second regression analysis, 64.8% of the variance in quality of life was accounted for by depressive symptomatology, migraine headache pain, and the chronic pain experience. The variance in both outcome variables, disability and quality of life, was accounted for by similar predictor variables: depressive symptomatology, the chronic pain experience, and migraine headache pain. Further study is needed to determine specific personal and illness-related factors, pain characteristics, and coping strategies used that may predict outcomes of migraine headache such as disability, quality of life, helplessness, and other as yet unidentified effects of migraine headache.     

Stem cell transplantation in advanced cutaneous T-cell lymphoma

Cutaneous T-cell lymphomas are a type of indolent non-Hodgkin's lymphoma where patients with limited skin disease can be successfully treated with a variety of skin-directed, systemic, and immunomodulating therapies, whereas durable remissions are difficult to achieve in patients with tumor, erythrodermic, or systemic disease. We describe a patient with cutaneous T-cell lymphoma and malignant cells constituting 99% of her peripheral blood lymphocytes who had a sustained complete response after an HLA-matched sibling allogeneic stem cell transplantation. We also review the current literature regarding both autologous and allogeneic stem cell transplantations for advanced stages of cutaneous T-cell lymphoma, discuss the importance of the graft-versus-tumor immunomodulatory effect in successful transplantations, and suggest that allogeneic stem cell transplantation deserves further consideration and study as a potential treatment for selected patients who are younger and at high risk.     

Dynamic changes in interneuron morphophysiological properties mark the maturation of hippocampal network activity

During early postnatal development, neuronal networks successively produce various forms of spontaneous patterned activity that provide key signals for circuit maturation. Initially, in both rodent hippocampus and neocortex, coordinated activity emerges in the form of synchronous plateau assemblies (SPAs) that are initiated by sparse groups of gap-junction-coupled oscillating neurons. Subsequently, SPAs are replaced by synapse-driven giant depolarizing potentials (GDPs). Whether these sequential changes in mechanistically distinct network activities correlate with modifications in single-cell properties is unknown. To determine this, we studied the morphophysiological fate of single SPA cells as a function of development. We focused on CA3 GABAergic interneurons, which are centrally involved in generating GDPs in the hippocampus. As the network matures, GABAergic neurons are engaged more in GDPs and less in SPAs. Using inducible genetic fate mapping, we show that the individual involvement of GABAergic neurons in SPAs is correlated to their temporal origin. In addition, we demonstrate that the SPA-to-GDP transition is paralleled by a remarkable maturation in the morphophysiological properties of GABAergic neurons. Compared with those involved in GDPs, interneurons participating in SPAs possess immature intrinsic properties, receive synaptic inputs spanning a wide amplitude range, and display large somata as well as membrane protrusions. Thus, a developmental switch in the morphophysiological properties of GABAergic interneurons as they progress from SPAs to GDPs marks the emergence of synapse-driven network oscillations.     

Statin use and knee osteoarthritis progression: Results from a post-hoc analysis of the SEKOIA trial

Objective

Epidemiological and experimental studies have suggested that lipid disorders might be involved in the pathophysiology of knee osteoarthritis (OA). Studies assessing the effect of statins on knee OA progression have shown conflicting results. We investigated the impact of statin use on radiological progression in patients with radiological and symptomatic knee OA.

Endothelial growth factor receptor inhibitors in recurrent metastatic cancer of the head and neck

Targeted therapy has become an important new class of therapeutic agents used in squamous cell carcinoma of the head and neck (SCCHN). Among them epidermal growth factor receptor (EGFR) inhibitors have been studied the most. Today, two classes of EGFR inhibitors are routinely used in the clinic; anti‐EGFR monoclonal antibodies and small‐molecule inhibitors of the EGFR tyrosine kinase activity. These agents have been used clinically in the recurrent metastatic (R/M) settings but only cetuximab has reached a regulatory approval. Current research is focused on innovative compound design, predictive biomarker discovery, and combination strategies in order to overcome resistance. Efforts should also be focused on endpoints other than overall survival, which is the current gold standard, such as surrogate endpoints. This article summarizes the clinical evidence of the anticancer activity of EGFR inhibitors in patients with R/M SCCHN, and analyzes the current, controversial clinical issues with respect to their interpretation. © 2015 Wiley Periodicals, Inc. Head Neck 38 : E2221–E2228, 2016     

Ammonium-chloride-induced prostatic hypertrophy in vitro: urinary ammonia as a potential risk factor for benign prostatic hyperplasia

To test the possibility that urinary ammonia could be a risk factor for benign prostatic hyperplasia (BPH), we explored the cellular effects of ammonium chloride (NH₄Cl) on prostatic cancer cells used as an experimental model. Following treatment of human prostatic cancer DU-145 cells with the varying concentrations of NH₄Cl for 3 days, cell growth was inhibited by approximately 50% at 5 mM NH₄Cl and almost completely inhibited at 10 mM NH₄Cl. However, the individual cell size in these treated cells became approximately 2-fold larger and cellular protein content was also up to 2.5-fold greater than in untreated cells. This protein increase appeared to result from the reduced protein degradation, verified by metabolic labeling with [¹⁴C]valine. Western blot analysis further suggested that such reduced protein turnover could in part be due to the inactivation of a lysosomal acid protease, cathepsin D. Taken together, these studies demonstrate NH₄Cl-induced hypertrophy in prostatic cancer cells, as evidenced by the growth inhibition, cell enlargement, and cellular protein increase. Therefore, ammonia is not an inert metabolic product; instead, its chronic effects on the prostate may ultimately lead to significant cellular and biochemical alterations of the prostate such as BPH. Received: 27 June 1998 / Accepted: 25 March 1999     

Abdominal aortic aneurysms: case report

A 71-year-old male presented to a chiropractic clinic with subacute low back pain. While the pain appeared to be mechanical in nature, radiographic evaluation revealed an abdominal aortic aneurysm, which required the patient to have vascular surgery. This case report illustrates the importance of the history and physical examination in addition to a thorough knowledge of the features of abdominal aortic aneurysms. The application of spinal manipulative therapy in patients with (AAA) is also discussed.